You must answer FOUR of the SIX questions. Use a SEPARATE answer book for EACH question.

Transcription

1 UIVERSITY F EAST AGLIA School of Pharmacy Main Series UG Examination DRUG DESIG AD MECHAISMS F DRUG ACTI PHA-5001Y Time allowed: 2 hours You must answer FUR of the SIX questions. Use a SEPARATE answer book for EACH question. This paper consists of 8 pages in total. Dictionaries are not permitted in this examination. otes are not permitted in this examination. Do not turn over until you are told to do so by the Invigilator. Do not take this question paper out of the examinations room. (PHA-5001Y) Module Contact: Dr Susan Matthews, PHA Copyright of the University of East Anglia Version 2

2 2 1. Answer ALL parts to (e). AZT is an antimetabolite drug used in the treatment of HIV. You are part of a drug development team involved in the development of AZT and improved analogues. AZT Explain, with the aid of diagrams, how AZT works. [30%] As part of a Quality Control (QC) process, you take an infrared (IR) spectrum of AZT. State the position of FUR key bands you would expect to see in the spectrum. For each band identify the responsible functional group. [20%] Using IR, would you be able to tell the difference between AZT and the natural equivalent nucleoside? Explain your answer. [15%] (d) Draw the structures of TW analogues of AZT you would expect to have the same mode of action. Justify your answer. [20%] (e) Your analogues go into Phase I clinical trials. Briefly explain what happens in these types of trials and their purpose. [15%]

3 3 2. Answer ALL parts to. rnithine decarboxylase catalyses the enzymatic conversion of ornithine to putrescine. -Methyl ornithine A is an inhibitor of this enzyme. Use the data provided in Table 1 to predict what type of enzyme inhibitor α-methyl ornithine A is. Fully explain your answer. [30%] Predict and draw the proton nuclear magnetic resonance (MR) spectra of ornithine and putrescine. Explain how differences between these two spectra could be used to monitor the ornithine decarboxylase catalysed reaction by proton MR spectroscopy. [50%] Which of the compounds B to E would be the best candidate to explore as another inhibitor that can act in the same way as α-methyl ornithine A. Explain your answer. [20%] TUR VER

4 4 3 Answer ALL parts to (d). The p53/mdm2 protein-protein interaction (PPI) is the most widely studied to date. Discuss the advantages and disadvantages of targeting PPIs when designing new drugs. [40%] Describe in detail, with the aid of diagrams, the p53/mdm2 PPI and the role it plays in cancer. [40%] Shown below is a molecule that has been found to inhibit the p53/mdm2 PPI. Suggest five possible interactions that compound A could have with the p53 and MDM2 proteins. [10%] (d) You are asked to make analogues of compound A that have a lower LogP. Using the Craig plot below suggest two such analogues that could be made by changing the methoxy group in compound A. Fully explain the alterations you have suggested. [10%]

5 5 4. Answer ALL parts to (d). You have been given the leaves of an Amazonian tree that has been used for many years to generate a herbal medicine by the indigenous people to treat cancer. Describe the steps you would take to isolate natural products from the medicine using a cancer activity-guided approach. [30%] This approach leads to the isolation of a natural product that has the following structure: It is an analogue of phloroacetophenone, derived from the polyketide biosynthetic pathway. Draw the biosynthetic pathway that leads to phloroacetophenone. [40%] Draw a sketch of the aromatic region of the 1 H MR spectrum for the natural product. Explain the reasoning behind your answer. [10%] (d) CYP-mediated metabolism of the natural product leads to the following product: (i) Give a brief mechanism of the CYP-mediated metabolism. [15%] (ii) How would this change affect the 1 H MR spectrum of the aromatic region? [5%] TUR VER

6 6 5. Answer ALL parts to (d). Loratadine is an inverse agonist of peripheral histamine H1-receptors. Et loratadine Describe the physiological response produced by the following ligands binding to a receptor. (i) (ii) An agonist An antagonist (iii) An inverse agonist [15%] A step from the synthesis of loratadine is shown below. Provide reagents and reaction conditions for this transformation. H t-bu H t-bu [20%] Question 5 continues

7 7 question 5 continued. A later step in the loratadine synthesis is the cyclization shown below. HF (i) Describe how you would monitor this reaction by IR spectroscopy. [10%] (ii) Provide a reaction mechanism using curly arrows for the cyclisation, including an explanation of why the reaction gives rise to a single product. [35%] (d) Loratadine is largely converted in the body (in vivo) to a major metabolite. Identify the structure of the metabolite and discuss whether the metabolism is beneficial or not in avoiding CS side effects. metabolism? MW 311 Et loratadine MW 383 [20%] TUR VER

8 8 6. Answer ALL parts to (d). Symplostatin A is a natural product that shows promising antimalarial activity. Provide a general mechanism for the hydrolysis of a peptide by a protease enzyme. [30%] It is thought that symplostatin A covalently inhibits malarial cysteine proteases. Provide a mechanism for the reaction of symplostatin A with the thiolate anion of a cysteine residue (see example below) to bring about covalent inhibition. [30%] Shown below is the major metabolite of symplostatin A. Based on the observation that this is the major metabolite of symplostatin A suggest an analogue of symplostatin A that will have a longer half-life in vivo. Fully explain your answer. [20%] (d) Suggest TW other metabolic conversions that could occur for symplostatin A. As part of your answer, draw the structure of the metabolites that would result from the conversion you have suggested. [20%] ED F PAPER