| Record 10040 View: Standard | Glossary HistCite Guide |
|
Author(s): Wan JQ; Xia Y; Liu Y; Wang MH; Rocchi P; Yao JH; Qu FQ; Neyts J; Iovanna JL; Peng L
Title: Discovery of Novel Arylethynyltriazole Ribonucleosides with Selective and Effective Antiviral and Antiproliferative Activity
Source: JOURNAL OF MEDICINAL CHEMISTRY 52 (4): 1144-1155
Date: 2009 FEB 26
Document Type: Journal : Article
DOI:
Language: English
Comment:
Address: Univ Aix Marseille 2, Dept Chim, CNRS, CINaM,UPR 3118,UMR 3118, F-13288 Marseille 09, France.
Wuhan Univ, Coll Chem & Mol Sci, State Key Lab Virol, Wuhan 430072, Peoples R China. Chinese Acad Sci, Shanghai Inst Organ Chem, Dept Comp Chem & Cheminformat, Shanghai 200032, Peoples R China. INSERM, U624, F-13288 Marseille, France. Rega Inst, B-3000 Louvain, Belgium. Reprint: Peng, L, Univ Aix Marseille 2, Dept Chim, CNRS, CINaM,UPR 3118,UMR
3118, 163 Ave Luminy, F-13288 Marseille 09, France. E-mail: ling.peng@univmed.fr
Author Keywords:
KeyWords Plus: TOBACCO-MOSAIC-VIRUS; HEPATITIS-C; PANCREATIC-CANCER; BITRIAZOLYL
COMPOUNDS; IN-VITRO; RIBAVIRIN; ACYCLONUCLEOSIDES; 1-<(2-
HYDROXYETHOXY)METHYL>-6-(PHENYLTHIO)THYMINE; NUCLEOSIDES; ANALOGS
Abstract: Novel ethynyltriazole ribonucleosides were synthesized using a simple and efficient two-step procedure involving Sonogashira coupling and subsequent ammonolysis. Compounds 2f and 3o inhibited hepatitis C virus (HCV) replication efficiently, whereas compound 3f demonstrated potent apoptosis-induced antiproliferative activity against pancreatic cancer MiaPaCa-2 cells both in vitro and in vivo. Most interestingly, the notable selective antiviral and antiproliferative activities were achieved respectively for 2f and 3f by modulating the ribose sugar moiety into deprotected and protected forms while retaining a similar trifluoromethylphenylethynyltriazole as the nucleobase. Preliminary structure-activity relationship study revealed that not only the ribose moiety but also the CF3 group at the p-position of the phenyl ring and the rigid triple bond functionality contributed critically to the observed antiviral activity of 2f against HCV and antiproliferative activity of 3f against pancreatic cancer. These two compounds constitute therefore promising leads in the search for new antiviral and anticancer candidates.
Cited References: AGROFOGLIO LA, 2003, CHEM REV, V103, P1875 ANASTASIA L, 2001, ORG LETT, V3, P3111 BEUTLER E, 1992, LANCET, V340, P952 CHRISTENSEN LF, 1972, J MED CHEM, V15, P735 CLAIRE S, 2001, NUCLEOSIDE MIMETICS COELMONT L, 2006, ANTIMICROB AGENTS CH, V50, P3444 DEFRANCESCO R, 2005, NATURE, V436, P953 FELD JJ, 2005, NATURE, V436, P967 GIROUX V, 2006, CLIN CANCER RES, V12, P235 GIROUX V, 2006, FASEB J, V20, P1982 GORDON CP, 2005, J MED CHEM, V48, P1 GRACI JD, 2002, VIROLOGY, V298, P175 HOCEK M, 2003, EUR J ORG CHEM JAN, P245 HOCEK M, 2005, J MED CHEM, V48, P5869 HONG Z, 2002, PROG DRUG RES, V59, P41 LI DH, 2004, LANCET, V363, P1049 LI W, 2008, TETRAHEDRON LETT, V49, P2804 LI W, CUMEDIATED SEL UNPUB LOAKES D, 2001, NUCLEIC ACIDS RES, V29, P2437 MIYASAKA T, 1989, J MED CHEM, V32, P2507 NEGISHI EI, 2003, CHEM REV, V103, P1979 PAESHUYSE J, 2006, HEPATOLOGY, V43, P761 REN J, 1995, NAT STRUCT BIOL, V2, P293 ROBINS MJ, 1965, J AM CHEM SOC, V87, P4934 ROCCHI P, 2004, CANCER RES, V64, P6595 SIDWELL RW, 1972, SCIENCE, V177, P705 TANAKA H, 1991, J MED CHEM, V34, P1394 TANAKA H, 1991, J MED CHEM, V34, P1508 WAN JQ, 2006, TETRAHEDRON LETT, V47, P6727 WU QG, 2004, HELV CHIM ACTA, V87, P811 XIA Y, 2005, HETEROCYCLES, V65, P345 XIA Y, 2006, BIOORG MED CHEM LETT, V16, P2693 ZHU RZ, 2007, TETRAHEDRON LETT, V48, P2389 ZHU RZ, 2008, BIOORG MED CHEM LETT, V18, P3321 |