HCI Prelim CHEM

HWA CHONG INSTITUTION This question booklet consists of 15 printed pages C2 PRELI MINARY EXAMINATION CHEMISTRY 9812 HIGHER 3: PHARMACEUTICAL CHEMISTRY 24 September 2009 2 h 30 min Do not open this booklet until you are told to do so. INSTRUCTIONS TO CANDIDATES 1) This paper consists of 15 printed pages (including this page). You should have a Data Booklet, a cover page and a set of writing papers. 2) Answer any five questions. 3) Write your name and CT clearly on the cover page and on all the work you hand in. 3) Begin each question on a FRESH sheet of writing paper. A nil return is necessary for any unattempted question. 4) At the end of the examination, fasten your cover page securely together with your answer scripts. INFORMATION FOR CANDIDATES The number of marks is given in brackets [ ] at the end of each question or part question. A Data Booklet is provided. You may use a calculator. You are reminded of the need for good English and clear presentation in your answers.

2 C2 Chemistry H3 Prelim 2009 9812/01/HCI 1 Analgesic drugs are a diverse group of compounds that are capable of relieving pain. They can be classified into two categories, the narcotic and non-narcotic analgesics. (a) Narcotic and non-narcotic analgesics act differently to prevent pain. Briefly describe the differences in their modes of action. [2] (b) State two sources for which potential drug candidates may be identified. [2] (c) Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the class of non-narcotic analgesics. They include the following molecules: Cl CH3 CO2H CH3 H3C ibuprofen CO2H OCOCH3 aspirin N H3CO O CH3 CO2H indomethacin NSAIDs work by preventing arachidonic acid from binding to the active site of cyclooxygenase. CO2H CH3 arachidonic acid The active site of cyclooxygenase consists of the following amino acid residues: amino acid serine arginine tyrosine R-group –CH2OH NH CH2 OHNH2N H The different modes of action for NSAIDs involves: (1) covalent modification of the serine residue in cyclooxygenase (2) reversible inhibition at the substrate-binding site (3) competitive inhibition of cyclooxygenase via interactions with arginine and tyrosine (i) Assign the NSAIDs modes of action (1) – (3) to ibuprofen, aspirin and indomethacin and justify your answer. Each NSAID should only be used once. [4] (ii) SC−558 is also a type of NSAIDs. Copy the molecule onto your answer sheet and indicate on the diagram two different types of molecular interactions it can have with the amino acids at the cyclooxygenase active site. N NS O O H2N CF3 SC–558 [2]

3 C2 Chemistry H3 Prelim 2009 9812/01/HCI The ether group in indo methacin can be formed via a nucleophilic substitution reaction. (d) (i) Draw the precursor and state the reagents and conditions required for the reaction to take place. [2] (ii) Suggest whether this reaction takes place via a S N1 or S N2 reaction. Justify your answer. [2] (e) Morphine belongs to the class of narcotic analgesics. OHO OH H N CH3 morphine Copy the structure of morphine onto your paper and assign the R,S configuration about all the chiral carbon centres in morphine as well as the E,Z configuration about the double bond. [3] (f) In the search for an alternative analgesics drug, a dipeptide was chosen as a lead compound and modified to give compound A. CH3 H N H O CO2HHS A Draw the Fisher projections for all the possible stereoisomers and indicate their stereochemical relationships. [3] [Total: 20m]

4 C2 Chemistry H3 Prelim 2009 9812/01/HCI One problem faced wit h penicillin-G, a useful antibacterial drug, was that it tends to break down in acid due to the hydrolysis of the  -lactam ring. The general structure of penicillin is shown below. 2 (a) N S O N H O R H CO2H CH3 CH3 penicillin Pharmaceutical chemists have modified the R group side chain in semi-synthetic penicillins to make them more resistant to acid-catalysed hydrolysis. (i) The rates of hydrolysis of the -lactam ring in penicillin-G, and two other analogues A and B were measured and recorded. The R group of penicillin-G, A and B are shown below. H H N S O NR CH3 O R in CH3 CO2H penicillin-G CH2R = A CHR = Cl B CHR = CH2CH3 By considering the mechanism of the -lactam ring-opening process, arrange these 3 compounds in order of increasing rate of hydrolysis. Explain your answer clearly. [3] (ii) Sulfones, a class of antibacterial drugs, are also used in the treatment of leprosy. A structure-activity relationship study was done to test the efficacy of sulfones against leprosy. One of the molecules studied was sulfone C. N N H2N NH2 CH2 NHCH3 S O O C Propose a 3-step synthesis of C using the following molecules. N N H2N NH2 SH CH2Cl NHCH3 State any other reagents and conditions you would use for each step. [3]

5 C2 Chemistry H3 Prelim 2009 9812/01/HCI In a hypothetical case study, pharmacologists discovered a receptor involved in mediating cellular growth in the brain. The endogenous agonist of this receptor in normal cells was found to be compound I. Tumour cells also contain this endogenous agonist, but they were found to have an extremely high level of I. They bind to the receptors causing harmful physiological effects. (b) O HO OH I A series of five different analogues of I was synthesized and tested in an in vitro cell line assay. The size of the tumour growth was graded on a 10 point scale (1 being small and harmless; 10 being huge and invasive). All tumours used in the experiment started with a scale of 5. After the compounds were added and incubated for 2 weeks, the size of the individual tumours was graded. The table shows the result of the test with I and its analogues: compound scale compound scale O HO OH I 7 O II 5 OH III 7 HO OH H3C CH3 HO IV 9 V 5 O HO OH NH2 + VI 2 (i) Explain clearly how agonists and antagonists differ in their interactions with receptors. [2] (ii) Using the data given, deduce which compounds are acting as agonists and justify your answer. [1] (iii) Based on the data given, suggest the functional groups in I and the types of intermolecular forces involved in binding I to the receptor. [2]

6 C2 Chemistry H3 Prelim 2009 9812/01/HCI Analogues II and III can be differentiated using IR spectroscopy. (c) Suggest how infrared spectroscopy could be used to distinguish these two compounds. [1] (d) Compound III was also analyzed using 1H NMR spectroscopy. (i) Explain why TMS is suitable as a reference in 1H NMR spectroscopy. [1] (ii) The use of Data Booklet is relevant to this question. Sketch the NMR spectrum of III in the presence of CDC l3, indicating clearly the following:  number of signals in the spectrum  integral of each signal  splitting pattern of each signal [4] (iii) Account for the chemical shifts of the two most deshielded NMR signals in your sketch in (d)(ii). [2] (iv) Describe and explain how the NMR spectrum will differ from your sketch in (d)(ii) when the solvent is replaced with deuterated water. [1] [Total: 20 m]

7 C2 Chemistry H3 Prelim 2009 9812/01/HCI 3 (a) Viruses are a type of pathogen which account for about 60% of illnesses. (i) Give a reason why it is particularly difficult to design effective antiviral drugs. [1] (ii) Some antiviral drugs may be described as monoclonal antibodies . What do you understand by the terms in italics? [2] (iii) Vidarabine, an analogue of the nucleoside adenosine, is an intravenously administered antiviral drug active against herpes viruses. Some of its drawbacks include:  limited solubility at physiological pH  sus