Synthesis and evaluation of analogues of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine as inhibitors of tumor cell growth, trypanosomal growth, and HIV-1 infectivity.
A well-defined series of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine analogues was designed and synthesized in order to further ascertain the optimal structural requirements for S-adenosylmethionine decarboxylase inhibition and potentially to augment and perhaps separate their antiproliferative and antitrypanosomal activities. Most structural modifications had a deleterious affect on both the antitrypanosomal and antineoplastic activity of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine. However, di-O-acetylation of the parent compound produced a potential prodrug that caused markedly pronounced inhibition of trypanosomal and neoplastic cell growth and viability. Moreover, the acetylated derivative of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine did inhibit HIV-1 growth and infectivity, whereas the parent compound did not.
Marasco
Canio J
CJ
Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Kramer
Debora L
DL
Miller
John
J
Porter
Carl W
CW
Bacchi
Cyrus J
CJ
Rattendi
Donna
D
Kucera
Louis
L
Iyer
Nathan
N
Bernacki
Ralph
R
Pera
Paula
P
Sufrin
Janice R
JR
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D014344:Trypanocidal Agents; C065859:MDL 73811; D012437:Adenosylmethionine Decarboxylase