NAME: ________________________ STUDENT No. ____________________

CHEMICAL BIOLOGY 4OB3

Term Test: 50 minutes ANSWER KEY Dr. A. Capretta February 24, 2015 This exam consists of 25 questions on 8 pages. You are responsible for ensuring that your copy of the exam is complete. Bring any discrepancy to the attention of the invigilator BEFORE you begin writing the test. Special Instructions: Circle the correct answer. Only questions written in PEN will be remarked. Answers in PENCIL will NOT be remarked. If the marker is unsure as to which answer you have chosen, it will be marked as incorrect. It is YOUR responsibility to ensure your test is legible. Answer ALL questions on the test paper in the space provided. PLEASE MAKE SURE YOUR NAME AND STUDENT NUMBER ARE ON THE TEST. _________________________________________________________________________________________ For marker's use only:

Total /50

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Question 1: The following structure is more active than morphine as an analgesic.

What is the principle reason for this? a. The extra acetyl group interacts with an extra binding region within the binding site by acting as a hydrogen bond acceptor. *b. The extra acetyl group masks a polar group allowing the structure to cross the blood brain barrier more efficiently. c. The extra acetyl group masks a polar group allowing the structure to cross cell membranes more efficiently. d. The extra acetyl group masks an alcohol group which would otherwise undergo a phase II metabolic conjugation reaction leading to rapid excretion of the drug. Question 2: The N-phenethyl analogue of morphine has an analgesic activity which is 14 times greater than that of morphine. What is the principle reason for this?

a. The aromatic ring of the phenethyl group interacts with an extra hydrophilic region of the binding site. *b. The aromatic ring of the phenethyl group interacts with an extra hydrophobic region of the binding site. c. The phenethyl group increases the hydrophobicity of the molecule allowing a greater percentage to cross the blood brain barrier. d. The phenethyl group acts as a steric shield to protect the amine group from drug metabolism. Question 3: The following structure was found to have an 800-fold increase in agonist activity when the group shown in the box was added. What drug design strategy is illustrated here?

*a. Extension. b. Rigidification. c. Substituent variation. d. Conformational blocking.

HO

O

O HNO

acetyl

HO

HO

O HN

HN

CH3

HO

HO

OH

OH

3

Question 4: Which of the following statements is true? *a. Hydrophobic compounds have a high value of P. b. Hydrophilic compounds have a high value of P. c. Acidic compounds have a high value of P. d. Basic compounds have a high value of P. Question 5: Which of the following statements is true? *a. The most stable conformation of a drug is not necessarily the active conformation. b. The active conformation is the most reactive conformation of a structure. c. The active conformation is the conformation adopted by a target binding site when it binds a drug. d. The active conformation can be determined by conformational analysis. Question 6: There are several strategies for stabilising susceptible bonds in peptides. Which of the following is not used in this respect? *a. Replacing a peptide link with an ester. b. Adding an N-methyl group to the peptide link. c. Using an unnatural amino acid. d. Replacing an L-amino acid with a D-amino acid. Question 7: Which of the following descriptions refers to the absorption process known as pinocytosis? a. The process by which a drug is 'wrapped up' by a protein in the cell membrane such that it can be carried across the cell membrane. b. The process by which small molecules can squeeze through the small pores that exist between different cells in the gut wall. *c. The process by which drugs of large molecular weight are enveloped by the cell membrane, leading to the pinching off of a membane bound vesicle which carries the drug into the cell. d. The process by which ion channels open to allow the crossing of ions across the cell membrane. Question 8: Which of the following sections of the digestive system has the lowest associated pH? *a. stomach b. duodenum c. jejunum d. ileum Question 9: Which of the following terms is used to describe a drug that binds to a receptor, fails to activate it and prevents the endogenous chemical messenger from binding? a. agonist *b. antagonist c. partial agonist d. inverse agonist

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Question 10: The following antibiotic structure (Dactinomycin) is an intercalating agent. Which region of the molecule is chiefly responsible for its ability to intercalate into DNA?

*a. The tricyclic system. b. One of the macrocyclic peptide rings. c. Both of the macrocyclic peptide rings. d. The amide bonds. Question 11: The following agent is called mitomycin C and is used as an anticancer drug against a variety of cancers.

The structure is a prodrug which is converted in the body to the active compound. What is the initial step in this activation process? a. Ring opening of the aziridine ring. b. Hydrolysis of the urethane group. c. Alkylation of the primary amino group. *d. Reduction of the quinone ring system. Question 12: Which of the following is a phase II metabolic reaction? a. Formation of a carboxylic acid from a primary methyl group. *b. Formation of a sulfate from an alcohol. c. Formation of a carboxylic acid and alcohol from an ester. d. Formation of a ketone at a benzylic carbon. Question 13: The following structure is calicheamicin g1 and is an anti tumour agent derived from a bacterium.

HNO

N NH2

O HN

O

O OO

O

N

N

HN O

O

ON

O

HN O O

ON N

OO

N

tricyclic system

amide bonds

cyclic peptides

O

N NH

O

O

O

H2N O

H2N

H

H

aziridine

urethane

quinonering

primaryamino group

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Which of the following functional groups is not involved in the mechanism of action? *a. Thioamide. b. Trisulfide. c. a,b-unsaturated ketone. d. Enediyne system. Question 14: Which of the following terms best describes a drug that binds to an active site and inhibits the enzyme, and where inhibition decreases when substrate concentration is increased? a. allosteric inhibitor b. irreversible inhibitor *c. reversible inhibitor d. suicide substrate Question 15. Structures (II-IV) are analogues of a lead compound containing an aromatic ring (structure I). Structures II and III had similar activity to the lead compound whereas structure IV showed a marked increase in activity. Which of the following explanations best fits the facts?

a. Introducing a nitrogen increases basicity and so increased basicity is good for activity. b. Introducing a nitrogen increases the polarity and water solubility of the analogues, and so increased polarity is good for activity. *c. Introducing a nitrogen means that an additional hydrogen bonding interaction is possible with an extra binding region in the binding site. d. Introducing a nitrogen removes an aromatic hydrogen. The aromatic hydrogen removed may have been bad for activity for steric reasons.

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Question 16. Which of the following symbols represents the concentration of a drug required to produce 50% of a maximum possible effect? a. IC50 b. Ki c. Kd *d. EC50 Question 17. Chlorpropamide has a longer antibiotic activity than tolbutamide.

Which of the following structures is the most likely metabolite of tolbutamide?

*a. Structure A. b. Structure B. c. Structure C. d. Structure D. Question 18. A lead compound contains a carboxylic acid functional group. This was esterified to give an analogue with an ester group. In vitro tests showed that the carboxylic acid was active whereas the ester was inactive. On the other hand, in vivo tests, where the test compounds were administered orally, showed that the ester was active, and the carboxylic acid was inactive. Which of the following explanations is not plausible? a. The carboxylic acid is not absorbed in the in vivo studies. *b. The ester is an important binding group but the carboxylic acid group is not. c. The ester is absorbed in the in vivo studies. d. The ester is metabolised to the carboxylic acid in the in vivo studies.

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Question 19. Which of the following properties of a drug is most likely to result in a minimum of side effects? a. Good oral absorption. b. Fast metabolism. *c. Target selectivity. d. Target affinity. Question 20. What is meant by ADME in pharmacokinetics? a. Affinity, dosage, marketing, efficacy. *b. Absorption, distribution, metabolism, excretion. c. Agonism, dependence, mobility, efficiency. d. Antagonism, deficiency, mean, efflux. Question 21. Which of the following functional groups cannot be formed by a metabolic reaction catalysed by cytochrome P450 enzymes? *a. Ethers. b. Ketones. c. Alcohols. d. Carboxylic acids. Question 22. Which of the following is one of the rules in Lipinski's rule of five? a. A molecular weight equal to 500. *b. No more than five hydrogen bond donor groups. c. No more than five hydrogen bond acceptor groups. d. A calculated logP value more than +5. Question 23. Which of the carbon atoms in the following structure is likely to be least susceptible to cytochrome P450 enzymes?

a. Carbon A. b. Carbon B. *c. Carbon C. d. Carbon D.

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Question 24. It is common practice to vary the length and size of alkyl groups when making analogues of a lead compound. Which of the following statements is true? a. Replacing a straight chain alkyl group with a branched alkyl group may increase activity by filling up a hydrophobic pocket and increasing hydrogen bonding interactions. *b. Increasing the chain length or size of an alkyl group may increase target selectivity if a hydrophobic binding region is more spacious in one binding site than another. c. Increasing the chain length or size of an alkyl group increases activity and selectivity by stabilising the analogue. d. Increasing the chain length of an alkyl group may increase activity by leading to better van der Waals interactions with a hydrophilic region of the binding site. Question 25: Cisplatin is used for the treatment of testicular and ovarian cancers.

Which of the following statements is untrue? a*. The amino groups are displaced before the drug becomes active. b. Intrastrand cross linking of DNA results from the action of the agent. c. Base pairing between cytosine and guanine is disrupted by the agent. d. The agent often results in nausea.

PtCl

Cl

NH3

NH3