Bhattacharya B K, Ojwang J O, Rando R F, Huffman J H, Revankar G R
Triplex Pharmaceutical Corporation, The Woodlands, Texas 77380, USA.
J Med Chem. 1995 Sep 29;38(20):3957-66. doi: 10.1021/jm00020a009.
Several novel 2,4-disubstituted-7-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl)pyrrolo[2,3-d]pyrimidines have been synthesized and evaluated for their anti-human cytomegalovirus (HCMV), anti-hepatitis B virus (HBV), and anti-herpes simplex virus (HSV) activities in vitro. These nucleosides were prepared starting from 2-amino-4-chloro-7-(2-deoxy-2-fluoro- 3,5-di-O-benzoyl-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (3), which in turn was synthesized by direct glycosylation of the sodium salt of 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (1) with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-D-arabinofuranosyl bromide (2). Displacement of the 4-chloro group of 3 with OH, NH2, NHOH, SH, and SeH nucleophiles furnished the corresponding nucleosides 6-8, 12, and 14, respectively. The 3'-deoxygenation of 2-amino-4-chloro-7- (2-deoxy-2-fluoro-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (4) and subsequent amination gave 2,4-diamino-2',3'-dideoxy derivative 19. Catalytic hydrogenation of 3 followed by debenzoylation afforded 2-aminopyrrolo[2,3-d]pyrimidine nucleoside 23. Among the compounds evaluated for their ability to inhibit the growth of HCMV (strain AD169) in MRC-5 cells using a plaque reduction assay, only 7 was significantly active in vitro with a 50% inhibitory concentration (IC50) of 3.7 micrograms/mL (TI > 125), whereas the IC50 value of ganciclovir (DHPG) was 3.2 micrograms/mL. Strain D16 of HCMV was more resistant to 7 (IC50 11 micrograms/mL) than the AD169 strain. When 7 was tested in combination with DHPG, the resultant anti-HCMV activity was found to be moderately synergistic with no evidence of antagonism. Nucleoside 7 also reduced episomal HBV replication in human hepatoblastoma 2.2.15 cells with an IC50 of 0.7 micrograms/mL (TI > 143). Development of cells harboring HBV which had become resistant to the drug was not observed with 7. Compound 7 also exhibited significant activity against herpes simplex virus types 1 and 2 (IC50 of 4.1 and 6.3 micrograms/mL, respectively) in Vero cells.
已合成了几种新型的2,4-二取代-7-(2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)吡咯并[2,3-d]嘧啶，并对其体外抗人巨细胞病毒(HCMV)、抗乙型肝炎病毒(HBV)和抗单纯疱疹病毒(HSV)活性进行了评估。这些核苷从2-氨基-4-氯-7-(2-脱氧-2-氟-3,5-二-O-苯甲酰基-β-D-阿拉伯呋喃糖基)吡咯并[2,3-d]嘧啶(3)开始制备，而3又通过2-氨基-4-氯吡咯并[2,3-d]嘧啶(1)的钠盐与2-脱氧-2-氟-3,5-二-O-苯甲酰基-α-D-阿拉伯呋喃糖基溴(2)直接糖基化反应合成。用OH、NH₂、NHOH、SH和SeH亲核试剂取代3的4-氯基团，分别得到相应的核苷6-8、12和14。2-氨基-4-氯-7-(2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)吡咯并[2,3-d]嘧啶(4)的3'-脱氧反应及随后的胺化反应得到2,4-二氨基-2',3'-二脱氧衍生物19。3经催化氢化反应后再进行脱苯甲酰基反应得到2-氨基吡咯并[2,3-d]嘧啶核苷23。在使用蚀斑减少试验评估其抑制MRC-5细胞中HCMV(AD169株)生长能力的化合物中，只有7在体外具有显著活性，其50%抑制浓度(IC50)为3.7微克/毫升(TI>125)，而更昔洛韦(DHPG)的IC50值为3.2微克/毫升。HCMV的D16株比AD169株对7更具抗性(IC50为11微克/毫升)。当7与DHPG联合测试时，发现其抗HCMV活性具有中度协同作用，没有拮抗作用的证据。核苷7还能降低人肝癌细胞2.2.15中游离型HBV的复制，IC50为0.7微克/毫升(TI>143)。未观察到携带对该药物产生抗性的HBV的细胞的产生。化合物7在Vero细胞中对1型和2型单纯疱疹病毒也表现出显著活性(IC50分别为4.1和6.3微克/毫升)。
