Medicinal Chemistry 562P Final Exam: Atkins, Rettie December 12, Part I, Atkins (18 pts)

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1 Medicinal Chemistry 562P Final Exam: Atkins, Rettie December 12, 2012 Part I, Atkins (18 pts) IA. 10 pts. For each statement indicate true or false. Please write the entire word. The Upper Level value (UL) is the dose of a vitamin that yields a toxic response in 50% of patients that receive it. The RDI for a vitamin is approximately 1.2 X (Estimated average requirement). Vitamin B6 is a water soluble vitamin that has no defined UL. All water soluble vitamins are unstable to heat used for cooking. The Daily Value (DV) for water soluble vitamins is always greater than the EAR. IB. 8 pts. The drug laropiprant is used in combination with high dose iacin (Tredaptive TM ) to raise HDL and lower LDL. Laropiprant is an antagonist of Prostaglandin D2 and Prostaglandin D3. Based on your knowledge of iacin s effects, what is a possible therapeutic strategy for using the combination? What other drug might be useful in combination with iacin used to control serum lipid profiles?

2 Part IC (18 pts) Rettie 1. (2 pts) Fill in the blanks. Etretinate (shown below) was a generation retinoid used to treat severe. C 2 H 5 CH 3 2. (5 pts) Etretinate, which has an unusually long half- life of 3 months, was removed from the market in Explain fully why it is no longer available and identify the active metabolite of the drug that replaced it. 3. (5 pts) Vitamin E can effectively quench lipid peroxyl radicals (R. ), in part, because of resonance stabilization. Draw the structure of the quenched lipid peroxyl radical and the resonance structures of the resulting vitamin E radical (show arrow pushing). CH 3 H 3 C H CH 3 R + R. à CH 3 4. (6 pts) Identify the three major (general) causes of vitamin deficiency and give a specific example of a group of people at risk for each one.

3 Medicinal Chemistry 562P Final Exam: Atkins, Rettie December 12, 2012 MULTIPLE CHICE QUESTIS - USE SCATR 62 points total

4 USE SCATR for Part II of Atkins and Rettie. IIA, Atkins. 32 pts. For each statement or description write the letter of the appropriate response. ne letter for each. 1. The vitamin deficiency associated with Pellagra is: A. iacin B. Pyridoxal C. Ascorbic Acid D. Thiamine 2. Which of the following is T supported by pyridoxal- or pyridoxamine- dependent enzymes? A. xidative decarboxylation B. Carboxylation of lipid precursors. C. β- elimination from amino acids. D. Racemization of amino acids. 3. Thiamin pyrophosphate is: A. Required to avoid getting pernicious anemia. B. Is used catalyze methyl transfer reactions. C. Is linked to polyglutamyl chains in vegetables. D. Is used exclusively for carbohydrate metabolism. 4. Leucovorin is used as a source of folate in patients on Methotrexate. Leucovorin: A. Is converted to 5, 10- methenyl THFA and provides a source of carbon used in purine and pyrimidine synthesis. B. Inhibits dihydrofolate reductase by forming a covalent adduct with it. C. Is used in combination with Vitamin B6 to lower homocysteine, which results in increased folate production. D. Inhibits thymidylate synthetase, which is required for synthesis of dtmp. 5. Vitamin B12: A. Includes in its structure a Mn +2 ion within a porphyrin ring. B. Is used for methyl transfer reactions and mutase reactions. C. Is found in high concentrations in citrus fruit. D. Contains a pyridine ring that acts as an electron sink. 6. Dehydroascorbic acid:

5 A. Is the reduced form of Vitamin C B. Is a chemical reductant for ferric iron in the diet. C. Acts as a radical scavenger and antioxidant. D. Is metabolized to oxalic acid, which is suggested to contribute to kidney stone formation. 7. Which of the following is not true about riboflavin? A. It is converted to FAD/FADH2 or FM/FMH2 after absorption. B. Responsible for intense yellow color of urine from patients on high dose vitamin B complex. C. Has some efficacy as a mosquito repellent. D. In its cofactor form it is critical for oxidation reduction reactions. 8. Biotin, or Vitamin B7, is: A. Effective in the treatment of brittle nails. B. A cofactor used in the recycling of folate metabolites to tetrahydrafolate. C. An antioxidant that scavenges free radicals. D. Effective in preventing hair loss. 9. In the conversion of an amino acid to the corresponding α- keto acid by Vitamin B6- dependent enzymes (transamination): A. The initial internal Schiff s base formed between co- factor and substrate is converted to an external Schiff s base, allowing for attack of water on the α- carbon of the amino acid. B. The Schiff base formed between the PLP co- factor and the enzyme is retained for the duration of the reaction. C. The initial external Schiff s base formed between co- factor and substrate is converted to an internal Schiff s base, allowing for attack of water on the α- carbon of the amino acid. D. The co- factor is first dephosphorylated by the enzyme, before forming a Schiff s base with the substrate. 10. Thiamin: A. Is used by enzymes for transfer of 3- carbon units between intermediates in the TCA cycle. B. Utilizes a urea group to stabilize the hydroxy- ethyl TPP intermediate used in several enzymatic reactions. C. Has some efficacy in some patients as a mosquito repellent if used for several days or weeks. D. Is required as a supplement in patients on isoniazid because the vitamin is inactivated via formation of adducts with the drug.

6 11. Which vitamer below will form a Schiff s base with an amino group in the active site of an enzyme. If none, write none. H H 2 H H P - H C H H 2 H H H P P - - A B C D. 12. Which form of riboflavin flavin below would be used by an enzyme to reduce fumaric acid to succinic acid, where R = the ribosyl adenine dinucleotide or mononucleotide. H C 2 H H H R R A. B. C. H Co H Fumaric acid D. propanol amine benzimidazole ribose Succinic acid

7 13. Which combination below is most likely to lower serum homocysteine levels? A. Vitamin C, iacin, and Vitamin B12. B. iacin, Biotin, and Vitamin B6 C. Vitamin B6, Vitamin B12, and Vitamin B1 D. iacin, Vitamin B6 and Vitamin B Which syndrome, condition or disease below is highly responsive to thiamin supplementation? A. Scurvy B. Alzheimer s disease C. Alcoholism D. Tuberculosis 15. Which of the following is T true for Vitamin C? A. It contains a chiral center and one stereoisomer promotes neural tube development. B. Used by Dopamine β- hydroxylase for the synthesis of norepinephrine. C. Used by proline hydroxylase for formation of collagen. D. Although data do not support the claim that it prevents the common cold, it may decrease the duration and intensity of a cold. 16. Which of the following has shown efficacy in the treatment of migraine headaches? A. Combinations of iacin, Vitamin B6, and Vitamin B12. B. Vitamin C. C. Riboflavin. D. Biotin.

8 IIB, Rettie, 30 pts. For each statement or description write the letter of the appropriate response. ne letter for each. 17. Which of the following is True about the fat- soluble vitamins? a) a deficiency state is rapidly brought on by poor diet, b) some can accumulate to toxic levels in the body, c) supplementation is necessary for much of the population, d) they serve as coenzymes for energy producing reactions. 18. Which of the following is False about Vitamin A? a) opsin binds trans- retinol reversibly via a Schiff base mechanism, b) night blindness results from depleted stores of retinyl palmitate in RPE cells, c) high intake is associated with increased risk for bone fractures, d) supplements usually provide pre- formed vitamin A as the acetate ester. 19. Pharmacologically active retinoids and carotenoids contain an intact; a) chromanol ring, b) β- ionone ring, c) naphthoquinone ring, d) sterol ring 20. Retinal is converted to retinoic acid by: a) ADH enzymes, b) ALDH enzymes, c) AKR enzymes, d) 15, 15 - dioxygenase. 21. The carotenoid, lycopene has been associated with benefit in preventing; a) hypercarotenosis b) macular degeneration c) prostate cancer d) Alzheimer s disease. 22. The kidney CYP27B1 enzyme carries out the following reaction on the vitamin D nucleus: a) 27- hydroxylation, b) 25- hydroxylation, c) 24- hydroxylation, d) 1- hydroxylation. 23. The D3- related compound shown below is; a) pre- vitamin D3, b) pro- vitamin D3, c) the circulating form of D3, d) the active hormone.

9 H H 24. The DV and UL for vitamin D are, respectively,: a) 30 and 400 IU, b) 400 and 4000 IU, c) 2000 and 5000 IU, d) 5000 and 10,000 IU. 25. The vitamin K co- enzyme directly participating in the gamma carboxylation of clotting factors is: a) phylloquinone, b) vitamin K hydroquinone, c) vitamin K quinone, c) d) vitamin K epoxide. 26. K1 is given routinely at birth the prevent neonatal hemorrhage because: a) breast milk is low in vitamin K, b) the gut is sterile at birth, c) placental transmission of vit K is low, d) all of the above. 27. nly 2R- alpha- tocopherols satisfy the body s requirement for vitamin E because all other forms exhibit; a) poor absorption, b) poor excretion, c) poor liver transport, d) poor protein binding. 28. Which of the following is False about vitamin E? a) α-, β-, γ- and δ- tocopherol have equivalent antioxidant potencies, b) It is a chain- breaking free radical scavenger, c) bleeding can be an adverse effect, d) deficiency causes neurological problems in humans. 29. xygen is reduced to water in four one- electron addition steps that involve formation of several RS (reactive oxygen species) according to the scheme below. 2 X Y Z H 2

10 Glutathione peroxidase and catalase both scavenge; a) X, b) Y, c) Z, d) none of the above 30. Riboflavin helps to reduce the damage caused by free radical reactions because; a) glutathione peroxidase requires ADPH, b) glutathione reductase requires ADPH, c) glutathione peroxidase requires FAD, d) glutathione reductase requires FAD. 31. Selenium has an important antioxidant role because it is a constituent of: a) glucose- 6- phosphate dehydrogenase, b) superoxide dismutase, c) glutathione reductase, d) glutathione peroxidase.