ANTINEOPLASTIC AGENTS

Prepared by
Chauhan suman B.
M.Pharm (1st sem.)
Pharmaceutical chemistry
• What is cancer?

 Cancer is term used for diseases in which abnormal cells divide without
control and are able to invade other tissues.
 Cancer cells can spread to other parts of the body through the blood and
lymph systems ,this process is called metastasis.
 1) Benign tumor : tumor cells grows only locally and cannot spread By invasion or
metastasis.
 Can be treated.
 2) malignant tumor: cells invade neighbouring tissues ,enter blood vessels and
metastasis to different sites .
 Causes death.

Benign tumor Malignant tumor

 During cell cycle,each cell
divided into two daughter cells
having identical genetic
Material.
4 phases of cell cycle:
1) S -phase : Phase of DNA
synthesis
2) G2- phase: -cell size and
duplicated chromosome
3) M- phase-: mitotis phase
Chromosome attachment to
spindle
4) G1- phase :Cells with
chromosone in nucleus .
5) G0 – phase : resting state
CDK ( cycling dependent
kinase) : overexpression of cdk
Produce cancer.
P53- tumor suppression protien

Check Point : critical control points where signals can regulate the cell
cycle.
Apoptosis: the cell breaks in to several apoptic bodies , the
orgrnells are still functional.
Necrosis: the cell membrane ruptures and release the cells
content the orgrnells are not functional.
 Risk factors :
 Tobbaco
 Alcohol
 Sunlight
 Ionising radiation
 certain chemicals And other substance
 some viruses and bacteria
 Family history of cancer
 poor diet,lack of physical activity
 Types of cancer :
 1) carcinoma: skin and organ cancer
 2) sarcoma: bone ,muscles,cartilage,fat or connective tissue
 3) leukemia: white blood cells
 4) lymphoma: Bone marrow derived cells or lymphatic system
 5) myelomas : B- lymphocytes
Classification of ANTINEOPLASTIC
agents:
 Phase specific agents
 Based on mode of action
 1) PHASE SPECIFIC agents : Acts particularly in phases of cell cycle and
1. more effective in proliferating cells.
G1- phase : vincristine

S phase : methotrexate,cytarabine,daunorubicin,doxorubicin

G2 phase: daunorubicin, bleomycin

M phase: vinblastin ,paclitaxel etc.

 Based on mode of action:
1) Alkylating agents:
 Nitrogen mustard- mec,hlOrethamine, Chlorambusin, melphalan, cyclophosphamide
. ( Cyclophosphamide is a prodrug – activated by cytochrome p -450 enzyme)
 Alkyl sulphate- busulfan
 nitrosoureas: carmustine,comustin
 Aziridines:. Thiotepa,benzotepa
 Altretamine:. Triethylene
 Methylhyradrazine : procarbazine
2) Antimetabolite:
 Pyrimidines: 5- flourouracil,capecitabine,floxuridine
 purines: 6- mercaptopurine,6- thioguanine
 Folic acid derivatives: methotrexate,trimethoprim
3) Antibiotics:
 Anthracyclines: doxorubicin
Bleomycins: bleomycinA2, bleomycinB2
 Mitomycins: mitomycinC, dactinomycin, actinomycin
4) plant products :
 Vinca alkaloids: vincristine, vinblastin
 camptothecin derivatives : camptothecin
 Epipodophyllotoxins: etoposide
 taxel derivatives: paclitaxel,
 Enzymes: L- asparaginase
5) Hormones:
 Estrogens: 17-B- estradiol, diethylstilbestrol
 progestins: progesterone
 testosterone
 Steroidal anti-inflammatory agents: prednisone
6) immunotherapy:
 Interferone- alpha- 2a
 Interferone- alpha- 2b
 Monoclonal antibodies: rituximab
 radiotherapeutics agents: sodium iodideI-131 , strontium chloride- 89
 Cytoprotectibg agents: mesna
 misellelaneous: cisplatin, carboplatins
1) Alkylating agents:
 Nitrogen mustard:

 Developed from mustard was gases of world war 1 which were highly reactive
vesicants.
 First chemicals used for cancer Rx.
 Not cell cycle specific , but still more active in dividing tissues.
 Lone pair containing nitrogen atom attacks on one of the chloroethane side chain
and form a highly electrophilic structure of azridine.
 Nucleophilic groups on various DNA bases ( N7 of Guanine ) radily attack the
electrophilic Azridine, resulting in irreversible alkylation of the DNA base.
 These reaction process is again repeated with other chloroethane side chain and
again form the covalent bond with N7 Guanine DNA and dimers us formed .
 It inhibit the DNA synthesis.
 SAR of nitrogen mustard:

 Aromatic substituents eg. Phenyl conjugated with the mustard nitrogen will
stabilize the lone pair of electrone through resonance.
 Resonance delocalization slows the rate of intra molecular nucleophilic attack ,
azridinium ion formation and DNA alkylation .
 slow reactivity , allows for oral administration and less severity of side effect.
 higher stability provides enhanced Tissue slelectivity time to reach cancer cells.
 Alkylsulphonate :

Busulfan
 • MOA : it inhibit the DNA replication by Alkylating the DNA .

 Nitrosourease:

 MOA : the isocynate portion of the molecule causes carbamylation of amino acids and
protiens resulting in inhibition of DNA repair .
 They may also inhibit several key enzymesof DNA synthesis and repair.
 Azridines:

Triethylene Melamine
Thiotepa. Benzotepa

 MOA: it act as nitrogen mustard at physiological PH and inhibiT the DNA

synthesis.
 SAR: when oxygen from TEPA replaced with sulfur , the compounds having
greater stability results in named as thiotepa.
 Antimetabolite:
 pyrimidines:

5- flUoro uracil. Floxuridine

MOA:

FdUMP- (5- fluoro- 2 deoxy- uridine monophosphate)

dUMP-( deoxy uridine monophosphate)
 Purine analoges:

MOA

(Inhibit conversion of
Inositole monophosphate
to alanine and guanine)
 Folic acid derivatives:

(PABA)
(Pteridine ring )

(Glutamyl
residue)
• SAR
• Antibiotics:

• Anthracyclins:

• Cytochrome p-450 reductase catalyse reduction of the

anthracyclin to semiquinoline free radicals – leads to breakge of
simple strand DNA.
SAR:
 Bleomycins:
 mitomycinC
 Mitomycins:

• MOA:
 Plant products :
 Vinca alkaloids :

 MOA:
 Epipodophyllo toxins:

 Taxol derivatives: paclitaxel

 MOA of paclitaxel:
 SAR of paclitaxel :
 Enzymes: L- asparaginase

 MOA:

 It is derived from bacterial cultures of E. Coli .

 Tumor cells used asparagine as a nutrient .
 It also decrease the plasma glutamine .
 The reduced level of asparagine and glutamine levels cause immediate inhibition of
protein synthesis and a delayed inhibition of DNA and RNA synthesis.
 Hormones :
 Estrogens :

 Progestins:
Testosterone:

Steroidal anti inflammatory agents:

 MOA of hormones:
 use in breast and prostate cancer .
 Hormones bind to cytoplasmic receptors and get translocated into the cell nucleus
and interact with the genome DNA .
 The hormones is this able to modulate Gene function and may alter cellular growth
control .
 Miscellaneous :

 MOA :

 Highly reactive pt- DNA complex is formed .

 Interstrand and intra strand cross link damage DNA.
 New generation drugs:
 1) Tazemetostat:
 Brand name – tazverik
 Use in the treatment of adult and adolescents aged 16 yr. And older with
metastatic ( when cancer cells spread other parts of body ) or locally advanced (no
spread) epithelial sarcoma .
 Not eligible for complete resection ( surgically removing all of a tissue structure
or organ ) .
 It act as potent selective EZH2 inhibitor.
 Blocks activity of the EZH2 methyltransferase which may help in keep the cancer
cells from growing .
 Orally available , small molecule selective and s- adenosyl methionine (SAM)
competitive inhibitor of histone methyl transferase EZH2 with potential
antineoplastic activity.
 Alter gene expression.
Synthesis:
 Avapritinib:
 Brand name : Ayvakit
 it is a tyrosine kinase inhibitor .
 Use for the treatment of tumors due to the specific rare mutation .
 Specifically for unresectable or metastatic gastrointestinal stromal tumor.

 it has a negative modulating effects on the transporters.

 Which resensitizes cancerous cells to treatment with chemotherapeutic agents like
paclitaxel.
Synthesis:
Thank you