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Western SOS Organic Chemistry 2223b

Western SOS Organic Chemistry 2223b. Moti Gulersen HBMSc mgulerse@uwo.ca Physiology Pharmacology/Toxicology. Metabolism of Glucose. Key Reactions…page 76. adding a phosphate to glucose Add: sugar = nucleophile, ATP = electrophile Remove: sugar = electrophile, ADP = nucleophile

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Western SOS Organic Chemistry 2223b

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  1. Western SOSOrganic Chemistry 2223b Moti Gulersen HBMSc mgulerse@uwo.ca Physiology Pharmacology/Toxicology

  2. Metabolism of Glucose

  3. Key Reactions…page 76 • adding a phosphate to glucose • Add: sugar = nucleophile, ATP = electrophile • Remove: sugar = electrophile, ADP = nucleophile • isomerization • base takes alpha-hydrogen • aldolase (retro-aldol; iminium ion in animals) • NADH = hydride donor (nucleophilic addition) • mutase – transferring functional groups • enolase = E2

  4. More info • Pyruvate dehydrogenase complex • why TPP? …decarboxylation • attack lipoic acid, removal of TPP • conversion to acetyl CoA via NAS • reduced lipoic acid oxidized back via FAD (remember NAD+?)

  5. More info • Aminotransferase reactions • PLP = amino-group carrier (usually bound to enzyme) • alpha-amino acid replaces enzyme, imine position switches • return hydrogen to “PLP” • hydrolysis of imine to make transfer • Practice questions • 49, 50, 51 • remember what nucleophile, electrophile

  6. Lipids:The Big Kahuna

  7. Start • Hydrolysis of ester in glycerol • acid = catalysis, base = completion • Cis vs. trans fatty acids • In lab prep of FA • CLAISEN CONDENSATION = aldol with esters • 1. attack of enolate to form beta-ketoester • 2. reduce/dehydrate/reduce • Can we do this in the body? Yes, but… • need modified claisen-type • diffusion problem • need bioreagents to reduce/dehydrate/reduce

  8. Biosynthesis • Modified claisen condensation • Thioesters instead of oxygen ester (why?) • Carbanion equivalents (malonyl thioester) • Concomitant attack (sound familiar? chymotrypsin) • Where does malonyl thioester come from? Biotin-dependant carboxylation • ATP phosphorylates HCO3- to form carboxyphosphate • Biotin attacks carboxyphosphate to make carboxybiotin • Thioester attacks carboxybiotin • Diffusion problem • Use FAS (ACP = acyl carrier protein, flexible) • Know what is E, Nu and malonyl always attached to ACP

  9. Biosynthesis • Reduction/dehydration agents • Reduction = NADPH, michael addition • Dehydration = base from enzyme • What do you need to elongate an existing fatty acid chain by 2 carbons? • Catabolism of Triglycerides • Hydrolysis via lipase • Phosphorylation and oxidation of Glycerol • Beta-oxidation of FA’s • Reverse of fatty acid synthesis BUT FAD used instead of NADPH to make C=C • Cysteine residue to “cleave”

  10. More info • Soap = metal salts of fatty acids (forms micelle) • Detergents = sulfonates or monoesters of sulfate, why? • Alkyl benzyl sulfonates • Formation of alkyl tail (electrophilic addition) • Attachment of tail to benzene (EAS) • Sulfonation at para position (EAS), why? • ***EDG vs. EWG***

  11. More info • Additives (phophate chelates) • Waxes = monoesters of long-chain alcohols and fatty acids • Phospholipids = glycerol esterified to two fatty acids and phosphate (various heads) • Prostaglandins = oxidation of arachadonic acid via cox-2 • inflammation • Leukotrienes = oxidation of arachadonic acid via 5-lipoxygenase • release in response to allergens • know inhibitors

  12. Terpenes • Head-to-tail linkage until 30 and 40 carbons • Count carbons and see if divisible by 5, every terpene has tertiary carbon • Biosynthesis • DMA-OPP (electrophile) vs. IPP-OPP (nucleophile) • makes geranyl-OPP  other monoterpenes derived or can elongate up until C20

  13. Origin of DMA-OPP and IPP-OPP • Aldol reaction between acetoacetyl thioester and acetyl thioester • Once that is completed, need to: • Lose carbon • Reduce tail and phosphorylate • OH on neck needs removal • Double bond between neck and head • 1. H2O/enzyme • 2. reduce twice using NADH to form mevalonic acid • 3. 3 ATP • 4. decarboxylation • Equals IPP-OPP, what about DMA-OPP? (isomerization)

  14. More info • Steroids = three 6-membered rings and one five-membered ring • Biosynthesis of Lanosterol • Oxidation of squalene sets of cascade • Hydride shift • Fat-soluble vitamins • Vitamin A (retinol)  light absorption • Vitamin E, K, D

  15. Practice Problems • 4, 7, 9, 10*, 11, 17, 23, 25, 26, 30, 35, 38, 45

  16. Nucleic Acids

  17. The good… • Purine (N9) vs. Pyrimidines (N1), tautomerism • Nucleosides vs. Nucleotides • Major groove vs. Minor groove • PCR • melt, anneal, elongate (add at 3’ OH) = 2x • Chain termination • adding labelled ddNTP without 3’ OH • radioactive ddNTPs vs. fluorescent ddNTPs • be careful with 3’5’, 5’3 • Pyrosequencing

  18. The tough…page 33 • Chemical synthesis of nucleic acids • 5’ OH protecting group = DMT • 3’ OH protecting group = polymer (remember?) • 1. coupling reaction • acid catalyzed (tetrazole) • 5’ OH = nucleophile • Phosphoramidite = electrophile • 2. Iodine (make P better electrophile, add H2O) • 3. TCA • remove CN (E2) and polymer using NH4OH

  19. Some more info • UV damage (C > B > A) • Carcinogens (benzene, PAH’s oxidized to epoxide then bind DNA) • Practice problems • 10, 11, 13, 14, 15 • know mechanisms, sequencing techniques (differences)

  20. Pharmaceutical Drugs

  21. Development • Find NME • Nautral, SARS, SGDD, HTS • Patent • Preclinical trials (ADMET + in vitro) • IND for FDA approval • Clinical trials (Phase I, II, III) • I = healthy, II = sick; short-term , III = doctor’s office; long-term • NDA for FDA approval • Marketing, post surveillance (Phase IV)

  22. Sulfanilamide • Prodrug • Inhibition of biosynthesis • pteridine derivative (activate first) to PABA = SN2 • Glutamic acid to carboxylate (activate first) = nucleophilic acyl substitution • Where does Sulfa come in? • Sulfa = PABA • Importance of pKa • to be or not to be (ionized)? Optimal = 6

  23. Some more info • Using light and chromophores for tissue destruction • PUVA (psoralens excite and cross-link) vs. PDT (photosensitizers excite and reaction with triplet O2 to form singlet) • Advantages/disadvantages of photofrin • Practice problems • 3, 6, 9, 14, 15

  24. Practice Exam Questions

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