Exam 3: Lecture 8, Medical Chemistry Cancer Drugs Part III Flashcards
Purine Antimetabolites
analogs of purine guanine in which carbonyl group is replaced with thiocarbonyl group.
metabolized to deoxynucleoides by HPRTase
inhibit many enzymes involved in purine metabolism
Purine Antimetabolite uses
treatment of acute leukemias
Purine Toxicity
bone marrow suppression
nausea
vomiting
Enzymes Purine antimetabolites inhibit
Primary target: AMP and GMP biosynthesis
primary action is by inhibition of enzyme
important fact about Purine antimetabolites?
They are prodrugs
Sugar-modified pyrimidine analogs
Cytarabine
Gemicitabine
Cytarabine
Inhibits conversion of cytidylic acid to 2’deoxycytidylic acid
causes miscoding after being incorporated into DNA
rapidly deaminated in body into inactive uric derivative, can only be give continuous IV infusion
~3hr 1/2 life
Enzymes Cytarabine inhibits?
also inhibits both DNA and RNA polymerases and nucleotide reductase enzyme needed for DNA synthesis
Gemicitabine
excellent anti tumor activity in vivo against variety of murine solid tumors
must 1st be phosphorylated to active triphosphate analogue, incorporated into DNA and cause cell death
~19hr 1/2 life due to difluorination
What deactivates Gemicitabine?
deaminase
Antitumor Antibiotics
known for long time, rejected due to toxicity
Bleomycin isolated from….
Streptomyces verticillus
Key to Bleomycin anti tumor activity?
tendency to form metal chelates
in cells form chelate with iron Fe2+
Bleomycin MOA
Chelate affects redox potential such that bound oxygen is reduced, converting into reactive radical species, the Hydroxyl radical which then binds to DNA and degrades it
Anthracycline inhibit….
Topoisomerase II
Anthracyclines are effective against….
more types of cancer than any other class but can cause Cardiotoxicity
Anthracycline MOA:
DNA intercalation followed by free radical damage to DNA,
Inhibitors top II -> form active Oxygen species -> DNA Damage
Valrubicin is…
a semisynthetic analog of Doxorubicin and has been used to treat bladder cancer
Antimitotic agents are….
molecules that target mitosis and inhibit cell division
Well known antimitotic drugs are..
Taxanes and Vinca Alkaloids
Both effective but limited by development of drug resistance and significant neurotoxicity
Vincristine and Vinblastine block mitosis by….
metaphase arrest by binding specifically with tubule and causing its depolymerization.
Portions of Vinca Alkaloids that are essential for high affinity binding?
Vindeline
Catharamine
Taxanes are…
very hard to synthesize because they have several chiral centers
produced semi synthetically
bind to B tubulin
Taxol has how many chiral centers?
11
What gives increased aqueous solubility for Docetaxel?
A Hydroxyl group
Hydroxyurea info
LMW w/ good oral bioavailability
Hydroxyurea MOA:
anticancer activity due to inhibition of ribonucleotide diphosphate reduction, leading to decreased levels of deoxyribonucleotides required for DNA synthesis
What phase is Hydroxyurea specific for?
S Phase and causes arrest at the G1-S interface
Antiestrogens nd Aromatase inhbitors
Tamoxifen
Anastrazole and Letrozole
Tamoxifen is….
estrogen agonist/antagonist (Partial agonist) that is used in treatment fo estrogen dependent breast cancer
Metabolism produces active metabolite 4-hydroxytamoixifen
Anastrazole and Letrozole are….
competitive inhibit of aromatase that selectively inhibit conversion of testosterone to estrogens in all tissues
Which enzymes do Anastrazole and other triazoles inhibit?
Aromatase enzyme by binding of N-4 nitrogen of triazole ring with heme iron atom of CYP19 eynyze complex
Anastrazole and Ketrozole are used for treatment of…
advanced breast cancer in postmenopausal woman w/ disease progression following tamoxifen therapy
