Abc

1. ANTI-NEOPLASTIC OR
ANTICANCER DRUGS

2. Classification of Anti-neoplastic Agents / Anticancer Drugs
1. Alkylating Agents
o Nitrogen mustards: Melphalan, Cyclophosphamide, Ifosfamide
o Nitrosoureas
o Alkylsulfonates
o Ethyleneimines
o Triazene
o Methyl Hydrazines
o Platinum Coordination complexes: Cisplatin, Carboplatin, Oxaliplatin
2. Antimetabolites
o Folate Antagonists: Methotrexate
o Purine antagonists : Mercapturine
o Pyrimidine antagonists: 5-Fluorouracil, Cytarabibe

3. 3. Natural Products
o Plant Products
 Vinca Alkaloids: Vincristine, Vinblastine
 Taxanes: Paclitaxel, Docetaxel
 Epipodophyllotoxins: Etoposide
 Camptothecins: Irinotecan
o Microorganism Products
 Antibiotics: Doxorubicin, Bleomycin
 Enzymes: L-Asparaginase

4. . Miscellaneous
o Hydroxyurea
o Imatinib Mesylate
o Rituximab
o Epirubicin
o Bortezomib
o Zoledronic Acid
o Geftinib
o Leucovorin
o Pamidronate
o Gemcitabine

5. 4. Hormones and Antagonists
o Corticosteroids: Prednisone, Dexamethasone
o Estrogens: Ethinyloestradiol
o Antiestrogens: Tamoxifen
o Progesteron derivative: Megestrol Acetate
o Androgen: Testosterone propionate
o Antiandrogen: Flutamide , Bicalutamide
o Aromatase inhibitor: Letrozole , Anastrazole
o 5-alpha reductase inhibitor: Finasteride
o GnRH Analogue: Leuprolide, Buserelin
o Growth Hormone, glucagon and insulin inhibitor: Octreotide

6. In syllabus
1. Tamoxifen = Antiestrogens
2. Fluorouracil = Pyrimidine antagonists
3. Mercapturine = Purine antagonists
4. Methotraxate = Folate Antagonists
5. And vincristine = Vinca Alkaloids

7. METHOTRAXATE (FOLATE ANTAGONISTS)
Pharmacokinetic data
Bioavailability : 17–90%
Metabolism : hepatic
Half-life : 3–15 hours (dose dependent)
Excretion : renal 48–100%

8. MECHANISM OF ACTION
Methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that
participates in thetetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about
one thousand-fold that of folate. DHFR catalyses the conversion ofdihydrofolate to the active
tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleosidethymidine,
required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine
synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA,
thymidylates,
The similar structure of dihydrofolic acid(top) and methotrexate bottom) suggests that
methotrexate is a competitive inhibitor

9. 4-nitrobenzoyl chloride L-glutamic acid
N-(4nitrobenzoyl)glutamic acid
N-(4-aminobenzoyl)glutamic acid
N-(4-methylaminobenzoyl)glutamic acid
2-amino-4-hydroxy-6-bromomethylpteridine
2,4,6-triaminopyrimidine
malonic acid dinitrile
guanidine
2,4,5,6-tetraaminopyrimidine
1,2-dibromopropionic aldehyde
2,4,6-triamino-5-nitrosopyrimidine

10. Structure Activity relationship
1. The binding ability of methotrexate to dihydrofolate reductase is because of diaminopyrimidine ring
which is protonated at physiological pH 6. As the pH increase the binding become weaker.
2. Alkylation of the amino groups lead to decreased activity.
3. Partial reduction ,removal or relocation of heterocyclic compounds lead to decreased activity.
4. Replacement of nitrogen by carbons in pyridine rings increased lipophilicity. For example Piritrexim and
Trimetrexate analogues of methotrexate with high lipophilicity as compare to methotrexate .
N
N
NH2
H2N

11. MERCAPTURINE (PURINE ANTAGONISTS)
6-mercaptopurine
Pharmacokinetic data
Bioavailability : 5 to 37%
Metabolism: xanthine oxidase
Half-life: 60-120 min longer for the active metabolite
Excretion: Renal

12. uric acid
barbituric acid
urea malonic ester
5-Nitroso-pyrimidine-2,4,6-trione
uramil
isocyanic acid
pseudouric acid 2,6,8-trichloropurine
9H-Purin-6-ol hypoxanthine

13. Structure Activity relationship
1. When hydrogen at position 6 of 6-MP is replaced by an alkyl, aralkyl, or aryl
group such substitution leads to decreased activity.
2. Substitution at position 2 with CH3, Cl, OH, or SH cause inactivation of 6-MP.
The exception to this is the 2-amino-derivative (thioguanine) which, like 6-MP, is a
close analog of a natural purine. Thioguanine is active.