ANTINEOPLASTIC AGENTS - 112.133.209.26:82

GURU NANAK INSTITUTE OF PHARMACEUTICAL SCIENCE

& TECHNOLOGYSODEPORE, KOLKATA- 700114, WEST BENGAL, INDIA

MAKAUT AFFILIATED , AICTE & PCI APPROVED, NAAC AND NBA ACCREDITATED

Dr. Sumana Chatterjee

Professor

ANTINEOPLASTIC AGENTS(PART - II)

PT513B: MEDICINAL CHEMISTRY II

B. PHARM THIRD YEAR, SEMESTER - 5

SESSION: 2020-21

Email: [email protected]

MEDICINAL CHEMISTRY II: PT513B

Credit: 4CO LABEL CO STATEMENT BTL

CO513B.1 Classify the therapeutic agents and outline the synthetic route

for the selective medicinal compounds of each category2

CO513B.2 Articulate on the mechanism of action of agents acting on

autonomous and central nervous system.3

CO513B.3Compare the relationship between the biological activity and

structure of therapeutic agents.6

CO513B.4Outline the rational use of Histamine receptor antagonists,

antibiotics, antineoplastic and antidiabetic drugs4

Department of Pharmaceutical Chemistry; Guru Nanak Institute of Pharmaceutical Science and Technology

TOPIC: ANTINEOPLASTIC AGENTS

Teaching Learning Objective (TLO) CO LABEL BTL

To explain neoplasia and classification of tumor CO:PT513B:1 2

To explain different treatment approaches of cancer CO:PT513B:1 2

To explain cell cycle and check points and etiology of cancerCO:PT513B:2 3

To explain Chemical Structure, Category, Use and mode of action of the following:

i.Mechlorethamine ii. Melphalan iii. Cyclophosphamide

iv. Chlorambucil v. ThioTEPA vi. Busulfan

CO:PT513B:4 4

Department of Pharmaceutical Chemistry; Gurunanak Institute of Pharmaceutical Science and Technology

LECTURE I

Definition, types and Characteristics of Tumor

Classification of Cancer on the basis of origin

Stages of Cancer and Treatment Approaches

Cell Cycle and Checkpoints

Apoptosis

Etiology of Cancer

LECTURE II

Mechanism of Alkylating Agents

Classification of Alkylating Agents

Chemical Structure, Category, Use and mode of action of the following:

Mechlorethamine Melphalan Cyclophosphamide Chlorambucil ThioTEPA Busulfan


TOPIC: AntiNeoplastic Agents (Part I)UNIT –I

PRE_REQUISITE

Fundamental knowledge about

• Physiology

• Biochemistry,

• Organic chemistry

• Drug receptor interaction

• Significance of drug

development

Alkylating Agents

• The alkylating agents are capable of forming covalent bonds with important biomolecules.

• The major targets of drug action are nucleophilic groups present on DNA, proteins and RNA.

• In DNA, the alkylating agent frequently forms either intrastrand or interstrand cross links to inhibit transcription.

• In RNA, only intra-strand cross links are possible.

• Alkylation of DNA is thought to lead to cell death.

• Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the

template function of DNA.

• There are several potential nucleophilic sites on

DNA, which are susceptible to electrophilic

attack by an alkylating agent:

Guanine: N-2, N-3, and N-7

Adenine: N-1, N-3

Thymine: O–6

Cytosine: N-3


The general mechanism for alkylation involves

Nucleophilic attack by –N=, -NH2, -OH, - O-PO3H of DNA and RNA while additional nucleophiles (-SH,

COOH, etc.) present on proteins may also react.

Anion formation increases the reactivity of the nucleophile compared with the un-ionized form (-O is more

nucleophilic than OH).

Reaction with water is also possible.

Reaction involves displacement of a leaving group on the electrophile by the nucleophile.

• Alkylation converts the base to an effective leaving

group.

• Altered base pairing away from the normal G-C: A-T

hydrogen bonds because of alterations in

tautomerization.

• The alkylation also leads to increased acidity of the N-1 nitrogen reducing the pKa from 9 to 7 to 8 giving rise to a

zwitterionic form that may also mispair

The alkylating

agents are are not

cell cycle–

specific agents.


Alkylating Agents

Nitrogen Mustard

Alkyl Sulfonates

Nitrosourea

Triazines

Platinum Containing

Ethyleneamine & Methyleneamine

Derivatives

Mechlorethamine, Cyclophosphamide,

Ifosfamide, Melphalan and Chlorambucil

Altretamine, ThiotepaBusulfan

Carmustine, Lomustine

Dacarbazine, Procarbazine, TemozolomideCisplatin, Carboplatin, Oxaliplatin


NITROGEN MUSTARDS

The nitrogen mustards are compounds that are

chemically similar to sulfur mustard or mustard gas

developed and used

in World War I.

They used to produce blisters as black mustard

seeds produce on exposure to the oil.

Sulfur Mustard is gas at room temperature.

Conversion of the sulfide to a tertiary amine resulted nitrogen mustards, which exist as solids at room The term

mustard was then Mustards such as mechlorethamine are classified as dialkylating agent.

A weakly electrophilic b-carbon atom of an aliphatic nitrogen mustard alkylating agent, such as mechlorethamine

(Mustine) is converted to more highly electrophilic aziridine anion by internal nucleophilic substitution b- Chlorine

atom.

Aziridine


Nucleophilic attack on N7 of guanine residue can then occur at the aziridinium carbon by an SN2 reaction type of

mechanism to relieve the small ring strain and neutralize the charge on nitrogen.

This process can then be repeated provided a second leaving group is present.

Mechlorethamine is highly reactive, in fact, too reactive and therefore nonselective, making it unsuitable for oral

administration and necessitating direct injection into the tumor.

The antidote sodium thiosulfate (Na2S2O3), a strong nucleophile, may be administered in case of extravasation.

Mechlorethamine

Significant Limitation of

Mechlorethamine

Lack of selectivity

Aziridinium ionMEDICINAL CHEMISTRY II: PT513B

Approaches To Overcome the Limitation

• Replacement of the weakly electron-donating methyl group with groups that were

electron withdrawing (-I).

• Attachment of nitrogen to a phenyl ring in the case of chlorambucil and melphalan.

Melphalan Attachment of the mustard functionality to a phenylalanine

moiety was not only an attempt to reduce reactivity but

also an attempt to increase entry into cancer cells by

utilization of carrier mediated uptake.

Melphalan was found to utilize active transport to gain

entry into cells, but selective uptake by cancer cells has

not been demonstrated.

Cyclophosphamide

Attachment of more highly electron-withdrawing phosphoryl function

does not allow aziridinium cation formation until the electron- withdrawing function

has been altered.

The drug could be selectively activated in cancer cells because they were believed to

contain high levels of phosphoramidase enzymes. This would remove the electron-

withdrawing phosphoryl function and allow aziridine formation to occur.

Melphalan

Cyclophospamide


• Cyclophosphamide is activated by cytochrome P450 to give a carbinolamine which undergo ring opening to

give the aldehyde.

• The increased acidity of the aldehyde -hydrogen facilitates a retro-Michael decomposition.

• The ionized phosphoramide is now electron-releasing via induction and allows aziridinium cation formation to proceed.

• Acrolein is also formed as a result of this process, which may itself act as an electrophile that has been associated with

bladder toxicity.

• Alternatively, the agent may be inactivated by alcohol dehydrogenase–mediated oxidation of the carbinolamine to give

the amide or by further oxidation of the aldehyde intermediate to give the acid by aldehyde dehydrogenase.

• To decrease the incidence of kidney and bladder toxicity, the sulfhydryl (MSH) containing agent mesna may be

administered and functions to react with the electrophilic species that may be present in the kidney.

Use & Dosage Forms of Mephalan

Melphalan is available in 2-mg tablets and 50-mg vials for

oral and IV administration in the treatment of multiple

myeloma, breast and ovarian cancer, and in high dose therapy

when bone marrow transplant.

Use & Dosage Forms of Cyclophosphamide

Cyclophosphamide is available in 25- and 50-mg tablets

for oral administration and 100-, 200-, 500-, 1,000-, and

2,000-mg vials for IV use in the treatment of breast

cancer, non-Hodgkin’s lymphoma, chronic lymphocytic

leukemia, ovarian cancer, bone and soft tissue sarcoma,

rhabdomyosarcoma, neuroblastoma, and Wilms tumor


Chlorambucil

UsesFor treatment of

• Chronic lymphatic (lymphocytic) leukemia

• Childhood minimal-change nephrotic syndrome

• Malignant lymphomas including lymphosarcoma, giant follicular lymphoma, Hodgkin's disease, non-Hodgkin's

lymphomas

Mechanism of Action

Alkylating agents work by three different mechanisms:

Attachment of alkyl groups to DNA bases, resulting in the DNA being

fragmented by repair enzymes in their attempts to replace the

alkylated bases, preventing DNA synthesis and RNA transcription

from the affected DNA.

DNA damage via the formation of cross-links (bonds between atoms

in the DNA) which prevents DNA from being separated for synthesis

or transcription.

Induction of mispairing of the nucleotides leading to mutations.

Chemical Name: 4-(p-bis(β-chloroethyl)aminophenyl)butyric acid

Dosage Forms Available:

2-mg tablets for oral administration in combination with prednisone and

as a single agent.

Adverse Effects include

o Dose-limiting myelosuppression

o Nausea and vomiting occur less often than

for mechlorethamine.

o Additional adverse effects include

hyperuricemia, azoospermia, amenorrhea,

seizures, pulmonary fibrosis, and skin

rash.

ChlorambucilMEDICINAL CHEMISTRY II: PT513B

• Thiotepa contains the thiophosphoramide functionality.

• Thiophosphoramide functionality is more stable than the

oxa-analog N, N′, N′′-triethylenephosphoramide (TEPA).

• It is metabolically converted to TEPA by desulfuration in

vivo.

• Thiotepa incorporates a less reactive aziridine ring

compared with that formed in mechlorethamine.

• The adjacent thiophosphoryl group is electron withdrawing

and, therefore, reduces the reactivity of the aziridine ring

system.

Thiotepa

• Although thiotepa is less reactive than many other alkylating agents, it has been shown to form cross-links.

• TEPA undergoes hydrolysis to give aziridine, which may function to monoalkylate DNA.

• The reactivity of aziridine generated by either route may be somewhat enhanced within cancer cells, where the pH is

normally reduced 0.2 to 0.4 pH units resulting in an increase in reactivity toward nucleophilic attack.


Mechanism of Action

• The alkyl group is attached to the guanine base of DNA, at the

number 7 nitrogen atom of the imidazole ring.

• They stop tumor growth by crosslinking guanine nucleobases

in DNA double-helix strands, directly attacking DNA.

• This makes the strands unable to uncoil and separate.

• As this is necessary in DNA replication, the cells can no longer

divide.

• These drugs act non-specifically.

Uses

Thiotepa is used to treat cancer. It works

by slowing or stopping the growth

of cancer cells.

Thiotepa is often given into the bladder to

treat bladder cancer.

Thiotepa is also used with other

medications to prevent rejection of a stem

cell transplant.

Dosage Forms of Thiotepa

Thiotepa is available in 15-mg vials for IV administration in

the treatment of bladder cancer, ovarian cancer, and breast

cancer.


Busulfun

• Busulfan utilizes two sulfonate functionalities as leaving groups separated by a

four-carbon chain that reacts with DNA to primarily form intrastrand

cross-link at 5-GA-3 sequences.

• The sulfonates are also subject to displacement by the sulfhydryl functions

found in cysteine and glutathione, and metabolic products are formed as a result

of nucleophilic attack by these groups to generate sulfonium species along with

methane sulfonic acid.

• This is followed by conversion to tetrahydrothiophene, and further oxidation

products are subsequently produced to give the sulfoxide and sulfone.

• The cyclic sulfone known as sulfolane may be further oxidized to give 3-

hydroxysulfolane

Busulfan


Uses & Dosage Form

Busulfan is available as 2-mg tablets for oral administration and

10-mL vials for IV administration in the treatment of chronic

myelogenous leukemia (CML) and in high-dose

therapy for refractory leukemia with bone marrow transplant.

Adverse Effects

Myelosuppression, nausea and vomiting

pulmonary symptoms including interstitial

pulmonary fibrosis, mucositis, skin rash,

impotence, amenorrhea, infertility,

hepatoxicity, insomnia, anxiety, and an

increased risk of secondary malignancies.

Mechanism of Action of Busulfun


REFERENCES

• John M. Beale, Jr & John H. Block (Eds) (2006). Wilson and Giswold’s Text

Book of Organic medicinal and Pharmaceutical Chemistry, London, Lippincott

William & Wilkin.

• Thomas M Lenke & David A Williams (Eds ) (2007). Foyes Medicinal

Chemistry, London, LEMKE, Wolters Kluwer & Lippincott Williams and

Wilkins.

Next Topic:…………. Antineoplastic Agents (Part III)

……. Antimetabolites

Department of Pharmaceutical Chemistry; Gurunanak Institute of Pharmaceutical Science and Technology

ANTINEOPLASTIC AGENTS - 112.133.209.26:82

Documents

Transcript of ANTINEOPLASTIC AGENTS - 112.133.209.26:82