Sugar-modified conjugated diene analogues of adenosine and uridine: synthesis, interaction with S-adenosyl-L-homocysteine hydrolase, and antiviral and cytostatic effects.
Moffatt oxidation of 2',3'-O-isopropylideneuridine (1a) and treatment of the crude 5'-aldehyde with formylmethylene-stabilized Wittig reagent gave the vinylogously extended 7'-aldehyde2a. Condensation of 2a with ethoxycarbonyl- or dibromomethylene phosphorane reagents gave the conjugated dienes 6a and 4a, respectively. Deacetonization gave diene ester 7a [5'(E),7'(E); with s-trans conformation] and dibromodiene 5a [5'(E)], respectively. Analogously, 2',3'-O-isopropylideneadenosine (1b) was Wittig-extended into the conjugated dibromodiene 5b [5'(E)] and dienoic ester 7b [5'(E),7'(E)]. Furthermore, palladium-catalyzed coupling of the vinyl 6'(E)-stannanes 14 with (E) and (Z) ethyl 3-iodoacrylate gave stereodefined access to dienoic esters 7 (E,E) and 16 (E,Z). Incubation of AdoHcy hydrolase with 100 microM of 5b resulted in partial inhibition of the enzyme without any apparent change in the enzyme's nicotinamide adenine dinucleoside (NAD(+)) content. In contrast, 7b and 16b produced time- and concentration-dependent inactivation of S-adenosyl-L-homocysteine (AdoHcy) hydrolase producing significant decreases in the enzyme's NAD(+) content. However, 7b and 16b upon incubation with AdoHcy hydrolase were not metabolized suggesting that these compounds are type I mechanism-based inhibitors. No specific antiviral activity was noted for 5a,b, 7a,b, and 16a,b against any of the viruses tested; dibromodiene 5b proved cytotoxic at a concentration > or =6.7 microM and cytostatic at > or =11 microM, while dienoic esters 16a,b showed activity against both varicella-zoster virus (at 10 microM, 16a) and cytomegalovirus (at 10 microM, 16a; 18 microM, 16b).
Wnuk
Stanislaw F
SF
Department of Chemistry, Florida International University, Miami, FL 33199, USA. wnuk@fiu.edu
Ro
Bong-Oh
BO
Valdez
Carlos A
CA
Lewandowska
Elzbieta
E
Valdez
Neida X
NX
Sacasa
Pablo R
PR
Yin
Dan
D
Zhang
Jinsong
J
Borchardt
Ronald T
RT
De Clercq
Erik
E
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000466:Alkadienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000466:Alkadienes; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D014529:Uridine