Exam 3; Lecture 4, Medical Chemistry Cancer Drugs Part I Flashcards
Benign neoplasm
not cancerous, do not metastasize
Malignant neoplasm
cancerous, metastasize
M phase drugs
Vina Alkaloids
Taxanes
G2 phase drugs
Podophyllotoxins
Topoisomerase inhibitors
S phase drugs
Antimetabolites
Topoisomerase inhibitors
Non phase specific drugs
Alkylating agents***
Antitumor antibiotics
Nucleoside vs nucleotides?
Nucleotides have phosphate group, nucleosides do not
Where is base and sugar moiety connection in purines?
N9
Where is base and sugar moiety connection in pyridines
N1
Largest class of anticancer drugs?
Alkylating agents
Which phase of cell cycle are alkylating agents most toxic?
G1 and S phase
3rd group attached to nitrogen of Nitrogen Mustards is primary determinant of….
chemical reactivity
oral bioavailability
nature and extent of side effects
(Alkylating Agents) Most common site of Alkylation is the….
N7 position of guanine
Bifunctional alkylating agents can produce…
inter and intra strand cross links
reacts twice
Why are alkylating agents most effective against rapid proliferating cells?
Rapidly proliferating cells have insufficient time to repair damaged DNA, whereas cells in G0 have time to repair
Mechlorethamine Hydrochloride (Mustragen)
prototype chemo drug
only ALPIHATIC nitrogen mustard in US market
Bifunctional alkylation, rapid hydrolysis
Strong EW effect of 2 chlorine reduce pKa
Very reactive, rapid and nonspecific alkylation = direct tissue damage
Too toxic for oral, marketed as salt to mix with water for IV
How to inactive mustragen if contact with skin?
2% sodium thiosulfate
this creates an inactive, highly ionized water-soluble thiosulfate ester that can be washed away
Mustragen uses?
Lung cancer, Hodgkins Disease
combo therapy with estramustine to treat prostate cancer
Mustragen Toxicity
Bone barrow suppression, high reactivity causes irritation at injection site
Melphalan uses
Ovarian carcinoma, multiple myeloma
Melphalan Toxicity
Mutagenic and may induce leukemia
bone marrow suppression
Melphalan
orally active but absorption can be erratic
reactivity reduce due to N being connected to aromatic ring
lower incidence of nausea/vomiting vs Mustragen
L-isomer transported into cell preferentially over D-isomer
Cyclophosphamide (Cytoxan)
most versatile and useful N mustard
Pro drug, bio activation mediated by CYP450
lowered Gi toxicity and less nonspecific toxicity due to activation in lever
Does not cross BBB
Polar functional groups increase water solubility, bioavailability, available as tablet or powder
much less reactive then mechlorethaine
Metabolic activation of cyclophosphamide
drug itself has no antineoplastic activity, unstable carbinolamine intermediate does
intermediate undergoes fragmentation to make acrolein and phosphoramide mustard.
mustard and aziridinum dvt effective DNA-cross linking agent
CYB2B6 will turn Cyclophosphamide to
Carbinolamine, allowing it to move into cell
inactivates S isomer
CYP3A4 will turn Cyclophosphamide to
inactive metabolites
inactivates R isomer
Cyclophosphamide uses
Breast and ovaries carcinoma
Hodgkin disease
given PO,IV,IM
Does MESNA prevent chloroacetaldehyde induced toxicity?
NO
CYP3A4 will turn Ifosfamide into….
Carbinolamine
Chloroambucil
t and metabolite are acidic and highly protein bound
Good oral bioavailability, decreased in presence of food
absorbed and undergoes metabolism to form phenyl acetic aid mustard as major metabolite which retains antineoplastic activity
Estramustine
weak alkylating agent, inhibition of cellular mitosis
can be given orally
utilizes estradiol carrier to selectively deliver drug to prostate tissue
derived by esterification at C17 w/phosphoric acid and carbamoylaton w/ N-mustard at C-3 OH
Rapidly dephosphorylated
formation of active estrogens is why drug not used to treat estrogen dependent tumors
phosphate imparts greater water solubility
