Exam 3; Lecture 4, Medical Chemistry Cancer Drugs Part I

Question 1

Benign neoplasm

Answer 1

not cancerous, do not metastasize

Question 2

Malignant neoplasm

Answer 2

cancerous, metastasize

Question 3

M phase drugs

Answer 3

Vina Alkaloids

Taxanes

Question 4

G2 phase drugs

Answer 4

Podophyllotoxins

Topoisomerase inhibitors

Question 5

S phase drugs

Answer 5

Antimetabolites

Topoisomerase inhibitors

Question 6

Non phase specific drugs

Answer 6

Alkylating agents***

Antitumor antibiotics

Question 7

Nucleoside vs nucleotides?

Answer 7

Nucleotides have phosphate group, nucleosides do not

Question 8

Where is base and sugar moiety connection in purines?

Answer 8

N9

Question 9

Where is base and sugar moiety connection in pyridines

Answer 9

N1

Question 10

Largest class of anticancer drugs?

Answer 10

Alkylating agents

Question 11

Which phase of cell cycle are alkylating agents most toxic?

Answer 11

G1 and S phase

Question 12

3rd group attached to nitrogen of Nitrogen Mustards is primary determinant of….

Answer 12

chemical reactivity
oral bioavailability
nature and extent of side effects

Question 13

(Alkylating Agents) Most common site of Alkylation is the….

Answer 13

N7 position of guanine

Question 14

Bifunctional alkylating agents can produce…

Answer 14

inter and intra strand cross links

reacts twice

Question 15

Why are alkylating agents most effective against rapid proliferating cells?

Answer 15

Rapidly proliferating cells have insufficient time to repair damaged DNA, whereas cells in G0 have time to repair

Question 16

Mechlorethamine Hydrochloride (Mustragen)

Answer 16

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

Question 17

How to inactive mustragen if contact with skin?

Answer 17

2% sodium thiosulfate

this creates an inactive, highly ionized water-soluble thiosulfate ester that can be washed away

Question 18

Mustragen uses?

Answer 18

Lung cancer, Hodgkins Disease

combo therapy with estramustine to treat prostate cancer

Question 19

Mustragen Toxicity

Answer 19

Bone barrow suppression, high reactivity causes irritation at injection site

Question 20

Melphalan uses

Answer 20

Ovarian carcinoma, multiple myeloma

Question 21

Melphalan Toxicity

Answer 21

Mutagenic and may induce leukemia

bone marrow suppression

Question 22

Melphalan

Answer 22

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

Question 23

Cyclophosphamide (Cytoxan)

Answer 23

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

Question 24

Metabolic activation of cyclophosphamide

Answer 24

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

Question 25

CYB2B6 will turn Cyclophosphamide to

Answer 25

Carbinolamine, allowing it to move into cell

inactivates S isomer

Question 26

CYP3A4 will turn Cyclophosphamide to

Answer 26

inactive metabolites

inactivates R isomer

Question 27

Cyclophosphamide uses

Answer 27

Breast and ovaries carcinoma
Hodgkin disease

given PO,IV,IM

Question 28

Does MESNA prevent chloroacetaldehyde induced toxicity?

Answer 28

NO

Question 29

CYP3A4 will turn Ifosfamide into….

Answer 29

Carbinolamine

Question 30

Chloroambucil

Answer 30

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

Question 31

Estramustine

Answer 31

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