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Medicinal Chemistry > Anticancer I > Flashcards

Anticancer I Flashcards

1
Q

What are the 7 classes of anticancer agents?

A 
Alkylating agents
Antimetabolite and nucleoside analogs
Antitumor antibiotics
Antimitotic agents
Miscellaneous antineoplastics
Hormonal therapy
Combination therapy
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2
Q

What are the different alkylating agents?

A 
Nitrogen mustards
Phosphoamide mustards
Nitrosoureas
Platins
Other alkylating agents
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3
Q

What is the main MOA of alkylating agents?

A

React with DNA, preferentially alkylating the N-7 position of guanine (most common)
Bifunctional alkylating agents product inter- or intra-strand crosslinks preventing DNA separation

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4
Q

What is the MOA of nitrogen mustards?

A

They activate the chloride

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5
Q

What are some nitrogen mustards?

A 
Melphalan
Cyclophosphamide
Ifosfamide
Chlorambucil
Estramustine phosphate
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6
Q

What are some other alkylating anticancer agents?

A

Busulfan (Myleran)
Thiopeta
Procarbazine (Matulane)
Dacarbazine

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7
Q

What is the MOA of nitrosureas?

A

Urea NH is deprotonated and the negatively charged oxygen displaces chloride to give a cyclic oxazolidine, which fragments to give 2-chloroethylisocyanate and vinyl diazohydroxide, which decomposes to give electrophilic vinyl cation

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8
Q

What are some nitrosureas?

A

Carmustine (BiCNU)
Lomustine (CeeNU)
Streptozin (Zanosar)

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9
Q

What are some platins?

A

Cisplatin

Carboplatin

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10
Q

What is the MOA of antimetabolites?

A

They care closely related to cellular precursors and thus they prevent use or formation of normal cellular products.

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11
Q

What are the MOAs of pyrimidine-based antimetabolites?

A

Inhibition of kinases
Inhibition of enzymes involved in pyrimidine biosynthesis
Incorporation into RNA or DNA, causes misreading
Inhibition of DNA polymerase

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12
Q

What is the role of folate?

A

DNA synthesis
DNA repair
DNA methylation
Cofactor

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13
Q

What are the active forms of folate?

A

Tetrahydrofolate and dihydrofolate

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14
Q

What do dihydrofolate reductase (DHFR) inhibitors do?

A

They inhibit DHFR, which leads to:
Decreased levels of FH2 and FH4
Decreased conversion of dUMP into dTMP
Decreased DNA synthesis

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15
Q

What are some DHFR inhibitors?

A

Methotrexate
Pemetrexed (Alimta)
Pralatrexate (Folotyn)

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16
Q

What does pralatrexate do?

A

Inhibits enzymes used in purine and pyrimidine synthesis:
thymidylate synthase
dihydrofolate reductase
glycinamide ribonucleotide formyltransferase

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17
Q

What does folinic acid do?

A

Adjuvant used in cancer chemotherapy to “rescue” bone marrow and GI mucosa cells from methotrexate

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18
Q

What is 5-fluorouracil?

A

“Mechanism-based” prodrug that acts as a suicide substrate and directly inhibits the thymidylate synthase

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19
Q

What are the 3 main active metabolites of 5-fluorouracil?

A 
Fluorodeoxyuridine monophosphate (FdUMP)
Fluorodeoxyuridine triphosphate (FdUTP)
Fluorouridine triphosphate (FUTP)
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20
Q

What is the MOA of 5-FU (specifically, it’s active metabolite FdUMP)?

A

Direct inhibition of TS via the formation of a ternary complex in the nucleotide-binding site. This blocks dUMP from accessing the binding site.
This leads to an increase in dUTP, which causes DNA damage

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21
Q

What are some other pyrimidine-based antimetabolites?

A

Cytarabine (ARA-C)

Gemcitabine

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22
Q

What are some purine-based antimetabolites?

A

6-mercaptopurine
6-thioguanine
Fludarabbine phoshpate (Fludara)
Cladribine

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23
Q

What is the MOA of 6-mercaptopurine?

A

Blocks the synthesis of PRA and PRPP

24
Q

What are some antitumor antibiotics?

A 
Bleomycins
Anthracyclines
Etoposide and teniposide
Camptothecins
Actinomycins
Mitomycins
25
Q

What are bleomycins?

A

Cytotoxic glycopeptides

26
Q

What is the MOA of bleomycins?

A

Chelates metail ions (Fe, Cu) producing a pseudo enzyme that reacts with oxygen to produce free radicals, causing DNA strand breaks

27
Q

What is required for bleomycin DNA strand breaking? How is this achieved?

A

Reactivation and reorganization of bleomycin

The key to reorganization is the linker and the flexibility of the bithiazole tail

28
Q

What are some topoisomerase poisons?

A

Amsacrine
Etoposide
Doxorubicin
Mitoxantrone

29
Q

What are the functions of DNA topoisomerase?

A

DNA replication
DNA recombination
Chromosome condensation/decondensation
Segregation of sister chromatids

30
Q

What do topoisomerase II poisons do?

A

Cause single and double strand DNA breaks
Increase in topoisomerase II levels - renders cell hypersensitive (more enzyme, more DNA breaks)
Stabilize topoisomerase II-DNA covalent complexes

31
Q

What does topoisomerase II catalytic inhibitors do (…not do)?

A

Do not cause DNA strand breaks

Do not stabilize topoisomerase II-DNA cleavable complexes (and may destabilize them)

32
Q

What is the MOA of anthracyclines?

A

intercalation followed by inhibition of topoisomerase II leading to DNA strand breakage and apoptosis
Additional mechanism: generation of free radicals

33
Q

What are the 5 clinically useful anthracyclines?

A 
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Valrubicin
34
Q

What limits the use of doxorubicin?

A

Cardiotoxicity; doxorubicin is a quinone and can be reduced to a semiquinone. The semiquinone reacts with oxygen to reform the quinone (redox cycling)
Doxorubicin also forms a strong complex with Fe3+, which can be reduced to Fe2+, which can form free radicals

35
Q

What limits the use of etoposide?

A

Myelosuppression

36
Q

What is the MOA of camptothecins?

A

Inhibitor of topoisomerase I (prevents realignment and resealing); leads to double stranded DNA breaks and cell death

37
Q

What is increases the water solubility of campothecins to create topotecan and Irinotecan?

A

Addition of basic amine side chains

38
Q

What’s the difference between topoisomerase I and II?

A

Top. I: single strand break

Top. II: double strand break

39
Q

What are some antimitotic compounds?

A

Vinca alkaloids
Taxanes
Epothilones
IXA

40
Q

What are the two conjoined groups of vinca alkaloids?

A 
Catharanthine moiety (indole, azonine, piperidine ring systms)
Vindoline moiety (dihydroindole, cyclohexane, pyrrolidine, piperidine)
41
Q

What is the MOA of vinca alkaloids?

A

Disrupt formation of mitotic spindles, inhibiting microtubule assembly

42
Q

What are some vinca alkaloids?

A

Vinblastine
Vincristine
Vinorelbine

43
Q

What is the MOA of taxenes?

A

They bind to tubular at a different site than vinca alkaloids
This stabilizes microtubules and prevent depolymerization, blocking mitosis

44
Q

What are some taxanes?

A

Paclitaxel (Taxol)

Docetaxel (Taxotere)

45
Q

What does vinblastine bind to the microtubule? What does paclitaxel bind?

A

Vinblastine binds to the plus end

Paclitexel binds on the interior surface

46
Q

What are epothilones?

A

They are macrocyclic lactones that have a MOA similar to taxanes but offer several advantages (don’t require Cremophor EL for water solubility)

47
Q

What is IXA used for?

A

Taxane-resistant breast cancer

48
Q

What growth factors do we often target with several drugs and monoclonal antibodies to control overgrowth of cells/tissues?

A 
Epidermal GF
Platelet-derived GF
Nerve GF
Vascular endothelial GF
Stem cell F
49
Q

What is the MOA of protein tyrosine kinase inhibitors

A

Kinase inhibitors mimic ATP to inhibit tyrosine kinases

50
Q

What is the first protein tyrosine kinase inhibitor on the market?

A

Imatinib (Gleevec) for chronic myelogenous leukemia

51
Q

What are other protein tyrosine kinase inhibitors?

A

Nilotinib
Dasatinib
Bosutinib
Ponatinib

52
Q

How do type I kinase inhibitors bind?

A

They bind to the active conformation of the kinase with the aspartate residue and the DFG motif pointing into the ATP-binding pocket

53
Q

How do the type II kinase inhibitors bind?

A

They bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket

54
Q

What are the limitations of kinase inhibitors?

A

Cardiotoxicity (CHF, decreased ejection fraction, ischemia, infarction)

55
Q

What are some anticancer monoclonal antibodies?

A 
Bevacizumab
Cetuximab
Ipilimumab
Nivolumab
Ofatumumab
Paitumumab
Rituximab
56
Q

What is the MOA of Bortezomib?

A

Inhibits proteosomes

57
Q

What is the MOA of dactinomycin?

A

Binds to DNA by intercalation, inhibiting DNA function

Medicinal Chemistry (13 decks)

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