UNIVERSITY OF EAST ANGLIA

School of Chemistry
Main Series UG Examination 2015-16

MEDICINAL CHEMISTRY

CHE-5150Y

Time allowed: 2 hours

Answer FOUR questions.

You are advised to spend an equal amount of time on each question.

All questions carry an equal number of marks.

Answer EACH question in a SEPARATE answer book.

The breakdown of marks within each question is indicated by the percentage figures
in brackets on the right.

Do not take this question paper out of the examinations room.

Notes are not permitted in this examination.

Do not turn over until you are told to do so by the Invigilator.

(CHE-5150Y) Module co-ordinator: Philip Page (CHE)

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1. Answer ALL parts (a) to (f).

(a) What is a prodrug? [10%]

(b) Which components of the morphine molecule are involved in binding to the
opioid receptor binding site? For each, indicate the nature of the binding
interaction.
[30%]

(c) Place these interactions in order of increasing interaction energy. [10%]

(d) Define the partition coefficient P within the context of drug design, and say
why the value of P is important. [10%]

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…/question 1 continued

(e) The following data were obtained as part of a study of the structure-activity
relationship in morphine. Explain the effect of the different substituents on log P and
the relative activity shown in the table.

Substituent at Substituent at Log P Relative activity

3 position 6 position
Morphine - OH - OH 0.89 1
Codeine - OMe - OH 1.19 0.2, injected peripherally
0.01, direct into brain
Heroin - OAc - OAc 1.58 2
6-Acetyl - OH - OAc 1.2 4
morphine
Levorphanol - OH -H 3.11 5
[40%]

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2. Answer ALL parts (a) to (c).

A small molecule has been shown to inhibit an enzyme in an uncompetitive manner.

(a) Describe how this small molecule interacts with and inhibits the enzyme. Use a
scheme including enzyme, substrate and inhibitor to illustrate your answer. Also use
a cartoon showing how the molecules interact. [50%]

(b) What impact does an uncompetitive inhibitor have on kcat and Km? Explain why
it has these effects. [30%]

(c) The IC50 and Ki are not the same, but can have the same value when the
substrate concentration is either well above or well below the Km for the substrate,
depending on the mode of inhibition. At what substrate concentration, high or low,
are the values of IC50 and Ki the same with an uncompetitive inhibitor? Explain your
answer. [20%]

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3. Answer ALL parts (a) to (d).

(a) Discuss why alkylating the bases of DNA provides a promising strategy for the
development of antitumour drugs. Why is the ability to ‘switch on’ this reactivity helpful
in developing a possible medicine based on DNA-alkylation chemistry? [10%]

(b) Explain how the DNA base adenine 1 pairs with thiamine 2, and sketch these
hydrogen bonding interactions between adenine and thiamine.

[10%]

(c) Some natural products are toxic because they contain organic functionality
that can alkylate DNA but lack the ‘switch’ discussed in (a). Give an example and
name the reactive functionality. [15%]

(d) Duocarmycin SA (3, (+)-DSA) is a promising lead compound for the

development of analogues that apply the DNA-alkylation strategy because it is only
active in the presence of DNA. When ‘switched on,’ DSA alkylates N3 of adenine 1.

(i) Identify the electrophilic centre of (+)-DSA involved in DNA alkylation,

and explain how the enone present in the structure of this natural product
helps to provide the required level of reactivity for the reaction with adenine
when in the ‘on’ state. [15%]
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…/question 3 continued

(ii) Draw a curly arrow mechanism to illustrate this

alkylation reaction, and draw the product (the rest of the DNA strand can be
omitted as in 1). [15%]

(iii) The amide and vinylogous amide functionality in

(+)-DSA provides the basis for the switching capability. Explain, with the aid of
diagrams, how this works mechanistically. [35%]

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4. Answer ALL parts (a) to (c). Include appropriate diagrams to support your
answers.

(a) What are the principal functions of DNA topoisomerases in cells? [25%]

(b) How do type I and type II enzymes differ mechanistically? [30%]

(c) Explain in detail, with examples, how quinolone antibiotics work. [45%]

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5. Answer ALL parts (a) to (c).

The fungal natural product rubrosafarin is a polyketide derived from seven acetate
units, and is therefore a heptaketide. As shown in the figure below, the heptaketide
precursor can adopt two possible folding patterns A and B that could lead to the
final structure. Using 13C2 sodium acetate feeding experiments and 13C-NMR analysis
of purified rubrosafarin, the incorporation pattern shown in bold was determined.
(Note: a bold bond indicates that this unit is derived from an intact unit of acetate;
ACP = acyl carrier protein).

(a) Redraw each of the folded heptaketides and circle the intact acetate units. Use
this information to determine which of A or B is the correct folding pattern. [20%]

(b) During the first round of chain elongation in fatty acid biosynthesis, the
3R-hydroxybutyryl-ACP intermediate is dehydrated in a stereospecific manner to give
trans-crotonyl-ACP. This reaction is catalysed by the enzyme β–hydroxyacyl
dehydratase (DH). The dehydration step occurs with stereospecific removal of the
pro-R hydrogen from C2 by an elimination mechanism that is thought to proceed
through an enolate intermediate.

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question 5 continues…/

Redraw the figure below, and complete the reaction scheme by drawing curly arrows
to show the movement of electrons during each step of the reaction sequence. Draw
the product trans-crotonyl-ACP by replacing the R group with the appropriate
structure.

[40%]

(c) The final step of fatty acid biosynthesis involves release of the fatty acid from
the ACP. This is catalysed by a thioesterase (TE).

Using curly arrows suggest a mechanism for the thioesterase-catalysed release of

palmitic acid from palmitoyl-S-ACP, showing clearly how the product carboxylic acid
is released and the catalyst regenerated. [40%]

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6. Answer ALL parts (a) to (d).

(a) Give a definition of each of the following:

(i) Chemotherapy
(ii) Antibiotic
(iii) Bacteriostatic agent [15%]

(b) The development of safe and efficient pharmaceuticals is very important. The
Therapeutic Index or T.I. is used as a measure of how safe a pharmaceutical is.

(i) What is the formula that defines the Therapeutic Index?

(ii) What numerical value of Therapeutic Index is associated with a safe
pharmaceutical? [20%]

(c) Prontosil, a sulfonamide derivative with the structure shown below, is inactive
against microorganisms in vitro, but shows activity in vivo. Explain why this is so and
draw the structure of the active compound derived from Prontosil.

[20%]
(d) Using the reagents indicated in the synthesis of the sulfonamide shown below,
identify and draw the structures of compounds X and Y. Your answer should make
FULL use of all the reagents, show mechanistic detail, and use ‘curly arrows’

[45%]
END OF PAPER

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