Medchem563_Exam1_2009 - Medicinal Chemistry 563P-502 I(18...

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Unformatted text preview: Medicinal Chemistry 563P-502 I. (18) Hour Examination II. (26) February 4, 2009 III. (16) A} IV. [a W (40) Write neatly. Confine your answers to the space provided. TOTAL (100) I. (18 points) A. (12 points) One of the major metabolites of norepinephrine is the structure shown. Write a chemical mechanism that accounts for its formation. Chemical intermediates, probable enzymes, mechanisms and arrow pushing is expected. '1 0‘“ 0‘1 9 OH OH \ z; I; I Hm cH-chiZNAa at"; ) W“ HO (,HCHZNHZ E3C CH/ ‘ / l~ i”. 1“? /LHI—.d2 U _+ EU 3:31 H, u ‘ A ‘ HO HO , 1A 9 l a z t . R A a vet _, '; 14w ,_ ~----‘;;fi:v 7;" a» ’w p ; ‘ . i F9“ 0"" ’1‘ "’0’; r9 tgd at at at; ol-k- («e on y; ' ~ 1 \ rift? M, ‘ i H “pm I """fl _4 (4‘1 w ark “0 LM\ 1 M A ‘5 /L' “C ~ . 3‘ ~40 w ,utsa... o a We? a“ a a e— m» i; g §lt3 \ ‘_ Hay ~ I ’3 ‘ n H D ~40” H «o “r 0‘4 sex mp nits 3’ t <atwfl “fi“” 4 f 6) “3H , «I 1 0 . J“ W in ‘1/ +14%? MM“ “SWAT; 2” {134:3 Ar: \ a. ’ ‘9 L M. " > ‘_ ” \Q/ 14' ~l~ NH 3 ' . \fi \ ‘ ; H0 ‘1 ‘5 g ' l H a H y a K“ My / «w» “to: s has - ,, - ,3. B3 (6 points) Aromatic hydroxylation of propranolol in vivo produces several potentially important metabolites, the most prominent being 4'-hydroxypropranolol. Write a rational chemical mechanism for its formation accounting for retention of about 60% of deuterium from 4'—deuterium labeled propranolol. ‘ . OH LYDLJSQ Eh; c1 mash: "‘ $4.. at a wax!" " my 6“\“3°‘ 3 I! “A “‘5” l 1 v t R = CHZCHCHZNHCH(CH3)Z LAVUUL. a M5 Ch wmac‘ii v m M \QITEJQ <31“? {7! OR OR in vivo E/ ——> I , ‘\ , D D OH t» 17""JQO a E O E / M 1 7.9.1.1. /_, AM E V. / \t _ ~€>PTfi *9 :‘ut W\ («\E >- i N at $1,, AK?” , DCH ‘ 19‘ 1) 19:5th II. (26 points) A. (8 points) Pyridoxal phosphate serves as a cofactor in the enzymatic decarboxylation of DOPA to dopamine. Given the initial imine, write a chemical mechanism, with intermediates and arrow pushing for formation of dopamine. /. 0 8H 90 H k“ *- s‘vle -—O—CH2 \ 0H .ermekt ~ l c, DOPA \N CH @A 3 HO \_ ’ Z CH — ’ dopamine + B. (18 points) For each, in two sentences (less than fifty words) explain why the following are potentially useful targets for development of drugs. 1. Inhibitors of COMT (catechol—O—methyl transferase) c 0 m2, gent:sz to. minimise M‘ ma M»; scam; @3wa omfiw‘» g o ail-Laws rwmafi w ML-Laiaeukc. {MgXx‘xIast (4:: Mfg, (ngmémimnli‘w Mu no ’H‘a wfiw vii-i US soLW a $4. 6?: who 0 M... / M c r QQEW‘AC‘ dank-9.. dnww wail...“ sa QWMVC \a\‘ "L ‘E' Wax firwsz" 2”“‘2' Mi» Lo 0\ 3‘ Pm: \ O *3 +\~L &M«,¢."\fa w‘fi L 4“ 7.,z/a’5 44,453. wheeuu <3 0cm qasam‘vw awe, \Q‘s . 2. Inhibitors of y-secretase Kw 62.4: task»: it?» is ON 61.1.3va asso¢x‘q‘¥<ak cp‘“L’\« 0. La; may“. a Q . \ ‘ ' t a? l \ .lk-Lu: @ML$.MA_Atg~ uuxbfi J~A¢$cr~buh3 ‘\Y\I\Jl_ Q>£¢x$tavk O @— QMQ~¢\A« a I]! \\\l .C(~D M *4“; tLW¥C&M W 9 £- Qwfifi Cat. 1 x.) V So C‘ \ l 1— ;knactg,“ 9-D grww:..wefira-m is swam, SbraAéal Qu- ‘w‘zwmlv'fi A\zJ~z‘W5 ~w d j‘ a A L‘ .44. . {—CC \ u MC pk,” , 2‘ QAuboi“\.o\/\ 94 ' SQQV Sf.‘ 5 gm ( “13' J J ‘9 0“!“ I? ) M 6* #3, F5?“ vol-2.5. ( a“ .T 5. )v'fliaaéa \( V e 3. A gonists at the nicotinic a4l32 receptor in the brain. Mfifil r‘\‘(Lo“L"\UL\‘L (14294065: are, +\-—~ Mger‘ wQu-HWCL— :JE'bF‘ taraxwku Afioetnslé Mme. \ow \‘x..«_\re»:~_:\—\3a¢\&sk Qer- 4k». {reg M», 4m.“ Q ofi A\mewm_r\% ds‘guxsa, «Ml» fiwkk‘fi ufi‘ék'k‘m’t' III. (16 points) A. (8) Write partial structures for each of the following compounds that shows how they exist at the pH given. Also indicate the absolute stereochemistry of the chiral centers in the third compound. _ CHz-(IZHCOOH H H H H S HNvN 1% H 044:2: HO 3 H 4 0 H0 H [AH rlHCH3 W wilwyoi l SO3H t H7 ,4 fl at pH 7.4 a P véfiéwé‘ [wag ; ‘ CF“5 (9 —-‘ :0 L}) 30m It mines tum p 7"" L?) B. (8) Carbamylcholine is hydrolyzed by AChE about 107 times more slowly than is acetylcholine. Write a chemical mechanism that accounts for this observation. AChE (acetylcholinesterase) is a serine esterase, with a catalytic triad of serine, glutamate, and histidine amino acid side chains. 0 CHz‘R 0 H + /_____< “ HZN —C '0 —CH2 —CH2—N(CH3)3 HN R = —CH—C--o‘ _ ’ l carbamylcholine I D histidine +NH3 915‘ 0 ll 0 kl — (2"0—(44; 9 LI I0 -(L H g N I 3“ i +' H? '— glutamic acid 0”}? g .L E) + I HOH2C_R \l __> K- _> C H’ q - w} 43 serine _/ < < [5 KL/ ) o p i (9 rte-5 ~ 5 A» 0 w “2 "' a; ‘4’» B“ :4. a W. ‘2; 0 e <2 "I? e i ..0—c> R/+\ é 2? ED OvIO’G/ME’VH' IV. (40 points) Compare and contrast the expected pharmacological properties and, where possible, the therapeutic uses expected for members of each pair of compounds. Provide a rationale for why these differences are expected. Indicate what biological target is important to each. Complete sentences are expected. A thq H 0120qu and H3C /©\ 033$,A) ' _ H3C;NCH2 CHz—s—CHZ-CHZNHil—Nchg, ea Wot/MW / w‘iw‘e‘ [Awms 80W“ (Ffiiuzom 5ER/b. Jaw—Wig catwawmgw f‘z— VJ. 9/9. aficLVé / fl "a"! t’rahgfiada¢é / . . QW'WZSQMW Wain/WM- B. HO OH @3014 and OCHZCIHCHZNHCH(CH3)2 . CHZNHC(CH3)3 “71¢ 4/4746” HO . t WG- ‘ 4 M“ W A —WK , N';é6“'M ( “W” ~ M magma gW~J-WW WM flMWMW-téj C. H3CO / l B" I: GN/CH3 O and HC’N+ H3CO \ H‘m "1CHZ-CI—iZli-o-CHz-CH2 H2 3 $ $5 H3CO / H2 _ 0~ 2Br a i mmmmmf» A l . kwMW \ t ‘W W “" W%Wum4¢»«%’ 4“” ‘ WW W» Wmuéfidh T ~414 aaabwdbt%wwwmfl} jbflfliawg w" ‘ “fife” flamm— W WW ' I , W W’k/ W m :, ~ ,gag/IaW Mmfl/M / WMWWWMX (WW CH3 (|)| d H CH C0 + an 3 2 >13 —s—CH2 -CH2 —N(CH3)3 H3C/ T U ‘CH3 H3CH2CO I N - I . A \- " A’ If“ — A arm/21% [WXWJ . W- a A W H OH CH —CH—NHCH HO and Q 2 I 3 ' CHZNHZ CH3 W H0 v . - M‘ . . WWW? W“ /M 23;? %% WW. M ...
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Medchem563_Exam1_2009 - Medicinal Chemistry 563P-502 I(18...

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