Migawa M T, Girardet J L, Walker J A, Koszalka G W, Chamberlain S D, Drach J C, Townsend L B
Department of Chemistry, College of Literature, Science and Arts, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
J Med Chem. 1998 Apr 9;41(8):1242-51. doi: 10.1021/jm970545c.
Several 2-substituted alpha-D- and alpha-L-lyxofuranosyl and 5-deoxylyxofuranosyl derivatives of 5,6-dicholro-2-(isopropylamino)-1-(beta-L-ribofuranosyl) benzimidazole (1263W94) and 2,5,6-trichloro-1(beta-D-ribofuranosyl)benzimidazole (TCRB) were synthesized and evaluated for activity against two herpesviruses (HSV-1 and HCMV) and for their cytotoxicity against HFF and KB cells. Condensation of 1,2,3,5-tetra-O-acetyl-L-lyxofuranose (2a) with 2,5,6-trichlorobenzimidazole (1) yielded the alpha-nucleoside 3a. The 2-bromo derivative and 2-methylamino derivative were prepared by treatment of 3a with HBr followed by deprotection or from methylamine, respectively. Compound 3a was deprotected and the resultant nucleoside used to prepare the 2-cyclopropylamino and 2-isopropylamino derivatives. The 2-alkylthio nucleosides were prepared by condensing 2a with 5,6-dichlorobenzimidazole-2-thione followed by deprotection. Alkylation of this adduct gave the 2-methylthio and 2-benzylthio derivatives. Condensation of 5-deoxy-1,2,3-tri-O-acetyl-L-lyxofuranosyl, prepared from L-lyxose, with 1 or 2-bromo-5,6-dichlorobenzimidazole (15), followed by deprotection, gave the 2-chloro or 2-bromo-5'-deoxylyxo-furanosyl derivative, respectively. The cyclopropylamino derivative was prepared from the 2-chloro derivative. All D-isomers were prepared in an analogous fashion from D-lyxose. Either compounds were inactive against HSV-1 or weak activity was poorly separated from cytotoxicity. In contrast, the 2-halogen derivatives in both the alpha-lyxose and 5-deoxy-alpha-lyxose series were active against the Towne strain of HCMV. The 5-deoxy alpha-L analogues were the most active, IC50's = 0.2-0.4 microM, plaque assay; IC90's = 0.2-2 microM, yield reduction assay. All of the 2-isopropylamino or 2-cyclopropylamino derivatives were less active (IC50's = 60-100 microM, plaque assay; IC90's = 17-100 microM, yield reduction assay) and were not cytotoxic. The methylamino, thio, and methylthio derivatives were neither active nor cytotoxic. The benzylthio derivatives were weakly active, but this activity was poorly separated from cytotoxicity. The alpha-lyxose L-isomers were more active in a plaque assay against the AD169 strain of HCMV compared to the Towne strain, thereby providing additional evidence of antiviral specificity.
合成了5,6 -二氯- 2 -（异丙基氨基）- 1 -（β - L -呋喃核糖基）苯并咪唑（1263W94）和2,5,6 -三氯- 1（β - D -呋喃核糖基）苯并咪唑（TCRB）的几种2 -取代的α - D -和α - L -呋喃来苏糖基及5 -脱氧呋喃来苏糖基衍生物，并评估了它们对两种疱疹病毒（HSV - 1和HCMV）的活性以及对人包皮成纤维细胞（HFF）和KB细胞的细胞毒性。1,2,3,5 -四 - O -乙酰基- L -呋喃来苏糖（2a）与2,5,6 -三氯苯并咪唑（1）缩合得到α -核苷3a。分别通过用HBr处理3a然后脱保护或用甲胺处理，制备了2 -溴衍生物和2 -甲氨基衍生物。对化合物3a进行脱保护，所得核苷用于制备2 -环丙基氨基和2 -异丙基氨基衍生物。通过使2a与5,6 -二氯苯并咪唑- 2 -硫酮缩合然后脱保护，制备了2 -烷硫基核苷。该加合物的烷基化得到2 -甲硫基和2 -苄硫基衍生物。由L -来苏糖制备的5 -脱氧- 1,2,3 -三 - O -乙酰基- L -呋喃来苏糖基与1或2 -溴- 5,6 -二氯苯并咪唑（15）缩合，然后脱保护，分别得到2 -氯或2 -溴- 5'-脱氧呋喃来苏糖基衍生物。由2 -氯衍生物制备了环丙基氨基衍生物。所有D -异构体均以类似方式由D -来苏糖制备。这些化合物要么对HSV - 1无活性，要么活性较弱且与细胞毒性难以区分。相比之下，α -来苏糖和5 -脱氧-α -来苏糖系列中的2 -卤代衍生物对HCMV的汤氏株有活性。5 -脱氧α - L -类似物活性最高，空斑试验的IC50 = 0.2 - 0.4μM；产量降低试验的IC90 = 0.2 - 2μM。所有2 -异丙基氨基或2 -环丙基氨基衍生物活性较低（空斑试验的IC50 = 60 - 100μM；产量降低试验的IC90 = 17 - 100μM）且无细胞毒性。甲氨基、硫基和甲硫基衍生物既无活性也无细胞毒性。苄硫基衍生物活性较弱，但这种活性与细胞毒性难以区分。与汤氏株相比，α -来苏糖L -异构体在针对HCMV的AD169株的空斑试验中活性更高，从而提供了抗病毒特异性的额外证据。
