Exam 3: Lecture 6, Medical Chemistry Cancer Drugs Part II Flashcards
Busulfan (Myleran) uses:
bone marrow transplantation
CML as conditioning drug
Busulfan (Myleran) Toxicity
Pulmonary fibrosis, hyperpigmentation, lowered blood platelet count and activity
Busulfan (Myleran) info
sulfuric acid ester with methane sulfuric acid acting as leaving group
1 or both methane ester can be displaced by N7 of guanine, meaning it can be bi-functional
admin oral/IV, neutral molecule with poor water solubility
Length of chain determines effect on DNA
Thiotepa info
less reactive, used for more than 50 yrs
at acidic pH, aziriuine group protonated to provide a reactive aziridinium ion that alkylates DNA = active
Metabolic desulfurization leads to toxic metabolite (TEPA)
Admin IV, PO unreliable
Thiotepa uses
Breast,ovarian, bladder cancer
Conditioning for Bone Marrow Transplant
Thiotepa Toxicity
Myelosuppression, damage to hepatic and renal system
Can TEPA alkylate DNA?
Yes, at N7 position of guanine typically
Procarbazine (Matulane) info
alkylation of DNA by free radical intermediates
** In addition to methylation of O6 of guanine, C8/N7 can be alkylated**
Drug metabolized and activated in the liver
O6 methylated guanine pair preferentially with….
Thymine, leading to point mutation resulting in cell destruction
Procarbazine (Matulane) Uses
Hodgkins Lymphoma and certain brain cancers
Procarbazine (Matulane) Side effects
inhibits enzymes involved in alcohol metabolism, disulfiram like effects
Procarbazine (Matulane) MOA inhibited by….
drug-drug interactions with other sympathomimetic drugs, tricyclic antidepressants and tyramine
Inhibition fo which enzyme causes Drug-drug interactions with Procarbazine?
CYP1A and CYP2B
Dacarbazine (DTIC) MOA:
Methylates DNA guanine via diazomethane and/or Methyl Carbocation generated in situ
O6 and N7 positions of guanine most vulnerable to triazine methylation
Dacarbazine (DTIC) bioactivated by…
CYP450
Dacarbazine (DTIC) Uses:
Admin IV
Malignant Melanoma, Hodgkins Lymphoma
Dacarbazine (DTIC) Toxicity:
Bone marrow suppression, Hepatotoxicity
Temozolomide (Temodar)
Prodrug which nonezymatically gets covered to MTIC, which alkylates DNA
Admin orally, rapid absorption
Temozolomide (Temodar) Uses
brain tumor
Nitrosourea dual MOA:
alkylate DNA and carbamylate proteins
Carmustine info
neutral molecule
highly lipophilic and poorly water soluble
Crosses BBB, used for several brain cancers
Lomustine Info
similar structure, solubility and activity characteristics of BCNU
Streptozocin info
composed of glycopyranose amino sugar and nitrosourea
Glycopyranose moeity imparts good water solubility = islet cell specificity
approved for treating metastatic cancer of pancreatic islet cells
Nitrosourea activity results from….
non-enzymatic decomposition
Carboplatin
less side effects than cisplatin
Oxaliplatin
improved water solubility over cisplatin
Cisplatin MOA:
acts by cross linking DNA (act as bifunctional ligands)
binding cisplatin affects both replication and transcription, and DNA repair. cant repair damage
**trans isomer well known to have faint cytotoxicity because its geometric structure allows less DNA adduct formation **
Antimetabolites info
structurally related to naturally occurring compounds req for normal reactions but diff enough to mess with function of cells
used in cancer treatment, interfere with DNA production
work during S-phase
also effect RNA synthesis, most widely used due to efficiency
** false substrates, to look like a super attractive version of endogenous substrate so it gets bound **
Folic Acid info
Essential dietary factor
converted by enzymatic reduction to tetrahydrofolate cofactors that provide C groups for synthesis of precursors of DNA and RNA
DHFR can be inhibited by….
methotrexate
Thymidylate synthase can be inhibited by….
5-Fluorouracil
Raltitrexed
Rate limiting step in getting to dTMP
Thymidylate Synthase
Without dTMP…
DNA will fragment and cell will die
5-Fluorouracil info
Thymidylate synthase inhibitor
mainly used in treatment of colorectal cancer and pancreatic cancer
5-Fluorouracil MOA:
transformed inside cell into cytotoxic metabolites that are incorporated into DNA/RNA.
S-Phase specific
C6 position of dUMP is….
highly electrophilic due to being surrounded by N and O atoms
In 5-FU, electrophilicity is further increased due to strong EW F group
Capecitabine
prodrug, enzymatically converted to 5-FU in tumor and phosphorylated by tumor-specific enzyme PyNPase
Oral admin, used in metastatic breast and colorectal cancers
Methotrexate info
analog of vitamin folic acid
competitively inhibits action of DHFR enzyme on folic acid, indirectly inhibiting thymidine nucleotide production
Given Oral, IM and IV
Used in treatment of ALL, and recently some autoimmune diseases
Rescue therapy for methotrexate
Leucovorin, converts to reduced folic acid dvts, has vitamin activity equivalent to folic acid
prevents lethal effects of methotrexate on normal cells
also inhibits active transport of methotrexate into cells
