Antineoplastic Drugs | Medicinal Chemistry | Dr. Aqsa Murtaza

 


PHARMA BY AQSA MURTAZA (PharmD)

Aim to help Pharmacy Students. We cover a wide range of topics, from Medicinal Chemistry, Pharmacology, and Drug Interactions to Medication Management and Disease State Management.


MEDICINAL CHEMISTRY

“Medicinal Chemistry is the science that deals with the discovery and design of new therapeutic chemicals and their development into useful medicines.”

ANTINEOPLASTIC DRUGS



5-Fluorouracil

INDICATION 

  • Head and neck cancer
  • Breast cancer
  • Liver cancer
  • Lung cancer

PROPERTIES

  • White crystalline powder
  • Odorless
  • Insoluble in chloroform
  • Slightly soluble in alcohol
  • Pyrimidine analog
  • Contraindicated in Pregnancy and lactation
  • IV and topical route of administration
  • CBC and Renal/Hepatic function must be monitored

MECHANISM OF ACTION

5- Fluorouracil inhibit the biosynthesis of DNA by interfering with the conversion of deoxyuridylic acid → thymidylic acid thus ↓se the thymidine level in the cell.
  • Produce effect in the S-Phase of the cell cycle.
  • Interact with Cimetidine, Metronidazole and Interferone.

ADR

  • Alopecia
  • Myelosuppression
  • Photosensitivity
  • Fluid retention
  • GI Ulcer
  • Nausea and Vomiting

 SAR

Fluorine is necessary for its affinity (binding); it can't be replaced with any other halogen group; otherwise, affinity will be lost.

Methotrexate (MTX)

INDICATION

  • Head and neck carcinoma
  • Breast cancer
  • Bladder cancer
  • Acute leukemia
  • In low doses, MTX is used in psoriasis and rheumatoid arthritis

PROPERTIES 

  • Folic acid analog
  • IV/IM/PO/IT forms are available
  • Yellow-orange crystalline powder
  • CBC and Hepatic/Renal function must be monitored
  • Specific to the S-Phase cell cycle

MECHANISM OF ACTION



ADR

  • Hepatotoxicity
  • Infertility
  • Nausea/Vomiting and Diarrhea
  • Myelosuppression
  • Rash
  • Alopecia

INTERACTION


  • Bcteriomycin and MTX have a synergistic effect.

STRUCTURAL ACTIVITY RELATIONSHIP

  • Replacement of glutamate tail with lipophilic agents can increase the transportation of the drug.
  • MTX binding with receptors depends upon a number of hydrogen. 
  • MTX functional activity depends on COOH and NH2.




Tamoxifen


INDICATION

  • Breast cancer
  • Advanced stage cancer
  • Female infertility
  • Male infertility
PROPERTIES
  • White crystalline powder
  • Oral and topical preparations are available
  • Estrogen antagonists
  • Vaginal bleeding or new breast lumps must be monitored

MECHANISM OF ACTION

It binds to estrogen receptors in the breast tissue and inhibits estrogen-induced growth of breast cancer.

ADR

  • Hot flashes
  • Vaginal bleeding
  • Nausea and Vomiting
  • Rashes
  • Hypercalcemia
  • Thromboembolism

DRUG INTERACTION

  • Warfarin
  • Rifampin

SAR

  • The alkylamino ethane side chain is important for antiestrogenic activity.
  • 4-hydroxytamoxifen will have a very high binding affinity.
  • Para hydroxylation of the phenyl ring on carbon 1 of butene can increase the potency of antiestrogen.

Vincristine

INDICATION

  • Acute lymphoblastic leukemia
  • Hodgkin and non-Hodgkin lymphomas
  • Breast cancer

PROPERTIES

  • Contraindicated during bronchospasm, pregnancy, and lactation
  • Intrathecal administration is also contraindicated 
  • IV
  • CBC, hepatic function, and peripheral neuropathy must be monitored
  • M-phase specific
  • The molecular formula is C46H56N4O10

MECHANISM OF ACTION

Vincristine blocks mitosis in metaphase, i.e. they are cell-cycle specific and phase specific.

ADR
  • Convulsion
  • Alopecia
  • Constipation
  • Jaundice
  • Neurotoxicity

DRUG INTERACTIONS





SAR

  • The indole ring in vincristine is thought to be important for its ability to bind to tubulin.
  • The N-oxide group in vincristine is important for its ability to cross the blood-brain barrier. The N-oxide group is thought to contribute to its ability to penetrate the brain.
  • The lactam ring in vincristine is important for its ability to bind to the vinca alkaloid binding site on tubulin. This binding site is specific to vinca alkaloids, and the lactam ring is thought to play a key role in the selective binding of vincristine to this site.




















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