Chapter 1 - Drugs and drug targets: an overviewpsbeauchamp/pdf/499_chap_1_49_pages.pdf · 2016. 4....

Drug (Medicine) - a natural or artificial substance given to treat or prevent disease or to lessen pain, a substance other than food (?) that causes a h i l i l h i h b d b h ( bl )

Chapter 1 - Drugs and drug targets: an overview

Examples of various types of medicines

physiological change in the body, use can be short term (acute problems) orregular (chronic problems) Drugs are classified in various ways. All drugs have some side effects and can possibly lead to addiction.

1 For the gastrointestinal tract (digestive system)2 For the cardiovascular system3 For the central nervous system4 For pain and consciousness (analgesic drugs)5 For musculo skeletal disorders5 For musculo-skeletal disorders6 For the eye7 For the ear, nose and oropharynx8 For the respiratory system9 For endocrine problems

Almost any chemical can affect a living organism. Any chemical that can affect the body is in a9 For endocrine problems

10 For the reproductive system or urinary system11 For contraception12 For obstetrics and gynecology13 For the skin

affect the body is, in asense, a "lead" compound. The more we know how a drug works (its mechanism of interaction) the better

14 For infections and infestations15 For the immune system16 For allergic disorders17 For nutrition18 F l ti di d (t b i li t)

of interaction) the betterwe can direct its usefulness and control its side effects.

1

18 For neoplastic disorders (tumors, benign or malignant)19 For diagnostics20 For anesthesia21 For euthanasia

Anatomical Therapeutic Chemical Classification System (ATC) - assigns ATC code = an alphanumeric code that assigns a drug to a specific class. Code = jargon, language of experts, not a common language of everyday people.First level

O

HO

OC03CA01

First levelThe first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:A Alimentary tract and metabolism B Blood and blood forming organs C Cardiovascular system D Dermatologicals

S

O

O

NH2

Cl

HN

O

D Dermatologicals G Genito-urinary system and sex hormones H Systemic hormonal preparations, excluding sex hormones and insulins J Antiinfectives for systemic use L Antineoplastic and immunomodulating agents M Musculo-skeletal system N Nervous system

Furosemide (Lasix) used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It has also been used to prevent and treat race horses for exercise-induced pulmonary hemorrhage

N Nervous system P Antiparasitic products, insecticides and repellents R Respiratory system S Sensory organs V VariousExample: C Cardiovascular system exercise induced pulmonary hemorrhage.Second levelThe second level of the code indicates the therapeutic main group and consists of two digits.Example: C03 DiureticsThird levelThe third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.p p g g pExample: C03C High-ceiling diureticsFourth levelThe fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.Example: C03CA SulfonamidesFifth level

2

Example: C03CA01 Furosemide

Fifth levelThe fifth level of the code indicates the chemical substance and consists of two digits.

Drugs can be differentiated by:

How they are administered ‐ consumed (liquid or solid by stomach or intestines), dissolved under tongue or in eyes, injected, inhaled, absorbed (patch, cream or ointment), insufflation (snorted), rectally (as a suppository), vaginally

Sources – plants, whole or parts (herbs and spices from stems, leaves, flowers, roots) or extracted substances (about 70% of pharmaceutical drugs come from natural products), organic synthesis (vast topic), synthesis by microorganisms (alcohol by yeast, penicillins, g y ( p ), y y g ( y y , p ,cephlosporins, cyphamycins, cyclosporins by fungi = yeast/molds, etc.), toxins (snakes, spiders, frogs, insects, puffer fish, algae red tides, etc.), genetically modified bacteria or yeast (to synthesize human insulin), animals (bovine or porcine insulin, Premarin as Hormone Replacement Therapy from horse urine blood thinning drug called ATryn isHormone Replacement Therapy from horse urine, blood thinning drug called ATryn, is made in the milk of genetically altered goats).

Often regulated into 3 categories: over the counter (OTC) available in supermarkets without any restrictions, behind the counter (BTC) can be dispensed by a pharmacist without doctor's

prescriptionprescription onlymedicine (POM) prescribed by licensed pharmacist (a doctor)

3

prescription only medicine (POM) prescribed by licensed pharmacist (a doctor)

H HeAtomic attraction for electrons

Review Topics: Polarity and Shape control the chemistry.Full shells (or subshells)

This is the goal.

n = 1 +1 +2

shielding = 0Ztotal = 1

Z ff ti = 1shielding = 0

Ztotal = 2

Zeffective = 2

(Where does polarity come from?)

Attractions are stronger across a row because the effective nuclear charge is larger.

valence electrons = bonding electrons (attracted by Zeffective)core electrons = full inner shells that shield Ztotal

Zeffective 1 Zeffective 2

+3

Li

n = 2+4

Be

+5

B

+6

C

+7

N

+8

O

+9

F

+10

Ne

radius = 52 pm radius = 31 pm

shielding = -2Ztotal = 3

Zeffective = 1shielding = -2

Ztotal = 4


Ztotal = 5


Ztotal = 6


Ztotal = 7


Ztotal = 8


Ztotal = 9


Ztotal = 10

Zeffective = 8

radius = 167 pm radius = 112 pm radius = 87 pm radius = 67 pm radius = 56 pm radius = 48 pm radius = 42 pm radius = 38 pm

+17

Cl

+18

Ar

n = 3Attractions are stronger up a column because the valence electrons

l t th+11

Na

radius 167 pm radius = 112 pm radius 87 pm radius 67 pm radius 56 pm radius 48 pm radius 42 pm p

+17 +18


Z 7shielding = -10

Ztotal = 18

Z 8

are closer to the same effective nuclear charge.

+11


Z ff i = 1

4

Zeffective = 7 Zeffective = 8Zeffective = 1radius = 190 pm radius = 79 pm radius = 71 pm

K (243 pm)Cs (298 pm)

Br (94 pm)I (115 pm)

Kr (88 pm)Xe (108 pm)

other radii

other radii

Volume of electron cloud compared to volume of nucleusVeV

43 (1.33)(3.14)(100,000)3 = 4 x 1015= =

electron clouds determine the overall volumeecore evalence

nucleusrern

3

Vn 3 ( )( )( , ) overall volumeof atoms

mass protonsmass electrons

18001

protons and neutronsdetermine an atom's mass=

valence

p,n

rn

mpme

=

1p = protons = constant # that defines the elementn = neutrons = varies = defines the isotopee = electrons = varies, depending on bonding patterns

i d100,000

associated termif electrons = protons (same # of e's and p's) atomif electrons < protons (deficiency of e's) cationif electrons > protons (excess of e's) anion

(eval) = valence electrons = The outermost layer of electrons, which determines the bonding patterns. The usual goal is to attain a noble gas configuration. This is accomplished by losing e's (forming cations) or gaining e's (forming anions) or sharing e's (covalent bonds)

( ) l Th i l ( ) f l ( ll f ll h ll b h ll ) Th ' h ld(ecore) = core electrons = The innermost layer(s) of electrons (usually full shells or subshells). These e's are held too tightly for bonding (sharing) and not usually considered in the bonding picture. These e's cancel a portion of the nuclear charge (called shielding) so that the valence e's only see part of the nuclear charge, called Zeffective.

5

Zeffective = (# protons) - (core e's) = the effective nuclear charge. This is the net positive charge felt by the valence e's (bonding and lone pairs). Zeffective = same # as the column of the main group elements.

Electronegativity, (chi), is the property that indicates an atoms attraction for electrons in chemical bonds with other atoms.

Approximate electronegativity values for some main group elements.

H = 2.2

pp g y g p(atoms in red have some biological significance)

Group 1AZeff = +1

Group 2AZeff = +2

Group 3AZeff = +3

Group 4AZeff = +4

Group 5AZeff = +5

Group 6AZeff = +6

Group 7AZeff = +7

Group 8AZeff = +8

He = noneV Cr Mn FeH 2.2Li = 1.0 Be = 1.5 B = 2.0 C = 2.5 N = 3.0 O = 3.5 F = 4.0 Na = 0.9 Mg = 1.2 Al = 1.5 Si = 1.9 P = 2.2 S = 2.6 Cl = 3.2 K = 0.8 Ca = 1.0 Ga = 1.6 Ge = 2.0 As = 2.2 Se = 2.5 Br = 3.0 Rb = 0.8 Sr = 0.9 In = 1.8 Sn = 2.0 Sb = 2.0 Te = 2.1 I = 2.7

3d elements4d elements

He noneNe = noneAr = noneKr = 3.0Xe = 2.6

1.65-1.90Co Ni Cu Zn

Simplistic estimate of bond polarities using differences in electronegativity between two bonded atoms.

0.4 considered to be a pure covalent bond (non-polar)id d b l l b d ( h i b l )

BA A B =bond polarity based on

0.4 < < (1.4 - 2.0)(1.4 - 2.0) <

considered to be a polar covalent bond (permanent charge imbalance)considered to be an ionic bond (cations and anions)

FHMgBr Br

Br =

=

Mg

= 1.8

F =

=

H

= 1.8TBP = 711oC TBP = 20oC

Rules can be ambiguous.

6

BP(ionic salt)

BP(molecular)

CuI (TBP = 1290oC NH3 (TBP = -33oC

1. Dispersion forces / van der Waals interactions / London forces (nonpolar attractions)

Dispersion forces are temporary fluctuations of negative electron clouds from one direction to another, relative to the less mobile and more massive positive nuclear charge These fluctuations of electronrelative to the less mobile and more massive positive nuclear charge. These fluctuations of electrondensity induce fleeting, weak dipole moments. Polarizability is the property that indicates how well this fluctuation of electron density can occur about an atom.

In a nonpolar molecule the and are centered on average This would seem tocentered, on average. This would seem toindicate that in nonpolar molecules there is no polarity or attraction between molecules. So why do such substances liquify and solidify? Why aren't they always gases?

and are not centered creating tempory polarity.

Fast moving electrons shift i i l i l

Dispersion Forces

+Z +Z +Z +Z

+ - + -position relative to slowmoving nuclei, creating a temporary imbalance of charge,

which induces a similar distortion of the electron

Weak, fluctuating polar forces of attraction between molecules.

distortion of the electronclouds in neighbor structures and a weak attraction for neighbor molecules.

+Z = nuclear protons = electron cloud

7

Periodic trends in polarizability, .

Zeff = +4 Zeff = +5 Zeff = +6 Zeff = +7

C N O F

F is like a marble.

ClPolarizability is greater because

Polarizability is larger with smaller Zeff because the electrons are not held as tightly so they are more easily

Br

Zeff = +7greater becausethere is a weaker hold on the electrons because they are farther away from Features that increase polarizability:

tightly, so they are more easilydistortable.

Br

Zeff = +7

the same effectivenuclear charge, so they are more easily distortable.

1. smaller Zeff, favors C > N > O > F

2. valence electrons farther from the l h Z i i il

I

nucleus when Zeff is similar I > Br > Cl > F.

I is like a cotton ball.

8Zeff = +7

The halogen molecules are similar in shape and l Th i th i i t d i

Phase at room temperature

200

250

I2bp

nonpolar. There is a smooth, increasing trend inboth melting and boiling points. This is suggestive of some factor increasing the forces of attraction between molecles of the halogen family as they get larger. The smooth trend in melting point is not typical because it can vary so much with differences

F2 = gas He = gasCl2 = gas Ne = gasBr2 = liquid Ar = gasI2 = solid Kr = gas

150

100 Br2

mp

typical, because it can vary so much with differences in shapes. The even change in melting points is observed here because the halogen molecules all have a similar, rigid shape.XX

Temp. (oC)

50

0

-50 Cl2The Noble gas molecules are similar in shape and

room temp 25oC

-100

-150F Kr

The Noble gas molecules are similar in shape andnonpolar. There is a smooth, increasing trend in both melting and boiling points. This is suggestive of some factor increasing the forces of attraction between molecles of the halogen family as they get larger. The smooth trend in melting point is not

Xe

bpmp

-200

-250

F2

273 absolute zero = 0 KHeNe

ArKr larger. The smooth trend in melting point is not

typical, because it can vary so much with differences in shapes. The even change in melting points is observed here because the halogen molecules all have a similar, spherical shape.

H2

9

-273 absolute zero = 0 K

Dispersion forces are cumulative, so when the contact surface area is larger, the interactions are stronger (because there are more of them). Higher molecular weight alkanes have more carbon atoms to interact than lower molecular weight alkanes (even though only similar weak dispersion forces are present in both).

Alkane boiling point Alkane boiling point From the examples above, you can see that even the weakAlkane boiling pointmethane, CH4 -162 ethane, C2H6 -89 73propane, C3H8 -42 47butane, C4H10 0 42pentane C5H12 36 36

Alkane boiling pointtridecane, C13H28 235tetradecane, C14H30 254pentadecane, C15H32 271hexadecane, C16H34 287heptadecane C17H36 302

CH4 CH4 Larger molecules have more contact surface area

p , ydispersion forces of attraction become significant when a large number of them are present.

pentane, C5H12 36 36hexane, C6H14 69 33heptane, C7H16 98 29octane, C8H18 126 28nonane, C9H20 151 25decane, C10H22 174 23

heptadecane, C17H36 302octadecane, C18H38 316nonadecane, C19H40 330icosane, C20H42 343henicosane, C21H44 356doicosane C22H46 369

CH3CH2CH2CH2CH2CH3

CH3CH2CH2CH2CH2CH3with neighbor molecules.Greater dispersion forces mean a higher boiling point.

decane, C10H22 174 23undecane, C11H24 196 22dodecane, C12H26 216 20

doicosane, C22H46 369tricosane, C23H48 380 triacotane, C30H62 450tetracotane, C40H82 563

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3

300 350 Boiling Point

Temp (oC)

100 150 200 250

300 p ( )

bp of water

-150-100 -50 0 50

mp of water

10C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20

Straight chain alkanes

In alkane isomers (having the same number of atoms, CnH2n+2), more branching reduces contact with neighbor molecules and weakens the intermolecular forces of attraction. Linear alkanes have stronger forces of attraction than their branched isomers because they have a greater contact surface area with their neighbor molecules. Branches tend to push neighbor molecules away. The strength of these interactions falls off as the 6th power of distance A structure twice as far away will only have 1/64 the attraction for itsfalls off as the 6th power of distance. A structure twice as far away will only have 1/64 the attraction for itsneighbor.

H2CH3C

H2CH3C

H2C CH3

CH

CH3

H3C CH3bp = -42oC bp = -0.5oCb 12oC

CH3 11 1

1 1

=6

6

H2CH3C

H2C CH3

bp = -0.5oC

referencedistance

More atoms increase the contact surface area with neighbor molecules (not isomers).

Less branching increases contact surface area with neighbor molecules in these isomers.

bp = -12oC 2164=

St di i f150oC

100oC

More efficient packing in lattice structure due to compact rigid shape = closer contact(higher mp).

bp = +106mp = +101

bp = +126

Stronger dispersion forces because of greater surface contact area in linear chain (higher bp).

100oC boiling point

50oC

Temp(oC)

(higher mp).p

t t

hot dog?

your finger?T = 75oC

meltingpoint

boilingpoint

0oC

25oC room temp water

freezing point0oCfar apart

( no interaction)larger

11

solid lattice, fixed, close positions

liquid, mobile, close positions

-50oC mp = -57gas, mobile,

separated, PV=nRT

energysmallerenergy

H H H

Hybridization explains the shapes we observe in organic and biochemistry.sp3 sp2 sp sp2 sp sp2

C

H

HH

C H

H

CH C H CbCa

H

H

Ca

ethane ethene allenetrigonal planar carbon atoms

C CH H

H H

H

H

tetrahedral carbon atoms

HCH bond angles 109o HCC bond angles 109o

trigonal planar carbon atoms

HCH bond angles 120o (116o)CCH bond angles 120o (122o)

ethynelinear carbon atoms

HCC bond angles = 180o

trigonal planar carbon atomsat the ends and a linear carbon atom in the middle

HCaH bond angles 120o HCaCb bond angles 120o

CaCbCa bond angles = 180o

H HH

Lone pairs can occupy a similar space to a bonded atom. (Zeff(C) = +4, Zeff(N) = +5, Zeff(O) = +6)

CH

H

N HCH N CbCa

H

H

NC NH H

H

H

methaniminemethanamine hydrogen cyanide ethenimine

C

H

HH

O

H

C OC OH

HCO O

12

Hcarbon monoxidemethanol methanal carbon dioxide

allylic carbocation(2D and 3D structures)

enolate anion(2D and 3D structures)

Resonance occurs through parallel p orbitals and stabilizes positive charge, negative charge, free radicals and neutral conjugated pi systems.

CH2C CH2

H(2D and 3D structures)

CH2C O

H(2D and 3D structures)

CH2C CH2

H

CH2C O

H

C C

H

H

C H

H

C C

H

H

C H

HC C

H

H

O

H

C C

H

H

O

H

H C H

H

H C H

H

allylic free radical(2D and 3D structures)

bezene resonance(2D and 3D structures)

CH2C CH2

H

C CH2H2C

H equivalentstructures

C C

H

H

C H

H

C C

H

H

C H

H

C

CC

CH H

HH

C

CC

CH H

HH

13

H HC C

CCH H

H H

C C

CCH H

H H

2a. Dipole-dipole interactions (in between polarity) - Dipole moments are less than full charges and the bonds are very directional (not "omni"), so attractions for neighbor molecules are weaker than is found in ionic salts. However, polar molecules usually have stronger attractions than nonpolar molecules of similar size and shape Boiling points are a better indication of the strength of attractions among neighborsize and shape. Boiling points are a better indication of the strength of attractions among neighbormolecules than melting points (when other factors are similar). A higher boiling point indicates stronger attractions. Molecular dipole moments are indicators of charge imbalance due to a difference in electronegativity , bond length and molecular shape.

nonpolar polar more polar

C

O

H HC

C

H H

H Hnonpolar polar

C

O

H H

more polar

resonanceTbp = 84oCC

C

H H

H H

0.208Aelectron proton

= 0.0 Dbp = -104oCmp = -169oCH2O sol. = 2.9mg/L

= 2.3 Dbp = -20oCmp = -92oCH2O sol. = 400g/L

K NA

versus

C

O

H H

= (q)x(d) = dipole momentq = charged = distance

= 1.0 Debye

pKa = 44 pKa = NAH H

CH

polarnonpolar

CN

more polar

resonanceCC

H

CN

bondCH3-X (D) d(pm) energyCH3-F 1.85 138.5 461CH3-Cl 1.87 178.4 356CH Br 1 81 192 9 297C

H

CN

= 0.0 Dbp = -81oCmp = -84oC

= 2.98 Dbp = +26oCmp = -13oC

CH

Tbp = 107oC

H H

versus

CH3-Br 1.81 192.9 297CH3-I 1.62 213.9 239

14

CH

H2O sol. = insolublepKa = 25

mp 13 CH2O sol. = misciblepKa = 9.2

What is the effect of "R" groups? Do they make the molecule more polar less polar or no different?

C NH polarnonpolar

Nmore polar

CN

H C

What is the effect of R groups? Do they make the molecule more polar, less polar or no different?Electron donation or electron withdrawal through sigma bonds is called an inductive effect.

CC

H3C

CH3C

= 0.78 Dbp = -23oC

= 3.92 Dbp = +81oC

CN

H3C

resonance

Tbp = 104oCC

CH

H3C

versus

mp = -102oCH2O sol. = insoluble

mp = -46oCH2O sol. = miscible

CH3C

polar O OOpolar polar

C

O

H H = 2 3 D

polar

C

O

H H

resonanceC

O

H3C H

2 68 D

C

O

H3C CH3

2 91 D

C

O

H3C H

resonanceC

O

H3C CH3

resonancepolar p

2.3 Dbp = -20oCmp = -92oCH2O sol. = 400g/L

= 2.68 Dbp = +20oCmp = -123oCH2O sol. = very sol.

= 2.91 Dbp = +56oCmp = -94oCH2O sol. = very sol.

15

2b. Hydrogen bonds - Hydrogen bonds represent a very special dipole-dipole interaction. Molecules that have this feature have even stronger attractions for neighbor molecules than normal polar bonds would suggest. Solvents that have an O-H or an N-H bond are called "protic solvents" and can both donate and accept hydrogen bonds (because they also have lone pairs of electrons). They generally have higher boiling points than similar sized structures without any "polarized hydrogen atoms". We call such interactions "hydrogen bonds". A molecule that has such a polarized hydrogen is classified as a hydrogenbond donor. A molecule that has a partial negatively charged region that can associate with such a hydrogen is classified as a hydrogen bond acceptor.

OH accepts

hydrogenHydrogen bonding holds the molecules more tightly to one another. This can be seen in higher boiling

O

HH

O

H

OH

donates hydrogen bond

hydrogen bond

to one another. This can be seen in higher boilingpoints among similar structures where hydrogen bonding is possible versus not possible. Many examples below show this property.

H donates h d

H Cl

H

O OHH3C H

accepts hydrogen bond

donates hydrogen bond

donateshydrogen bond


O

OH

H

H


hydrogen bond

CH3C

O H

C CH3

O

CC3

H HCH3C CH3

N O NH

Hthree hydrogen bonds in G-C base pair two hydrogen bonds in A-T base pairH

N

N

N

N

O

HDNA

N

N

NH

N

N

N

DNAN

O

H

N H

16

N H

H

O DNAguanine cytosine

NDNA

N

O DNAadenine thymine

Which base pair binds more tightly, GC, AT or are they about the same?

Provide an explanation for the different boiling points in each columnProvide an explanation for the different boiling points in each column.

HFbp = +20oCmp = -84oC

H2Obp = +100oCmp = 0oC

NH3bp = -33oCmp = -78oC

CH4bp = -164oCmp = -182oC

4B 5B 6B 7B

Hebp = -269oCmp = -272oC

8B

T

100

50

boiling points (oC)H2O

p = 1.86 D = 1.8

bp = -85oCmp = -114oC

p = 1.80 D = 1.2

bp = -60oCmp = -82oC

p = 1.42 D = 0.8

bp = -88oCmp = -132oC

mp 182 C = 0.0 D = 0.3

bp = -112oCmp = -185oC

HClH2SPH3

p = 0.0 D = NA

bp = -246oCmp = -249oC

Ne

Temp(oC)

0

-50SiH4

SnH4

SbH3NH3

HF

H2S

H2SeH2Te

HCl HBr

HIAsH3

= 1.0 D = 1.0


p = 1.0 D = 0.4


p = 0.0 D = 0.0

bp = -62oCmp = -111oC

mp 185 C = 0.0 D = 0.3

bp = -88oCmp = -165oC

SiH4HBrH2SeAsH3

GeH4

p = 0.0 D = NA

bp = -185oCmp = -189oC

Ar

-100

-150CH4

GeH4

PH3HCl

AKr

p = 0.8 D = 0.8

p = ? D = 0.4

mp 111 C = 0.0 D = 0.0

p = 0.0 D = 0.2

p = 0.0 D = NA

-200

-250

-300

HeNe

Ar


bp = -2oCmp = -49oC


bp = -52oCmp = -146oC

HIH2TeSbH3SnH4bp = -153oCmp = -157oC

Kr

row2

row3

row4

row5

-300 = 0.4 D = 0.5

p = ? D = 0.1

p = 0.0 D = 0.2

mp 146 C = 0.0 D = 0.2

= 0.0 D = NA

Column shifted down one row.

17

H2C O

Offer explanations for the following observations.

H2

H3CC

CH3 H3CO

CH3

= 0.08 Dbp = -42oC

o

= 1.30 Dbp = -22oC

o

H3C

2C

O

= 1.69 Dbp = +78oC

H

= 20oC = 100oCmp = -188oCH2O sol. = 0.004 mg/L

mp = -141oCH2O sol. = 71g/L

H2C OH C CH H3C CH3

pmp = -114oCH2O sol. = miscible

H2CH3C O

CH2

CCH2

CH2

OCH2

= ? Dbp = +36oC

= 1.15 Dbp = +35oC

H3C CH3H3C CH3

CH2

CCH2

= 1.66 Dbp = +118oC

H3C OH

= -1oC = 83oCpmp = -130oCH2O sol. 0 mg/L

pmp = -116oCH2O sol. = 69 g/L

mp = -90oCH2O sol. = 73 g/L

18

The types of interactions between molecules depends on functional groups and solvation. Organic functional groups are mostly similar to biochemical functional groups.

OO OOO

O

CR

O

OC

R

O

OC

R

O

Cl

CR O

R

CR NC

O

RH

H

Hanhydridescarboxylic acids esters acid chlorides amides (1o 2o 3o)

CR NH HC

O

C

O

NR

H

anhydridescarboxylic acids acid chlorides amides (1 , 2 , 3 )

OR SRR HC

R R Hnitriles aldehydes ketones alcohols thiols amines (1o, 2o, 3o)

OR

R

SR

RN

R O NR O

OXR

X = F, Cl, Br, I

ethers thioethers halogend

CR C HCC

HH

ethers sulfides compounds nitro compoundsnitroso compounds

N There is chemical logic for all of these functional groups. You have to

19

HRalkenes alkynes aromatic heteroaromatic

groups. You have tounderstand how they react to plan strategies in drug design.

O

HO

OH

HO

O

HO

O

HO

Biochem structures are more like names of your classmates. Every one has to be learned individually. (* = chiral center). Stereochemistry is critical part of each structure.

* * * *OH

OHHO

HOO

OHHO

HO

aldose

OH

OHHO

O

OHHO

HO

hemi-acetal

acetalpyranose

*

* **

**

*

24 i

*

* *

**

* *

*

acetal

OH

OHHO

HO

O

OHO

hemi-ketal ketal

pyranose

O OH

OH

HO

O

OH

OH

*

* * *

24 stereoisomers25 stereoisomers 210 stereoisomers and

multiple ways to attach

**

OHOketonse

OH

OHHO

OOH

OHHOfuranose

O

OH

HO

HO

glycosidesH HH H

**

* **

**

** *

* *

23 stereoisomers 24 stereoisomers

29 stereoisomers and

N

N

N

N

1

2

34

56 7

8

9

H

N

N

H

1

2

34

5

N

N

N

N

1

2

34

56 7

8

9

HN

N

N

N

1

2

34

56 7

8

9

H

H2N

steriodshormones

2 stereoisomers andmultiple ways to attach

N

6 7purine imidazole

N

NH2

HN

O

3

HN

O

adenine

6 7

guanineNH2 O

H2NC

C

HR

O34

5

hormonesproteinsfatty acidsglyceridesneurotransmittersand on and on...

S

20

N

pyrimidine

N

NH

O

cytosine

HN

NH

O

thymine uracil

NH

O

H2N C

OHamino acids(20 essential,

there are 100s of others)1

2 6

S

Famous DrugsPsychoactive drugs - chemical substances that affect the function of the central nervous system, altering perception, mood or consciousness: ethanol (depressant:wine beer, hard liquor, chough medicines, etc.), nicotine (stimulant: cigarettes, cigars, pipes, patches, drops, etc.) and caffeine (stimulant, estimated used by 90% of the population: coffee, tea, chocolate, etc.) are the most widely consumed psychoactive

O CH3

drugs used worldwide and are also considered recreational drugs since they are usedfor other than medicinal purposes

H3C

H2C

OH

ethanol

N

N N

N

O

H3CN

H

CH3ethanolnicotinecaffeine

N NO

CH3

N

21

Other recreational drugs: hallucinogens (LSD), opiates (morphine, heroin) and amphetamines (phenethylamine has been used to treat ADHD narcolepsy and obesity methamphetamines) also(phenethylamine has been used to treat ADHD, narcolepsy and obesity, methamphetamines), alsouse can be spiritual or religious (mescaline from peyote used by indigenous peoples for about 6,000 years, cannabis (THC = tetrahydrocanabinol) used for spiritual purposes for about 4,000 years)

Lysergic acid diethylamide (LSD)

morphine(and heroine)

HOphenethylamines

(huge variety) NH2Omescaline

ON

H O

HO

H

HN

RN

RR2

R3

(huge variety) NH2O

O

O***

* *

One Hundred Years of Solitude (1967) 7 generations of Buendia family in Columbia

features mescaline and ghostsGabriel García Márquez

E i h i l k d li

NCH3

H

H

HO

NCH3

R

R4

R5

R6

**

*

*

Epinephrine, also known as adrenalin

HN

CH3

CH

HO

OHHN

tetrahydrocanabinolTHCOH H

N

O O

Methylphenidate(ritalin)* = chiral center

* *

HN

CH3 methamphetamine (racemic, free base) l th h t i ( k ) d

CH3HO

O

H

HN

**

*

* *

22

CH3levomethamphetamine (weaker) anddextromethamphetamine (stronger)

O O9

Therapeutic Index = toxic dose (50% of subjects) / effective dose (50% of subjects), a safe drug has a high number and a dangerous drug has a low number. Or, some define it as the safe amount of drug in the blood.

Digoxin cardiac glycoside from foxglove plant: 0.8 to 2.0 ng/mL

H

HOC38H58O14

Mol. Wt.: 738.86

therapeutic amount = 2 x 10-9g / mL = 3 x 10-12 moles / mL = 8 x 10-5g / 40L

H OH

H

O

O

O

O

O

HO O

complicatedmedicine

HOHOHO

(8x10-5g / 40L)(1 mol/800g)(1023 molecules/mol) = 1x1017 moleculesmoleculescell =

100,000,000,000,000 cells = 1x103 moleculescell

lithium: 0.8 to 1.2 meq/L (toxic over 1.5 meq/L)OH O

O

O

O

LiLilithium citrate - used to treat bipolar depression

therapeutic amount = 1 x 10-3meq Li / L 0 33 10-3 l lt / L

C6H5O7Li3

Mol. Wt.: 201

O OLi

= 0.33 x 10-3 mmoles salt / L = 0.2 g salt / 40L

older methodLD50 = lethal dose, 50% of subjects

simplemedicine

23

= , jED50 effective dose, 50% of subjects

(0.2g / 40L)(1 mol/200g)(6x1023 molecules/mol)(3 Li/molec.) = 18x1021 moleculesLi+cell =

100,000,000,000,000 cells= 2x107 Li+

cell

Water distribution in people is estimated to be 48 ±6% for females and 58 ±8% water for males (averages). Water constitutes as much as 73% of the body weight of a newborn infant. Body water and salt is regulated by hormones (anti‐diuretic hormone = ADH = vasopressin), aldosterone and atrila natriuretic peptide.

Body water can be broken down into the following compartments:

Intracellular fluid (about 2/3 of body water). Per Guyton: in a body containing 40 liters of fluid, about 25 liters is intracellular, which amounts to 62.5% (5/8), close to the 2/3 rule of thumb

Extracellular fluid (1/3 of body water). Per Guyton: in a body containing 40 liters of fluid, about 15 liters is extracellular, which amounts to 37.5%, close to the 1/3 rule of thumbthumb.

Plasma (1/5 of extracellular fluid). Per Guyton: of the 15 liters of extracellular fluid, plasma volume averages 3 liters. Interstitial fluid (4/5 of extracellular fluid),

ll l fl id ( k " hi d " ll i d i l l i ) i idtranscellular fluid (a.k.a. "third space," normally ignored in calculations), inside organs, gastrointestinal, cerebrospinal, peritoneal and ocular fluids.

Estimates are for about 6 quarts of blood flow per minute, 83 gallons per hour and

24

q p , g p2,000 gallons per day. Blood circulates through the body in about 1 minute.Video of blood flow: http://www.brainstuffshow.com/blog/how‐fast‐does‐blood‐flow‐throughout‐the‐human‐body/

Pain relivers = analgesia, relief from pain. (many possibilities, example here = Tylenol)Tylenol or paracetamol or acetaminophen or APAP most commonly used medication for pain and fever

N

H The good: It is used to treat pain and fever and appears to act centrally in the brain, rather than peripherally in nerve endings. It is often sold in combination with other drugs (cold medications and opioid pain medications for cancer or after surgery). Its mechanism of action is not

Tylenol or paracetamol or acetaminophen or APAP - most commonly used medication for pain and fever

HOO

Toxic metabolite

g y)well understood. It is thought to inhibit COX enzymes (cyclooxygenase 1 (has isoleucine at position 523 in active site) and cyclooxygenase 2 (has smaller Val523 there), 65% homologous and very similar active sites), which prevents metabolism of arachidonic acid to 'unstable' protaglandin H2, which is converted to pro-inflamatory compounds. It

Tylenol (MW = 151)

N

H

Toxic metabolite p g , p y palso may inhibit the uptake of anandamide, increasing concentrations of endogenous cannabinoids, modulating pain pathways and lowering body temperature. It may also block synthesis of nitric oxide. The half life in adults is about 3 hours, but is longer in infants, so the dose gets progressively lower the younger the patient.

The bad: Use at high dosages can cause liver failure. It is the most common cause of liver failure in the US and UK. Damage to the liver, or hepatotoxicity, results not from acetaminophen itself, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). which depletes the liver's natural antioxidant glutathione and directly

OO

N-acetyl-p-benzoquinoneimine (NAPQI)

p g y y g p

depletes the liver s natural antioxidant glutathione and directlydamages cells in the liver, leading to liver failure.

( Q )

valine

H N CO

isoleucineTypical dose = 2 tablets = 625 mg = 0.625 g = 0.0041 mole = 2.5 x 1021 molecules x 5 times/day = 1022 molec/day

25

H3N CO2H

H3N CO2H

# molecules/cell = 1022 molec/1014 cells = 100,000,000 molecs/cell

12

34

56

7

8O

HO1

23

45

6

7

8

HO

HO

O

1 3 5

We need this from our diet.

enzyme89

1011

1216

1718

linoleic acid (LA)18:2n-6

O 89

1011

12

1718

-linolenic acid (LA)18:3n-6

O

dihomo--linolenic acid (LA)20:3n-6

HO 12

34 5

6

7

89

1016

1718

1920

enzymereactions

(add a double bond)

enzymereactions

(add 2 carbons)

Linoleic acid is an essential, polyunsaturated fatty acid used in the biosynthesis of arachidonic acid (AA) and thus some prostaglandins, O

12

1314

15

16 12

1314

15

16 1112

1314

15

O

Our bodies can do this as part of our fatty acid metabolism.

enzymereactions

(add a double bond)p g ,

leukotrienes (LTA, LTB, LTC), and thromboxane (TXA). It is found in the lipids of cell membranes. It is abundant in many nuts, fatty seeds and their derived vegetable oils. It comprises over half (by weight) of

HO 12

34 5

6

7

891719

arachidonic acid (AA)20:4n-6

NH

12

34 5

6

7

8917

1819

20

HO

enzymereactions

)

p ( y g )poppy seed, safflower, sunflower, corn, and soybean oils. It must be consumed for proper health. A diet only deficient in linoleate (the salt form of the acid) causes skin scaling, hair loss, and poor wound healing in

910

1112

1314

15

16

1718

1920

O

10

1112

1314

15

161820

anandamide - fatty acid neurotransmitter and found as the natural receptor for 9-THC compounds in enzyme

ihair loss, and poor wound healing in rats

HO

O

12

34 5

6

7

8

9prostaglandin H2(blood clotting, immune response) O

as the natural receptor for -THC compounds incannabis (tetrahydrocannabinol in marijuana).

reactions

R8

9O

OO

8 9

10

R

O8 9

10

Roxygenor

P-450

26

810

111213

141516

1718

1920

(blood clotting, immune response) O

O

OH

R

10

11

12

OO

10

1112R

O10

1112Rprostaglandin H2

https://en.wikipedia.org/wiki/Prostaglandin_H2(prostaglandins are 20 carbon

compounds that do many things,p y g ,stop bleeding, part of immune response, cause inflammation, temperature control, etc.)

27

How does acetaminophen cause liver damage? We need to look at some related biomolecules. You are not responsible for these mechanisms.

FAD / FADH2 - Flavin adenine dinucleotide (oxidation - reduction) - used to deliver hydride to C=C or take hydride from CH-CH (fatty acid metabolism, etc.)

FAD - flavin dinucleotide (a hydride acceptor)

N H

BH

simplified structures for FAD and FADH2

CC

R

R

R

R

BH

C

R

R C

R

R

HH

N

N

N

H

Hydride transfer reduces FAD to FADH2.

R R

hydride transfer from FADH2. reduces C=C, makes FAD

N

N

HH

HRN

H

FADH2 - flavin dinucleotide (a hydride donor)

N

B

C

H

R C

R

R

B

CC

R

R

R

R

HOOH

O P

O

O

O P

O

O

OO

N

N

N

NH2

FAD - flavin dinucleotide (a hydride acceptor)

actual

N N O

OHHO

OHN

Nstructure

N N O

R

N N O

R

28

NNH

Oatypical nitrogen (electron poor)

NNH

O

resonanceN

NH

Oonly 6 e-

Aldopentoses - 5 carbon aldehyde carbohydrates, naturally occuring carbohydrates tend to be D, 3 chiral centers leads to 23 = 8 possible stereoisomers (naturally occurring aminoacids tend to be L with "S" chirality)

OH OH OH OH

*** * * * *HO O

OHOHD-arabinose

O H

HO O

OHOHD-lyxose

O H

HO O

OHOHD-ribose

O H

HO O

OHOHD-xylose

O H

* * * * * * * * * *

HHO

H OH

H OH

HHO

HO H

H OH

OHH

H OH

H OH

OHH

HO OH

H OH

S

R

R

S

S

R R R

R

R

R

S

H2COH

H2COH

H2COH

H2COH

enantiomer enantiomer enantiomer enantiomer

Ketopentoses - 5 carbon ketone carbohydrates, naturally occuring carbohydrates tend to be D, 2 chiral centers leads to 4 possible stereoisomers (naturally occurring aminoacids tend to be L with "S" chirality)

OH OH

HO OH

O

OH

OHD-ribulose

HO OH

O

OH

OHD-xylulose

** * *N

NN

N

NH2

P OO

O

5-phosphate

O

H OH

OH

O

HO H

OH

R

R

S

N

O

OHOH

HH

HH

O

P OOadenosine

ribose1

23

4

5can

rotate here

29

H OH

H2COH

H OH

H2COH

R R

enantiomer enantiomer

adenosine monophosphate (AMP)

Keto / Enol tautomerization is a common transformation, happens twice in glycolysis.

O R S S R R S

D-glucose

BH

OOH

OH

HOHO

HO

* = chiral center**

* * *25 = 32 possible stereoisomers for cyclic glucose

RRRR

SSSS

SRRR

RSSS

RSRR

SRSS

RRSR

SSRS

RRR

SSS

SSR

RR

RSS

SR

SR

RS

O

H

HOOHBH

O

H

HOOHH

BH

OHOOHH

****

RS

SR

RR

SS

SR

RS

SR

RS

Henzyme enzymeH

H OHOHOB

H

OHO OH

B

H

OHO O

D-glucose-6-phosphate24 = 16 possible stereoisomers

endiol D-fructose-6-phosphateO3P O3P O3P-2 -2 -2

p

OOBH

OOH

BH

OOHP

O

O P

O

OP

O

O

H

H OH

H

OH

O

H

O

O

O OOHenzymeenzyme

30

B

HB

D-glyceraldehyde-3-phosphate endiol dihydroxyacetonephosphateMost of life makes D carbohydrates, though some bacteria can make both kinds (self defense).

NAD+ and NADP+ - nicotinamide adenine dinucleotide (hydride acceptor)

NN

NH2CONH2

3

4

5Why is C4 l hili ? similar role inN

NNOHH

HH

P

O

O

OP

O

OH2C

O

CH2O

=

O

OH HO

NN

R

t lsimplified

1

26electrophilic? similar role in

organic chem: Jones, PCC, Swern oxidation

OHOH NADP+ has a phosphate here.

actualstructure

p structure

NADH and NADHP - nicotinamide adenine dinucleotide (hydride donor)

NH2CONH2H

HH4aH4b

N

NN

N

OP

O

OP

O

OH2C CH2O

=

OH HO

NN

H

Why is H4 nucleophilic?

similar role in organic chem: NaBH4, LiAlH4

OHOH

HH

HH

OOO

O HOR

NADPH has a phosphate here.

N

N

HBH

N

N

Transfers 2e-s and 2H, possibly as hydride and a proton or in free radical transfers.

NAD+

H FAD( i lifi d)

NADH

B BH

N

N

H FAD

NADHreverse

31

HNR

H

H

(simplified)oxidized FADH2

(simplified)reduced

NR H NRH

H

(simplified)oxidized

O

O

Ofatty acid chain

BHN

FADfatty acid catabolism - most reactions in biochemistry are under enzyme controlB

BH

O H

B H

R

O

O

O

RO

enzyme ester

hydrolysis

OR

OO OO

O

R

P

O

O

O

mixed anhydride

S

O

R

ENZ-1

acyl-CoA high energy thioester

H

H H

H

N

H

R

triglyceride - fatty acid chains are often 16-18 carbons long

O P O

O

O P

O

O P

OATPENZ-1S

H H

N

N

H

H

B

FADH2

acyl CoA (2 carbons shorter,

cycle repeats) hydroxythioester ketothioester

HBB H

B H

NAD+

FADH2

S

O

R

ENZ-1

H

H

S

O

R

ENZ-1O H

H

B

S

O

R

ENZ-1O

B H

S

O

R

ENZ-2

cycle repeats),-unsaturated thioester

-hydroxythioester-ketothioester

B H

N RH

H

N R

NADH

HB

H

O HB H

H HR

H H

ENZ-2SS

O

ENZ-1

HB

All of this is "Co-A"

CoA S

H

B

acetyl CoA - involved

O P

O

O

O P

O

O

OO

N

N

N

NH2

OH

O

NH

O

NH

HS

Thiol esters form here.

All of this is Co-A

lThis is an acetyl group

S

O

CoAENZ-1 S

H

32

yin many biochemical

cycles in the bodyHO

OHNO

S CoAAcetyl Co-A =

actualstructure

simplified structure

Co-AHS

acetyl grouprepeat

O

O

R

saturated fatty acid chain (no C=C bonds)fatty acid structuresO

HO 1 34

56

78

9 11 Lauric acid, C12

1

234

5678

910

1112

O

O

O

RO

R

4 6 8 10 12O

HO 1 34

56

78

910

1112

1314

O

Myristic acid, C14 tetradecanoic acid

dodecanoic acid

R

triglyceride - triester of glycerol HO 1 34

56

78

910

1112

1314

1516

O

HO 1 3 5 7 9 17

Palmitic acid, C16hexadecanoic acid

Stearic acid C18

O

O

RHO 1 3

45

67

89

1011

1213

1415

1617

18Stearic acid, C18octadecanoic acid

O

HO 1 34

56

78

9 1011

cis-9-Octadecenoic acidOleic acid, 18:1 cis-912

1314

1516

1718

O

12

34

567

89

= D = double bond

O

O

O

RP

O

O

HO N

CH3

CH3

O1

23

45

6HO

Linoleic acid, 18:2n-618:2 cis,cis-9,12

O

HO 1 34

56

78

9 1011

12 1314

1516

1718

1234

567

89

l i id (LA)

O

diglyceride - phosphatidyl choline

HO N CH3

CH3

9 10

HO 12

34 5

6

7

8917

1819

20

arachidonic acid (AA)20:4n-6

7

89

101117

18

linoleic acid (LA)18:2n-6

O

oleic acid (LA)18:1n-9

What came first in life?

9 10

11 12

13 14

15 16

17 18

87

65

43

21O

33

10

1112

1314

15

16182011

12

1314

15

16

17What came first in life?amino acids proteins, nuclotide bases RNA DNA,fats & lipids membranes,carbohydrates structure, energy,...or some combination of all of these

17 181

HO

Example of cytochrom P-450 oxidative enzymes, common in the liver, protoporphyrin, the iron sits in the middle of a complicated heme molecule. There are over 21,000 distinct P-450 enzymes known.

FeN

N

N

N

N NFe

simplified structure,binds to enzyme through a sulfur

+3

+3

HO2C

NNg

enzyme, cysteine

S

Enz

Fe+3

All extraneous parts are left out to show only the iron atom in an oxidized state

anchored to enzyme2

CO2H

Enz

S HB

ready for oxidation reactions shown below(symbolic cytochrom P-450 enzymess)

atom in an oxidized state.y

The proteins are complicated and can hold iron‐hemeand can hold iron‐hemecomplexes.

34

1.�Ferric iron ion abstracts an electron from flavin mononucleotide (FADH2), an enzyme co-factor, and is reduced from +3 to +2.2.�Iron gives up an electron to make a bond with oxygen. (+2 to +3).3 �O b l f fl i l id (FADH FAD) f

Steps shown below in cytochrome P-450 oxidations (and next slide)

3.�Oxygen atom abstracts an electron from flavin mononucleotide (FADH FAD), an enzyme co-factor.4.�FAD gets reduced by NADH (hydride donor) and picks up a proton to reform FADH25.�The basic oxygen anion picks up a proton (or two?) from an acidic enzyme site.6.�A weak O-O bond breaks homolytically or heterolytically, and releases water. 7.�An electron is supplied from iron to stabilize the oxidized oxygen atom. +3 to +4, which is nowpp yg ready to oxidize bio-molecules.

B H1e-

OO

Fe+3 FADH2 OO

OO

1

A

Fe+2 Fe +3 FADH

Fe

O

+3

+H+

1 2 3

5NAD+ NADH

FAD

OH

B HHH

45

heterolyticH2O

Possible leakage of hydroxyl di l ( l d

Fe

OO

+3

Fe

OO

+3Fe+4

O

678, 9, 10

(see next)Fe+3

homolytic

heterolyticreactiveperoxide

35

radicals (extremely dangerousin the body), but also part of body's immune defense in all out warfare, collateral damage possible.

OHEvery step represents a protein target for a

medicine. Side effects occur when other biochemical reactions are also affected.

8.�The free radical-like oxygen atom converts a C-H bond to an C-OH bond via free radical chemistry9.�The free radical-like oxygen atom converts a C=C bond to an epoxide via free radical chemistry10. The free radical-like oxygen atom converts a N or S lone pair to an N-O or S-O bond.

Th i i d d b k t F +3 t b i th ll i

Nature's magic tricks.

The iron is reduced back at Fe+3 to begin the process all over again.

CCO

H

O CH OH

sp3 C-H bonds alcohols8

hydrophobic hydrophilic

The free radical-like oxygen atom abstracts a hydrogen atom from a C-H bond in the enzyme cavity, forming an O-H bond and a carbon free radical.

Fe +4 Fe +4The carbon free radical abstracts hydroxyl (OH) from iron, making an C-OH bond where a C-H bond had been. The iron is reduced back at Fe+3 to begin the process all over again.

Fe +3hydrophobicbecomes....

hydrophilic

9

O O

C C

O

RR R

RC C

R

R

R

R

CR

R

C

R

R

O

HH

B

C C

RR

HO

OH

RR

Diols are much more

hydrophilic

The free radical-like oxygen atom adds to a C=C bond (alkene or aromatic) in the enzyme cavity, forming a O-C bond and a carbon free radical.

Fe +4 Fe +4The carbon free radical abstracts the oxygen atom from the iron, making an epoxide ring. The iron is reduced back at Fe+3 to begin the process all over again. Reactive epoxides can be opened up to diols (more water soluble).

Fe +3epoxidesB HDiols are much morewater soluble, can be eliminated from the body.

alkenes or aromaticshydrophobicbecomes....

R

S R

sulfursubstrate

R

S R

sulfurS R

ON

RR/H

O

O OFe +3

10

36

(1e-) sulfursubstrate R

R

sulfoxides, further oxidation is possible, all the way to sulfate, SO4

-2

R

N-oxides, further oxidation is possible, all the way to nitrate, NO3

-1

R

Fe +4 Fe +4(nitrogen too)

Toxicity of acetaminophen

H H

N-hydroxylation by cytochrome P-450 (too much acetaminophen uses up all the capacity of the enzyme to oxidize target molecules)H

HO

N

OFe +4

O

HO

N

O

H

Fe +4

O

N

Fe +3

O

( 20%)

OH

H

acetaminophenHO

HOO

gluconidationconjugation

( 50%)

sulfonationconjugation

( 30%) NH

H

B HToo much acetaminophen uses

h idi i

NO

HO

O

OHOO

N

O

B Hup the P-4450 oxidizing powerof the liver. Other compounds that need oxidation are not oxidized and can build up to toxic levels.

OOH

BOH

OH

HOS

O OO

Conjugation joins xenomolecules with biomolecules, usually helps to eliminate them from the body in the

makes thesemore water soluble

O

N

O

Toxic metabolite(see next slide)

usually helps to eliminate them from the body in theurine (kidneys) or feces (intestines).

Furanocoumarins are found in citrus fruits and can cause similar problems when taking

37

N-acetyl-p-benzoquinoneimine (NAPQI)OO O

similar problems when takingcertain medicines.

Psoralen is a mutagen found in grapefruit, and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation and can form monoadducts and covalent interstrand cross-links (ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis (cell death).

Tylenol 100,000,000 molecs/cell

OHS

glutathione (5mM in cells)(about 300,000,000 / cell)

Vol 10-13 L

Glutathione is an important reducing agent in body (can provide electrons from sulfur).

O2C

O

N

HH3N O

N

H O

O

Vol 10 13 L

RS

H

Glutathione also protects against toxicity by conjugating with metabolites, making them water soluble and

glutathioneHH3N O

glutathione conjugation with NAPQI

BBH H

excreting them. The bodies store of glutathione is used up reacting with NAPQI.

glutamic acid(backwards) cysteine glycine

g(tripeptide)

N

O

RS

H

B

HO

N

O

SR

glutathione

OHO

Other important anti-oxidants found in the body: glutathione, vitamin C and vitamin E. All protect against free radical damage in the body. Food can be medicine too, and food can be toxic!

O OHO O O

OHHO

HO

HO

HO

vitamin E (-tocopherol)electron rich anti-oxidant

fat soluble (in membranes)there are several variations

38

HO

vitamin C (ascorbic acid)electron rich anti-oxidant

water soluble (blood and cytosol)

O

Possible membrane damage from free radicals and possible protection from vitamins E and C.

HO

O O

Osaturated fatty acid chain

HO

OH

OO

Osaturated fatty acid chain

The damage

dangerous

O

O HO O

O

O

Free radicals reacting with unsaturated fatty acid pi bonds

diglycerides in cell membranes

uncontainedfree radical

unsaturated cis fatty acid chains in cell membrane

HO O OHO

unsaturated fatty acid pi bondscan possibly cross link fatty acid chains, making cell membranes more rigid and less functional over time, leading to cell death.

O

O

O

saturated fatty acid chain

O

O

O

saturated fatty acid chain

OH

unsaturated cis fatty acid chains in cell membrane

O

continueddamage

39

The protection

O

resonance and inductive effects stabilize radical so it does not do damage

HO

hydroxyl free radical

O

O

R

H

O

O

R

H

O

O

R

H

resonance

vitamin E located in cell membranes quenches radicals

O

O

OH

OOO

HO H

H Bhydroxide isneutralized by body's buffer system

vitamin C reduces vitamin E back to normal and ultimately washes out of the bodyHO

HO

OH R

OH

OO

O

H

H R

O

O

O

O

H

H

O

O

O

O

H

RR

washes out of the body

B

HO

resonance

O R

vitamin E is recharged and still in cell membrane

OH ROHO RR

Bprotects a second time

O

O

O OHO vitamin E ( tocopherol)

and still in cell membraneOO

O R

oxidized vitamin C formwashes out of the body

40

O O

OHHO

HO

HOvitamin C

water soluble (blood and cytosol)

O

HO vitamin E (-tocopherol)electron rich anti-oxidantfat soluble (membranes)

= diglycerides, helps compartmentalize aqueous regions in the body, cell membranes mitochondria vacules cell membrane (lipid bilayer)OH

cholesterol - helps stabilize cell membrane and source of all other body steroids

membranes, mitochondria, vacules,nucleus, etc. exocytosis - cell transports proteins to outside

endocytosis - cell transports proteins to insidemembrane proteins

Na+ion channels

HO

OH

mitochondriagolgi apparatus

ribosomes

endocellularprotein

HO

steroids.

G coupled protein complex, 1/3 of all medicines act on

G proteins.

exocellularprotein

nucleus

ribosomesd l i

ribosomes

NH3O2C

OH

HO

DNA histonesp

+

chromosomeschromatin

endoplasmic reticulum

lysosomeOHHO

RNA transscription

translationproteins

Ca+2Ca+2

Ca+2Ca+2

Ca+2ion channels

cell membrane

K+

mitochondria vaculecarbohydratesfats, lipids, other biochemicals

ion channels

41

Biomolecules: proteins (aminoacids), carbohydrates (sugars), lipids (cholesterol) and fats (diglycerids, triglycerids), DNA and RNA, vitamins, co-factors, minerals, combinations of all of the above, etc.

allosteric

Can be the key that turns on the enzyme engine. Can amplify

100s to 1000s of cycles.

enzymeactivesite

allostericsite

allostericactivator

binding at allosteric site

turns on enzymeenzymeactive

site

allostericsite

activator

Aenzymecatalyst

enzymet l t

alloster.

alloster.

site

substrate

site

substrate binds at catalytic site

Acatalyst catalyst

allostericactivator

enzymeallosteric

site alloster.

allostericactivator

allostericactivator

reactsagain

enzymeactive

site

site

substrate

A enzymecatalystsubstrate

reacts

enzymeactive

site

allostericsite

product

B

Benzymeactivesite

allostericsite

enzymecatalyst

enzymecatalyst

productreleases alloster.alloster.

Every step is a potential attack site for a medicine. Usually, earlier is better.B

A B C Dreaction 1enzyme a

reaction 2enzyme b

reaction 3enzyme c

1A 100 B(x 100) (x 100) (x 100)

10,000 C 1,000,000 D

42

possible amplification of signal

possible feedback inhibition

Problem - The terms "hydrophilic" and "hydrophobic" are frequently used to describe structures that mix well or poorly with water, respectively. Biological molecules are often classified in a similar vein as water soluble (hydrophilic) or fat soluble hydrophobic). The following list of well known biomolecules are often classified as fat soluble or water soluble. Examine each structure and place it in one of these two categories. Explain you reasoning. R

OHO

P

O

O

a b

HO Ar

N

Ar

H2N

Ar

O H

vitamin A OH

OO

c O

changes with its biochemistry, serves many roles in body

N

Hvitamin B6

(pyridoxine)OHO

HO OH

HOd

OH

OH

vitamin C(ascorbic acid)

O

vitamin E (-tocopherol)

43

Problem - Bile salts are released from your gall bladder when hydrophobic fats are eaten to allow your body to solubilize the fats, so that they can be absorbed and transported in the aqueous blood. The major bile salt glycolate, shown below, is synthesized from cholesterol. Explain the features of glycolate that makes it a good compromise structure that can mix with both the fat and aqueous blood. Use the 'rough' 3D drawings below to help your reasoning, or better yet, build models to see the structures for yourself (though it's a lot of work).

OH

H

H H

N HH

H Hsynthesized in many,

many steps in the body

OHO

OHO HO

HOH O

Ocholesterolglycolate(bile salt)1. source for steroids and bile acids syntheses in the body

2. important constituent of cell membranes2. transported in blood to delivery sites via VLDL LDL HDL

VLDL = very low density lipoprotein, has high cholesterol concentrationLDL = low density lipoprotein, has medium cholesterol concentrationHDL hi h d it li t i h l h l t l t t ti

All polar groups are on the same face. Which side faces water and which side faces fat molecules? (See structures below.)HDL = high density lipoprotein, has low cholesterol contcentration ( )

HO OH

OH

OHCO2

representation of cholesterol as a long flat shape

representation of bile acid (glycolate) as a long bent shape havingtwo different faces, one polar and one nonpolar

OH

Glycolate has a nonpolar, hydrophobic face that can cover the inside of a fat ball and a hydorphilic face that can point outward toward the aqueous blood, which allows fats to be transported throughout th b d t h f t t ll d

OH

OH

OH

HO

HO

HOO2C

blood

H2O

H2OH2O

bloodH2O blood

CO2

the body to reach fat storage cells andother essential locations. There is a whole family of bile acids that are produced from cholesterol. The body produces about 1 gram of cholesterol each day and about half of that is converted into bile acids that are released into the intestine to help

CO2O2C

HOO2C

nonpolar fats and cholesterol

inside

blood

H2OH2O

blood

44

OH

OH

OHp

absorb fats. About 12-18 grams of bile acids are released each day and most of that is reabsorbed and recirculated (95%). The rest is lost in the feces. The body's store of bile acids is about 4-6 grams.

HO

HO

HO

blood

H2Oblood

H2ObloodH2O

blood

H2O

= water moleculeG = H - TS

Water molecules rigidly order themselves around a nonpolar molecule. This is an entropy expense (S is lower) and increases

G H TS

nonpolar

p ( )free energy, G (less favorable).

Weak dispersion forces.

nonpolar

Nonpolar molecules associate together, separate from water. The water molecules are less structured, more disordered this way. This is

i (S i hi h ) d

p

hydrophobic effect

nonpolaran entropy gain (S is higher) andfree energy, G is more negative (favorable). Nonpolar molecules are said to be hydrophobic. The nonpolar compounds float or sink

nonpolar

p pbased on relative density.

compound density dipole momentwater 1.0 g/cm3 1.8 Doctane 0.8 g/cm3 0 D

45

carbon tetrachloride 1.6 g/cm3 0 D

Biopharmaceutics Classification System - classifies drugs according to their solubility and permeabilty or absorption properties. This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparisonp ( ) p p y pto the intravenous injection. All those factors are highly important because 85% of the most sold drugs in the United States and Europe are orally administered.

According to the Biopharmaceutics Classification System, drug substances are classified as follows:

Class I - high permeability, high solubility. Compounds that are well absorbed and their absorption rate is usually higher than excretion. Example: metoprolol

Class II - high permeability, low solubility. The bioavailability of these products is limited by their solubility A correlation between the in vivo bioavailability and the in vitro solubility can be foundsolubility. A correlation between the in vivo bioavailability and the in vitro solubility can be found.Examples: glibenclamide, bicalutamide, ezetimibe, phenytoin

Class III - low permeability, high solubility. The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-i i l d i i h l I i i b li d E l i idiintestinal duration time, then class I criteria can be applied. Example: cimetidine

Class IV - low permeability, low solubility. These compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected. Example: hydrochlorothiazide, Bifonazoley

•A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

•A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans

46

is determined to be > 90% of an administered dose in comparison to an intravenous reference dose.

•A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes in a volume of < 900 ml buffer solutions.

OHN

OHMetoprolol, (tradename Lopressor) is used to treat high blood pressure, various heart problems and migraine headaches. It may be combined with the diuretic hydrochlorothiazide. Metoprolol was first made in 1969 It is available as a generic drug In 2013 it was

Class I - high permeability, high solubility

O

1969. It is available as a generic drug. In 2013, it wasthe 19th most prescribed medication in the United States.

O O OClass II - high permeability, low solubility

O O

NH

SNH

NH

Glibenclamide is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfonamide antibiotics. It

ClClass III - low permeability, high solubility

closely related to sulfonamide antibiotics. Itwas developed in 1966.

HN Cimetidine (Tagamet) is a histamine H2 receptor

i h i hibi h id d i I i

Class IV - low permeability, low solubility

N

N SNH

N

NH

CN

antagonist that inhibits stomach acid production. It ismostly used in the treatment of heartburn and peptic ulcers. It was discovered in 1971 and marketed in 1976.

p y y

N

N

Bifonazole is an imidazole antifungal drug. Bifonazole is marketed under the trade mark Canespor in ointment form

47

form.

Pharmacokinetics - what the body does to the drug (the fate of the drug in the body)

Pharmacodynamics - what the drug does to the body (mechanism of drug action on the target site)

A common descriptor describing the fates of drugs inside the body is ADME

Absorption - the process of a substance entering the blood circulation.

Distribution - the dispersion or dissemination of substances throughout the fluids and tissues ofp gthe body.

Metabolization (or biotransformation, or inactivation) – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into secondary metabolites.

Excretion - the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.

The two phases of metabolism and excretion can also be grouped together under the title li i i Th d f h di i h i l h d i l i f b ielimination. The study of these distinct phases involves the use and manipulation of basic

chemical concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients (substances added to stabilize the drug), the characteristics of the appropriate biological membranes and the way that

b t th th h t i ti f th ti th t i ti t th d

mouth stomach intestines blood liver kidneys urine

blood brain barrier?

substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug.

Pharmacokinetics

drug

Pharmacodynamics

i t ti

48

ve

various tissues

kidneys

lymphatic system

urine

feces interstitial tissues

targetinteraction

Naming systemsLetters and numbers are used for drugs in early research (lead compounds). Letters are specific to the research company undertaking the research and numbers are for the specificspecific to the research company undertaking the research and numbers are for the specificcompound being studied.Book examples of anti-HIV drugs.Ro31-8959 ABT-538 MK-639 l h(Roche) (Abbott) (Merck)

saquinavir ritonavir indinavir

N i C i i F t

names in testing

T d

early research

Norvir Crixivan

Fortovase 200 mg of saquinavir in a gel-filled beige-colored capsule.

Fortovase Trade names

different formulationsInvirase 200 mg of saquinavir as the mesylate salt in a brown/green capsule

Generic drugs are not allowed to use the trade name used by the originator of the drug.

formulations

49

NHN

OH2N

saquinavir

O

N

SN

S

ritonavir

OH

indinavir

OOHN

OH

N

H

HN O

O

OH

HN

HN O

NN

NH

O N

OHOHN

Saquinavir is an antiretroviral drug used Rit i i ti t i l di ti d I di i i t i hibit d

H

O

NH

N

O

NH

Saquinavir is an antiretroviral drug usedtogether with other medications to treat or prevent HIV/AIDS. Typically it is taken orally with ritonavir or lopinavir/ritonavir. It is in the protease inhibitor class and works by blocking

Ritonavir is an antiretroviral medication usedalong with other medications to treat HIV/AIDS. The combination treatment is known as highly active antiretroviral therapy (HAART). It is taken by mouth and used to inhibit the enzyme that metabolizes other

Indinavir is a protease inhibitor usedas a component of highly active antiretroviral therapy to treat HIV/AIDS. Unfortunately, indinavir wears off quickly after dosing, so requires very precise dosing everyy g

the HIV protease. Saquinavir was first sold in 1995. As of 2015 it was not available as a generic medication and wholesale cost is about $4.50 per day ( $1500/year).

inhibit the enzyme that metabolizes otherprotease inhibitors. leading to higher concentrations of those other medications. It first came into use in 1996 and costs between $10 and $55 per day, depending on the dose ( $11,000/year).

q y p g yeight hours to thwart HIV fromforming drug-resistant mutations.

50

The development of indinavir started from renin inhibitors previously made by Merck that showed inhibition of HIV protease enzymes. Renin (angotensinogenase) helps to regulate extracellular fluid and arterial vasoconstriction by

Design of indinavir (Crixivan®) - HIV medicine

p y ( g g ) p g yinhibiting the conversion of angiotensinogen (from the liver) to angiotensin I, which is converted by angiotensin converting enzyme (ACE) to angiotensin II, which is the most vasoactive peptide. It narrows the blood vessels, retains sodium ions in the kidneys and acts on the CNS to stimulate thirst to retain water and reduces urine loss and causes the post pituitary gland to release vasopressin. All of this helps to regulate blood pressure in a very complicated sequence of steps and illustrates the incredibly complex network of interactions that must be considered when designing a drug. The b t d f th i i hibit f HIV i hibiti ll d L 364505 Thi th t ti i t f i di ibest compound from the renin inhibitors for HIV inhibition was called L 364505. This was the starting point for indinavir.

L364,505 was a potent inhibitor of HIV protease. However, its antiviral activity was low due to poor pharmacokinetics (vulnerable to degradative enzymes, rapid biliary clearance (gall blader) and poor oral absorption) Several smaller

OPh

P' = right half of moleculeP = left half of molecule

(gall blader) and poor oral absorption). Several smallermolecules were made in hopes to find one with similar activity.BocPhePhe

N LeuPheNH2

H OHPh IC50 = is the amount of an inhibitor to decrease a biological

Phe = phenylalanine and Leu = leucine amino acids

removed

L364,505 (IC50 = 1 nM)Ph

OPh

O

process by half. It is a measure of the effectiveness of asubstance in inhibiting a specific biological or biochemical function.

The left two "Phe" amino acids could be removed without loss of activity (from the P side) against HIV protease. It lacked any activity against renin (that's a good thing).

N LeuPheNH2

H OHPh

O

(Boc)removed

51

PhL682,679 (IC50 = 0.6 nM) removed

next slide

OPh

O

P = left half of molecule P' = right half of molecule

The right two amino acids (Phe and Leu) could be removed and replaced with a benzyl group (compound II). A drop in activity occurred, but it did not dissappear, which meant they could keep trying to make improvements.

N NH

H OHPh

O

compound II (IC50 = 111 nM)compound II (IC50 = 111 nM)

OPh

OIt was thought that greater rigidity would help fit

more rigid

N N

H OHPh

O

d ( )H

It was thought that greater rigidity would help fitbetter in the binding pocket, so an indan derivative was made (compound III). Five fold improvement in the IC50 was observed, but III had poor oral bioavailability and poor water solubility. It was thought that introducing a polar substituentPh

compound III (IC50 = 21 nM) It was thought that introducing a polar substituentwould help.

OPh

O

N

O

NH

H OH

O

An "OH" was added and antiviral activity increased 70 fold, but there was still poor oral bioavailability and poor water solubility.

OH

52

L 685,434 (IC50 = 21 nM)

H

greater polarity

P = left half of molecule P' = right half of molecule A nitrogen atom was introduced to the right side (P') of the molecule to help oral bioavailability and water solubility Amolecule to help oral bioavailability and water solubility. Amolecular modeling exercise was carried out (in silico) and showed that the aromatic rings were pointing away from the active side and faced out towards the enzyme surface. It was felt that it should be possible to add substituents "para" on the aromatics which could increase water solubility, but not interfere with the active site leading to L 689 502 The morpholine group is know

OPh

O

active site, leading to L 689,502. The morpholine group is knowto increase water solubility and was connected with a hydroxyethylene spacer.

N NH

H OH

O

L 689,502 (IC50 = 0.45 nM)OH

N

OThere was a slight drop in activity, but the antiviral activity went up as a result of improved penetration of the cell. Oral bi il bilit l i d t 5%

ON bioavailability also improved to 5%.

Unfortunately, animal studies showed liver toxicity.

It was known that the HIV active site was symmetrical, so a decision was made to combine two different features that were both effective on the different sides of the molecule. Roche already had an anti-HIV drug on the

O

NH N

H

N

H O

HN

N

y gmarket, called saquinavire (Ro-8959/003). Merck decided to join the two together.

H N NH

H OH OH

O NH2

H

H

53

saquinavire (Ro-8959/003), Roche saquinavire combined with compound III on next slide

P = left half of molecule P' = right half of moleculeL 704 486 was less active as an inhibitor of the HIVL 704,486 was less active as an inhibitor of the HIVenzyme, but the decahydroisoquinoline ring provided greater water solubility and greater bioavailability (15%). Anti-viral activity was still weak. It was decided to switch in a piperizine ring. This would allow functionalization on the #4 nitrogen atom to help with binding in the S3 subsite (It could be

O

NH

H O

help with binding in the S3 subsite. (It could bemade hydrophobic or hydrophilic.) The additional amine would also increase water solubility and bioavailability.

H NH

H

NH

OH OH

L 704,486 (IC50 = 7.6 nM)

H

S2'S2L 732,747 had improved inhibitor activity on the enzyme and better anti-viral activity

N

O

N

ON

S3

y yin cell bases assays. It was co-crystallized with the enzyme and an X-ray structure determined. This revealed that the S2 and S2' pockets were filled and the benzoyl group on the piperazine fitted in the lipophilic S3 binding pocket There was

12

3

N

N NH

OH OH

O

O

S1

lipophilic S3 binding pocket. There wasstill problems with crossing the cell membrane. High activity means nothing if the drug cannot get inside the cell. Many derivatives were made and it was found that replacing the phenyl ring with a piperidine ring which was weakly basic

3

4

54

S1S1'L 732,747 (IC50 = 0.5 nM)

piperidine ring, which was weakly basicand improved water solubility.

P = left half of molecule P' = right half of molecule

H

S2'S2

OON

H

S3

N

N NH

OH OH

O

O

O S1S1'L 732,747 (IC50 = 0.5 nM)

S2 S2'

This is indinavir. It was introduced in 1996 and is still used today. It has negligible

OON

H

S3 used today. It has negligibleinhibition of mamalian proteases, yet is active against both HIV-1 and HIV-2 proteases. It has better oral bioavailability than saquinavir and is less bound by l tei ( l 60%)

N

N NH

OH OHON

55

plasma proteins (only 60%).O

Indinavir (MK 639, L 735,524) (IC50 = 0.56 nM)

S1S1'

Chapter 1 - Drugs and drug targets: an overviewpsbeauchamp/pdf/499_chap_1_49_pages.pdf · 2016. 4....

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