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The Chemistry of Life

The Age of the Molecule, Roy. Soc. Chem. 1999. p. 229-258

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• Friedrich Wöhler in 1828 showed that urea, an “ organic “ compound, could be made(converted) from a salt (“ inorganic “) mineral.

NH4+ -OCN

heat

H2NC

NH2

O

Ammonium cyanate Urea

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Herbal/ Microorganism-derived Medicines

1500 BC- Ebers papyrus.本草綱目 - 이시진 , 명東醫寶鑑 - 허준 , 조선

London Pharmacopoeia,1809 (Unknown at the Molecular level).

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Simvastatin

H

O

O

O

O OH

고지혈증 치료제, 200억불/20조원 ( 82억불- 10조원/ 년-2002년Pfizer-리피토) (62억불-MSD-Zocor-2002년)–Sonata 150만대

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The First Synthetic Drug

• Methylene Blue (Dye)- Malaria, 1891 Paul Ehrlich – The first person to use synthetic co

md. as a drug-the Magic Bullet concept. infectious disease, parasite disease.

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Gerhard Domagk- the First Antibacterial drug (septicemia- 패혈증 ). 1927

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• Alexander Fleming- Antibacterial activity found of Penicillium notatum (1928).

• Oxford Group- H. Florey, E. Chain, Clinical trial, chemical identification -1941, World War II. (1945년 노벨의학상 )

• American group- Scale-up production Penicillium chrysogenum.

Wonderful Penicillins

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• Stereochemistry of the chemical structure of Pen G.- Dorothy Hodgkin.Oxford U.(1945).

1964 년 노벨화학상 .

• First synthesis-John Sheehan (M.I.T.), 1957.

• Eli Lilly-Penicillin V Semisynthsis –Orally active.

• The supreme achievements of Drugs in 20th C.-Penicillin, Aspirin.

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Life Expectancy

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Proteins- Workhorses of life

• 1930 년까지 - Protein : random aggregates of amino acids by amide bonds.

X-ray crystallography : alpha-helix 구조 (Linus Pauling, Caltech.).

Amino acid sequences 결정 - Frederick Sanger (Cambridge U.) 1945. 노벨화학상 2 번 수상

Myoglobin, haemoglobin 의 3D- 구조 결정됨 - folds, the alpha-helix, beta sheet.(X-ray 이용 ). John Kendrew (Cambridge U.)-1958 년 . 노벨화학상

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Protein StructuresProtein Structures Protein StructuresProtein Structures

-helix reverse turn

-sheet

Primary structurePrimary structurePrimary structurePrimary structure Secondary structureSecondary structureSecondary structureSecondary structure Tertiary structureTertiary structureTertiary structureTertiary structure

Chemistry5/ 31/ 05 첨단화학

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The first enzyme, Lysozyme 의 X-ray 구조 결정 - David Phillips-( Oxford U.) 1968.

구조결정으로 유기합성 시작됨 -Solid Phase Synthesis ribonuclease 효소 (124 amino acids, 전채 17% yield) 합성함 - Bruce Merrifield (Rockefeller U.) 1969.

Almost Life processes : Interactions of Proteins with Small organic molecules.( hormones, neurotransmitters, vitamins, carcinogens).

단백질이 작은분자를 둘러쌈 . Binding 과 촉매작용 .

Proteins: enzyme catalyst of biochemical reactions or receptors of cell membranes.

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Why do different stereoisomers have different biological properties?

A chiral molecule must fit into a chiral receptor at some target site to exert its biological action.

C C

Mismatched

Fear fight hormone.Lock & Key type Binding - Emil Fischer

The Adrenaline cascadeNH

OHHO

HO

CH3

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enzyme(rest state)

normalsignal

activatedactivatedenzymeenzyme

inactivatedinactivatedenzymeenzyme

falsesignal

Drug Action

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Structure of DNABuilding

blocks

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RNA

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James Watson & Francis Crick (1953)Discovery of DNA double helix

Structure : how DNA could replicate itself.: how genetic information be stored/

transmitted.Unwinds each strand : blueprint for

production of a new strand.

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Bases pairing via HB

RNA (ribonucleic

acid)

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Genetic Code

• DNA provides the blueprint(genetic information) to RNA (messenger-RNA), in turn provide the genetic code for protein/enzyme production, and thus establishes the hierarchy of the cell.

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Biosynthesis of ProteinsBiosynthesis of Proteins Biosynthesis of ProteinsBiosynthesis of Proteins

CellCell

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Genetic Code

4 x 4 x 4 = 64 combinations

Triplet sequences of nucleotide bases -Codon-Rosetta Stone

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Rise of Genetic Engineering

• Restriction enzymes: that could cut DNA at specific sites.

• S. Cohen at Stanford used DNA ligase and Restriction enzymes to cut and join DNA from two different organisms to generate the first recombinant DNA.

• Determination of the natural DNA sequence to construct DNA to order.

• Genome Sequences- the complete sequences of genes in cell’s nucleus (human genomes).

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Role of DNA in Drug Design

• Structure & Function of DNA : benefits in drug design.

• The endpoint of drug molecule-receptor complexes: activation or repression of DNA replication or transcription.- Drug Design

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Anticancer Drugs

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- the Organic elements found in living organisms- carbon compounds

H C N O F

PSi S Cl

BrI

- DNA, RNA, amino acid, proteins, lipid, carbohydrates…-medicine, dyes, polymers, plastics, food additives, -pesticides, fragrant…

• Organic (nonmetal) Elements and Life

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Antiviral Drugs

AZT (Zidovudine)Wellcome,1987

George Hitchins, 1988 Nobel Prize

Medicine

HIV virus

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Chemistry and Gene Therapy

• GDEPT :

Gene Directed Enzyme-activiated Prodrug Therapy(GDEPT) resulted inhibition of DN

A replication.

The Role of Chemists : Design highly specific Prodrugs and novel Delivar

y systems.

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Future challenges for Chemistry in Biology and Medicine

Penicillin, Aspirin, Simvastatin

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반응메커니즘(Reaction Mechanism-

Multimedia)