MCQ Quiz: Medicinal Chemistry of Oncology Drugs

Welcome, PharmD students, to this advanced MCQ quiz on the Medicinal Chemistry of Oncology Drugs! The design and development of effective anticancer agents rely heavily on understanding their chemical structures, physicochemical properties, and how these features dictate their interactions with biological targets and overall pharmacological profiles. This quiz will test your knowledge on the structure-activity relationships (SAR), chemical mechanisms of action, metabolic pathways, and prodrug strategies pertinent to various classes of oncology drugs, from traditional cytotoxics to modern targeted therapies. Let’s explore the chemical intricacies of fighting cancer!

1. The primary mechanism by which classical alkylating agents like nitrogen mustards exert their cytotoxic effect involves the formation of _______ with DNA.

• a) Hydrogen bonds
• b) Covalent bonds, leading to alkylation and cross-linking of DNA strands
• c) Ionic bonds
• d) Van der Waals forces

Answer: b) Covalent bonds, leading to alkylation and cross-linking of DNA strands

2. The reactivity of nitrogen mustards as alkylating agents is attributed to their ability to form highly reactive _______ intermediates.

• a) Aziridinium ions
• b) Carbanions
• c) Free radicals
• d) Nitrenium ions

Answer: a) Aziridinium ions

3. Cisplatin, a platinum-based anticancer drug, forms intra-strand and inter-strand cross-links in DNA, primarily at which site on guanine bases?

• a) N1 position
• b) N7 position
• c) O6 position
• d) C8 position

Answer: b) N7 position

4. Antimetabolites exert their anticancer effects by:

• a) Directly alkylating DNA.
• b) Interfering with the synthesis or function of essential cellular metabolites, often by mimicking endogenous nucleosides, purines, or pyrimidines, or by inhibiting key enzymes in nucleic acid synthesis.
• c) Stabilizing microtubules.
• d) Binding to growth factor receptors.

Answer: b) Interfering with the synthesis or function of essential cellular metabolites, often by mimicking endogenous nucleosides, purines, or pyrimidines, or by inhibiting key enzymes in nucleic acid synthesis.

5. Methotrexate is a structural analog of folic acid. It inhibits dihydrofolate reductase (DHFR), an enzyme crucial for:

• a) Oxidizing DNA.
• b) Regenerating tetrahydrofolate, which is essential for the synthesis of thymidylate and purines.
• c) Hydrolyzing peptide bonds.
• d) Polymerizing tubulin.

Answer: b) Regenerating tetrahydrofolate, which is essential for the synthesis of thymidylate and purines.

6. 5-Fluorouracil (5-FU) is a pyrimidine analog that, after intracellular conversion to its active metabolites (e.g., FdUMP), primarily inhibits which enzyme involved in DNA synthesis?

• a) DNA polymerase
• b) Topoisomerase I
• c) Thymidylate synthase
• d) Ribonucleotide reductase

Answer: c) Thymidylate synthase

7. The anthracycline antibiotics (e.g., doxorubicin) possess a planar tetracyclic ring system which allows them to _______ DNA, interfering with DNA and RNA synthesis.

• a) alkylate
• b) intercalate between base pairs of
• c) hydrogen bond with
• d) methylate

Answer: b) intercalate between base pairs of

8. The quinone moiety in anthracyclines like doxorubicin is also involved in generating _______, which can cause DNA damage and cardiotoxicity.

• a) Acetyl groups
• b) Reactive oxygen species (free radicals)
• c) Methyl groups
• d) Folic acid derivatives

Answer: b) Reactive oxygen species (free radicals)

9. Vinca alkaloids (e.g., vincristine) are plant-derived compounds that bind to _______ and inhibit its polymerization, leading to mitotic arrest in M phase.

• a) DNA
• b) Ribosomal RNA
• c) Tubulin (the protein subunit of microtubules)
• d) Topoisomerase II

Answer: c) Tubulin (the protein subunit of microtubules)

10. Taxanes (e.g., paclitaxel) also target microtubules but, unlike vinca alkaloids, they work by:

• a) Preventing tubulin polymerization.
• b) Promoting tubulin polymerization and stabilizing microtubules, preventing their dynamic disassembly required for mitosis.
• c) Directly cross-linking DNA.
• d) Inhibiting dihydrofolate reductase.

Answer: b) Promoting tubulin polymerization and stabilizing microtubules, preventing their dynamic disassembly required for mitosis.

11. Podophyllotoxins like etoposide are topoisomerase II inhibitors. From a medicinal chemistry perspective, their complex polycyclic structure interacts with the enzyme-DNA complex to:

• a) Prevent ATP binding to kinases.
• b) Stabilize the “cleavable complex,” leading to permanent DNA strand breaks.
• c) Directly alkylate guanine bases.
• d) Inhibit microtubule depolymerization.

Answer: b) Stabilize the “cleavable complex,” leading to permanent DNA strand breaks.

12. Camptothecins (e.g., irinotecan, topotecan) are natural product derivatives that selectively inhibit which enzyme?

• a) Topoisomerase II
• b) DNA polymerase
• c) Topoisomerase I
• d) Thymidylate synthase

Answer: c) Topoisomerase I

13. Imatinib mesylate, a tyrosine kinase inhibitor (TKI), was designed to specifically inhibit the BCR-ABL kinase. This specificity is achieved through structural features that allow it to bind to:

• a) The DNA binding domain of BCR-ABL.
• b) The ATP-binding pocket of the BCR-ABL kinase domain.
• c) The cell surface receptor for BCR-ABL.
• d) Ribosomal RNA.

Answer: b) The ATP-binding pocket of the BCR-ABL kinase domain.

14. Monoclonal antibodies (mAbs) used in oncology often target cell surface receptors or antigens. The “-ximab” suffix in a mAb name (e.g., rituximab) indicates it is a:

• a) Murine antibody
• b) Chimeric antibody (part mouse, part human)
• c) Humanized antibody
• d) Fully human antibody

Answer: b) Chimeric antibody (part mouse, part human)

15. Trastuzumab (Herceptin) is a humanized monoclonal antibody. Its medicinal chemistry involves designing the antibody to bind with high affinity and specificity to:

• a) The CD20 antigen on B-cells.
• b) The extracellular domain of the HER2 receptor.
• c) Vascular Endothelial Growth Factor (VEGF).
• d) Programmed Death-1 (PD-1) receptor.

Answer: b) The extracellular domain of the HER2 receptor.

16. Tamoxifen, a Selective Estrogen Receptor Modulator (SERM), has a chemical structure that allows it to bind to the estrogen receptor (ER). In breast tissue, it generally acts as an:

• a) ER agonist, promoting tumor growth.
• b) ER antagonist, blocking estrogen’s effects and inhibiting growth of ER-positive tumor cells.
• c) Aromatase enzyme inhibitor.
• d) Alkylating agent.

Answer: b) ER antagonist, blocking estrogen’s effects and inhibiting growth of ER-positive tumor cells.

17. Aromatase inhibitors are classified into steroidal (Type I, e.g., exemestane) and non-steroidal (Type II, e.g., anastrozole, letrozole). Non-steroidal aromatase inhibitors typically bind _______ to the active site of aromatase.

• a) Covalently and irreversibly
• b) Reversibly, often through coordination with the heme iron atom
• c) To an allosteric site
• d) To DNA directly

Answer: b) Reversibly, often through coordination with the heme iron atom

18. Many anticancer drugs are administered as prodrugs. Cyclophosphamide, an alkylating agent, is a prodrug that requires metabolic activation by _______ to form its active cytotoxic metabolites.

• a) Renal enzymes
• b) Gastrointestinal flora
• c) Hepatic cytochrome P450 enzymes
• d) Plasma esterases

Answer: c) Hepatic cytochrome P450 enzymes

19. Capecitabine is an oral prodrug that is converted in a series of enzymatic steps, with the final conversion to _______ occurring preferentially in tumor tissue (due to higher thymidine phosphorylase levels).

• a) Methotrexate
• b) Doxorubicin
• c) 5-Fluorouracil (5-FU)
• d) Cisplatin

Answer: c) 5-Fluorouracil (5-FU)

20. The chemical stability of anticancer drugs is a critical medicinal chemistry consideration. For example, the beta-lactam ring in some older investigational agents was a source of instability. For current cytotoxic agents, what is a common stability concern for DNA alkylators?

• a) They are too stable and do not react.
• b) Their high reactivity makes them prone to hydrolysis or reaction with nucleophiles before reaching their DNA target if not formulated or handled properly.
• c) They only degrade in acidic conditions.
• d) They are only stable in powdered form.

Answer: b) Their high reactivity makes them prone to hydrolysis or reaction with nucleophiles before reaching their DNA target if not formulated or handled properly.

21. The presence of specific functional groups on a drug molecule can dictate its susceptibility to metabolic inactivation. For example, ester-containing drugs may be hydrolyzed by:

• a) CYP450 oxidases
• b) Esterases in plasma or tissues
• c) Glucuronosyltransferases
• d) Sulfotransferases

Answer: b) Esterases in plasma or tissues

22. Medicinal chemistry strategies to overcome drug resistance in cancer can include:

• a) Designing drugs that are not substrates for efflux pumps (e.g., P-glycoprotein).
• b) Developing agents that can bypass the resistance mechanism (e.g., targeting a different pathway).
• c) Creating new analogs that can bind to mutated target proteins.
• d) All of the above.

Answer: d) All of the above.

23. Platinum-based drugs like cisplatin, carboplatin, and oxaliplatin differ in their chemical structures, particularly in their ligand groups. These differences primarily affect their:

• a) Mechanism of DNA binding (all form adducts).
• b) Spectrum of activity against different cancer types (somewhat).
• c) Pharmacokinetic profiles and toxicity profiles (e.g., nephrotoxicity, neurotoxicity).
• d) Color in solution.

Answer: c) Pharmacokinetic profiles and toxicity profiles (e.g., nephrotoxicity, neurotoxicity).

24. Many tyrosine kinase inhibitors (TKIs) are designed to mimic _______ and compete for its binding site on the kinase.

• a) DNA
• b) RNA
• c) Adenosine triphosphate (ATP)
• d) A specific growth factor ligand

Answer: c) Adenosine triphosphate (ATP)

25. The selectivity of TKIs for specific kinases over others is a major medicinal chemistry challenge and is often related to:

• a) The overall size of the molecule only.
• b) Subtle differences in the ATP-binding pocket or nearby regions of different kinases, allowing for differential binding affinity.
• c) Their route of administration.
• d) Their ability to cross the blood-brain barrier.

Answer: b) Subtle differences in the ATP-binding pocket or nearby regions of different kinases, allowing for differential binding affinity.

26. “Humanization” of murine monoclonal antibodies (e.g., changing from “-omab” to “-zumab”) is a medicinal chemistry/biotechnology approach to:

• a) Increase their binding affinity for the target.
• b) Reduce their immunogenicity in humans and prolong their half-life.
• c) Make them orally bioavailable.
• d) Decrease their manufacturing cost.

Answer: b) Reduce their immunogenicity in humans and prolong their half-life.

27. Antibody-Drug Conjugates (ADCs) like ado-trastuzumab emtansine combine a monoclonal antibody with a potent cytotoxic agent via a chemical linker. The linker’s chemistry is crucial for:

• a) Increasing the antibody’s size.
• b) Ensuring stability in circulation but allowing cleavage and release of the cytotoxic agent specifically at the tumor site or within cancer cells.
• c) Making the antibody target different antigens.
• d) Improving the taste of the drug.

Answer: b) Ensuring stability in circulation but allowing cleavage and release of the cytotoxic agent specifically at the tumor site or within cancer cells.

28. The chemical properties of methotrexate (e.g., its dicarboxylic acid structure) contribute to its:

• a) High lipophilicity and easy passage across cell membranes by passive diffusion.
• b) Requirement for active transport systems (e.g., reduced folate carrier) for cellular uptake and its renal excretion.
• c) Inability to inhibit DHFR.
• d) Volatility at room temperature.

Answer: b) Requirement for active transport systems (e.g., reduced folate carrier) for cellular uptake and its renal excretion.

29. The solubility of an oncology drug is a critical physicochemical property that influences its:

• a) Color
• b) Formulation options (e.g., for oral or IV administration) and absorption.
• c) Mechanism of action.
• d) Ability to cause hair loss.

Answer: b) Formulation options (e.g., for oral or IV administration) and absorption.

30. The log P (octanol-water partition coefficient) value of an anticancer drug gives an indication of its:

• a) Acidity (pKa)
• b) Molecular weight
• c) Lipophilicity/hydrophilicity, which affects membrane permeability and distribution.
• d) Melting point

Answer: c) Lipophilicity/hydrophilicity, which affects membrane permeability and distribution.

31. The nitrogen atoms in the purine and pyrimidine rings of antimetabolites are often key sites for:

• a) Forming covalent bonds with DNA.
• b) Interacting with enzyme active sites (e.g., via hydrogen bonding) or undergoing metabolic transformations.
• c) Chelation with metal ions.
• d) Redox reactions.

Answer: b) Interacting with enzyme active sites (e.g., via hydrogen bonding) or undergoing metabolic transformations.

32. For platinum-based drugs, the “leaving groups” (e.g., chloride in cisplatin, cyclobutanedicarboxylate in carboplatin) influence the drug’s:

• a) Color.
• b) Reactivity (rate of aquation and DNA binding) and toxicity profile.
• c) Target specificity (all target DNA).
• d) Cell cycle specificity.

Answer: b) Reactivity (rate of aquation and DNA binding) and toxicity profile.

33. A common strategy in medicinal chemistry to improve a drug’s pharmacokinetic profile, such as increasing its half-life, might involve:

• a) Decreasing its molecular weight significantly.
• b) Modifying its structure to reduce susceptibility to metabolic enzymes or enhance plasma protein binding.
• c) Making it more water-soluble to enhance renal excretion.
• d) Increasing its reactivity.

Answer: b) Modifying its structure to reduce susceptibility to metabolic enzymes or enhance plasma protein binding.

34. The presence of an aromatic ring system in many anticancer drugs (e.g., some TKIs, anthracyclines) often contributes to:

• a) High water solubility.
• b) Interactions with biological targets through pi-pi stacking or hydrophobic interactions.
• c) Rapid renal excretion.
• d) Inability to cross cell membranes.

Answer: b) Interactions with biological targets through pi-pi stacking or hydrophobic interactions.

35. The development of resistance to imatinib can occur through point mutations in the BCR-ABL kinase domain. Medicinal chemists have designed second- and third-generation TKIs (e.g., dasatinib, nilotinib, ponatinib) that:

• a) Target a completely different pathway.
• b) Can bind effectively to some of these mutated forms of BCR-ABL.
• c) Are less potent than imatinib.
• d) Only work against non-mutated BCR-ABL.

Answer: b) Can bind effectively to some of these mutated forms of BCR-ABL.

36. Many orally administered small molecule kinase inhibitors are substrates for _______, which can significantly impact their oral bioavailability and contribute to drug-drug interactions.

• a) Only renal organic anion transporters (OATs).
• b) Cytochrome P450 enzymes (especially CYP3A4) and/or efflux transporters like P-glycoprotein.
• c) Only plasma esterases.
• d) Amylase in the gut.

Answer: b) Cytochrome P450 enzymes (especially CYP3A4) and/or efflux transporters like P-glycoprotein.

37. From a medicinal chemistry perspective, the concept of “privileged structures” refers to molecular scaffolds that:

• a) Are unique to only one drug.
• b) Can bind to multiple biological targets (e.g., different kinases) and are often used as starting points for drug discovery.
• c) Are inherently toxic.
• d) Cannot be synthesized.

Answer: b) Can bind to multiple biological targets (e.g., different kinases) and are often used as starting points for drug discovery.

38. The acidity or basicity of ionizable functional groups in an oncology drug (defined by its pKa) is critical because it affects its:

• a) Color in solid form.
• b) Degree of ionization at physiological pH, which influences solubility, absorption, distribution, and target binding.
• c) Molecular weight.
• d) Ability to form free radicals.

Answer: b) Degree of ionization at physiological pH, which influences solubility, absorption, distribution, and target binding.

39. Drug metabolism studies are crucial in oncology drug development to identify:

• a) The most aesthetically pleasing formulation.
• b) Active or toxic metabolites, pathways of elimination, and potential for drug-drug interactions involving metabolizing enzymes.
• c) The patient’s preferred dosing schedule.
• d) The best marketing strategy.

Answer: b) Active or toxic metabolites, pathways of elimination, and potential for drug-drug interactions involving metabolizing enzymes.

40. Which property is often desired for a systemically acting anticancer drug to reach its target in solid tumors?

• a) Extremely high water solubility and poor lipid solubility.
• b) Appropriate balance of lipophilicity and hydrophilicity to allow for membrane permeation and distribution into tumor tissue.
• c) Very large molecular size ( > 2000 Da for small molecules).
• d) Rapid and complete binding to plasma proteins, leaving no free drug.

Answer: b) Appropriate balance of lipophilicity and hydrophilicity to allow for membrane permeation and distribution into tumor tissue.

41. The pharmacophore of methotrexate includes a pteridine ring, p-aminobenzoic acid, and glutamic acid moieties, making it structurally similar to:

• a) Purines
• b) Pyrimidines
• c) Folic acid
• d) Steroids

Answer: c) Folic acid

42. A key medicinal chemistry difference between vincristine and vinblastine, both vinca alkaloids, lies in a minor structural change (formyl vs. methyl group on the vindoline moiety), which results in:

• a) Identical potency and toxicity profiles.
• b) Significant differences in their neurotoxicity profiles and spectra of antitumor activity.
• c) One being orally active and the other not.
• d) One targeting DNA and the other microtubules.

Answer: b) Significant differences in their neurotoxicity profiles and spectra of antitumor activity.

43. Many anticancer drugs, especially cytotoxic agents, have a narrow therapeutic index. This medicinal chemistry and pharmacology challenge means that:

• a) The drug is effective over a very wide dose range.
• b) The dose required for therapeutic effect is very close to the dose that causes significant toxicity, requiring careful dosing and monitoring.
• c) The drug has very few side effects.
• d) The drug is always safe regardless of the dose.

Answer: b) The dose required for therapeutic effect is very close to the dose that causes significant toxicity, requiring careful dosing and monitoring.

44. The chemical structure of bleomycin is complex and includes a metal-binding region (often chelating Fe(II)) which is essential for its mechanism of:

• a) Inhibiting thymidylate synthase.
• b) Binding to microtubules.
• c) Generating DNA-cleaving reactive oxygen species.
• d) Alkylating guanine.

Answer: c) Generating DNA-cleaving reactive oxygen species.

45. Structure-Activity Relationship (SAR) studies for a class of anticancer drugs aim to:

• a) Only determine the cost of synthesis.
• b) Understand how specific structural features of the molecules relate to their biological activity, potency, selectivity, and pharmacokinetic properties.
• c) Find the most toxic compound in the series.
• d) Only study the drug’s formulation.

Answer: b) Understand how specific structural features of the molecules relate to their biological activity, potency, selectivity, and pharmacokinetic properties.

46. From a medicinal chemistry standpoint, “soft drugs” are designed to:

• a) Be very potent and long-acting.
• b) Be active locally and then rapidly metabolize to inactive, non-toxic products upon entering systemic circulation, minimizing systemic side effects.
• c) Have a very hard physical consistency.
• d) Be difficult to synthesize.

Answer: b) Be active locally and then rapidly metabolize to inactive, non-toxic products upon entering systemic circulation, minimizing systemic side effects. (This principle is more common in other therapeutic areas but can be applied).

47. The formulation of poorly water-soluble anticancer drugs (e.g., paclitaxel originally) often presents a medicinal chemistry and pharmaceutical challenge, sometimes requiring specialized vehicles like:

• a) Saline solution only.
• b) Cremophor EL or albumin-bound nanoparticles (e.g., nab-paclitaxel).
• c) Simple sugar solutions.
• d) Olive oil for IV administration.

Answer: b) Cremophor EL or albumin-bound nanoparticles (e.g., nab-paclitaxel).

48. Understanding the chemical basis of an anticancer drug’s interaction with efflux transporters like P-glycoprotein is important because:

• a) It ensures the drug will always be effluxed.
• b) It can help predict multidrug resistance and inform strategies to overcome it (e.g., co-administration of P-gp inhibitors, or designing non-substrate drugs).
• c) It only affects oral bioavailability.
• d) It guarantees increased drug efficacy.

Answer: b) It can help predict multidrug resistance and inform strategies to overcome it (e.g., co-administration of P-gp inhibitors, or designing non-substrate drugs).

49. Many kinase inhibitors used in oncology end with the suffix “-tinib” (e.g., imatinib, erlotinib, gefitinib). This nomenclature often indicates that they are:

• a) Monoclonal antibodies.
• b) Small molecule tyrosine kinase inhibitors.
• c) Hormonal therapies.
• d) Antitumor antibiotics.

Answer: b) Small molecule tyrosine kinase inhibitors.

50. The medicinal chemistry of hormonal agents like aromatase inhibitors involves designing molecules that can specifically interact with and inhibit the aromatase enzyme, thereby blocking:

• a) Testosterone synthesis directly.
• b) The conversion of androgens to estrogens.
• c) The binding of estrogen to its receptor.
• d) DNA replication.

Answer: b) The conversion of androgens to estrogens.