Module Contact: Dr Paul McDermott, PHA Copyright of the University of East Anglia Version 1

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1 UIVERSITY F EAST AGLIA School of Pharmacy Main Series UG Examination LIFE SCIECES CHEMISTRY PHA-1ECY Time allowed: 2 hours You must answer FUR (4) of the SIX (6) questions. Use a SEPARATE answer book for EACH question. This paper consists of 10 pages in total. Dictionaries are not permitted in this examination. otes are not permitted in this examination. Do not take this question paper out of the examinations room. Do not turn over until you are told to do so by the Invigilator. PHA-1ECY Module Contact: Dr Paul McDermott, PHA Copyright of the University of East Anglia Version 1

2 Page 2 1 Answer ALL parts:,, (c), and (e). The aflatoxins are amongst the most carcinogenic compounds known to man. It is thought that the toxicity of the aflatoxins is due to the generation of epoxide metabolites that alkylate DA. Assign the configuration of both of the chiral centres in aflatoxin B1. Fully explain how you have assigned the configurations. (c) Draw ALL of the possible stereoisomers that can exist for aflatoxin B1 and describe the stereochemical relationship between EACH of the compounds you have drawn. Fully explain your answer. If you had a crude sample of aflatoxin B1, you could assess its enantiomeric purity by comparing the specific rotation of your sample with a literature value. Fully explain how you would carry out this study. (e) Briefly describe a method by which you could chemically convert aflatoxin B1 to the carcinogenic epoxide. Shown below is the structure of a purine base that is found in DA as well as the structure of the carcinogenic epoxide. Redraw these structures in your answer book and suggest a mechanism by which the aflatoxin epoxide could alkylate the purine base. Fully explain your answer.

3 Page 3 2 Answer ALL parts,, (c), (e) and (f). Betamethasone 17-valerate is activated in the body by hydrolysis. It is a prodrug of betamethasone. (c) Fully explain the concept of a prodrug. Include in your answer FIVE (5) ways in which prodrugs can improve the pharmacokinetic profile of a drug molecule. Fully describe the hybridisation state and geometry of the two atoms in betamethasone that have been labelled A and B. Betamethasone is UV active. Redraw the structure of betamethasone in your answer book and highlight the part of the molecule that you think is the chromophore. Include in your answer the types of electronic transition that are possible for this chromophore. Triamcinolone acetonide is another prodrug of an anti-inflammatory adrenocorticoid that is activated by hydrolysis. Using the structure of triamcinolone acetonide that you have drawn in your answer book, highlight the functional group in this molecule that is susceptible to hydrolysis. [5%] question 2 continues on next page... TUR VER

4 Page 4...question 2 continued (e) (f) Provide a full curly arrow mechanism for the hydrolysis of this functional group, including all charges and structures for any intermediates. State what class of lipid betamethasone belongs to and then BRIEFLY describe TW (2) other classes of lipid. For both of the lipid classes that you describe include a representative structure and a biological role that these lipids perform. [15%]

5 Page 5 3 Answer ALL parts,, (c),, (e) and (f). What are the advantages of using aromatic molecules in drug design? Benzalacetone is an intermediate in the synthesis of warfarin. Provide a chemical mechanism for the reaction shown above, including curly arrows, charges and structures for all intermediates, and explain what is happening in each step. Shown below are two steps in the synthesis of the SAID ibuprofen (one of your top 25 drugs). (c) Briefly explain the regioselectivity observed in step 1. [5%] Provide a full curly arrow mechanism for step 1, including all charges and structures for any intermediates. (e) What type of reaction is shown in step 2? [5%] (f) Provide a full curly arrow mechanism for this reaction including all charges and structures for any intermediates. TUR VER

6 Page 6 4 Answer ALL parts,, (c),, (e) and (f). Below is a segment of RA. H 2 P P H H H 2 H H 2 P H Redraw the structure in your answer book and label the following: i. 5 -end ii. 3 -end iii. ucleotide iv. ucleoside v. Sugar vi. Phosphate vii. Parts of the structure which would not be found in DA [35%] (c) In basic conditions, RA is unstable. Draw a curly arrow mechanism for the internal hydrolysis of RA. Using the full name for each of the bases, state the sequence of this piece of RA.

7 Page 7 (e) (f) Using single letter abbreviations, state the sequence of this piece of RA. [5%] You are interested in taking an IR spectrum of this fragment of RA. State the position of FUR (4) main bands (and corresponding functional group bonds) you would expect to see in the spectrum of this sample. If you were to take an IR spectrum of an analogous sequence of DA, would you be able to tell the DA apart from the RA by IR spectroscopy? Explain your reasoning. TUR VER

8 Page 8 5 Answer ALL parts:,, (c),, (e) and (f). A reference table of amino acid structures is provided on the next page of this exam paper. Shown below is the structure of amoxicillin, a moderate spectrum antibiotic that it is one of your top 25 drugs. (c) State which is the most basic nitrogen in the structure of amoxicillin. Fully explain your answer. There are TW (2) acidic hydrogens in the structure of amoxicillin. Redraw the structure of amoxicillin in your answer book and highlight both of the acidic hydrogens and fully explain why each of these hydrogens is acidic. Many penicillins are not orally available because the cyclic amide functional group (the β-lactam) is easily hydrolysed under physiological conditions. Provide a full curly arrow mechanism including all charges and structures for any intermediates for the acid catalysed hydrolysis of the β-lactam ring of amoxicillin. Would the product of this reaction be more or less water soluble than amoxicillin? Fully explain your answer. The structure of amoxicillin resembles that of a peptide which allows it to be accepted into the active site of transpeptidase (an enzyme which crosslinks peptide chains to give the bacterial cell wall its strength). Ala-Glu-Lys-Ser (e) Draw the full structure of the peptide sequence shown above. (f) State the type of interaction each of the amino acid residues could have with the active site of an enzyme or protein.

9 Page 9 This is a list of the 20 common amino acids in humans. They have been arranged alphabetically to be used as a reference source. TUR VER

10 Page 10 6 Answer ALL parts:,, (c), and (e). The biosynthesis of glutamic acid from α-keto-glutaric acid is a vital reductive amination process because all other amino acids are made from glutamic acid via transamination. (c) (e) Briefly explain why reductive amination is a better method for secondary amine synthesis compared with the simple reaction of an alkyl halide with a primary amine. Provide a full curly arrow mechanism for the imine formation step, including all charges and structures for any intermediates. Suggest alternative chemical reagents that could be used to carry out the reduction step. For the reaction you have suggested provide a full curly arrow mechanism including all charges and structures for any intermediates. What would be the key difference between the reaction you have suggested and the enzymatic reduction shown above? [5%] What is the definition of a catabolic reaction? Provide examples of two different catabolic reaction pathways found in primary metabolism. [25%] ED F PAPER