Hall I H, Hall E S, Chi L K, Shaw B R, Sood A, Spielvogel B F
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559-7360.
Anticancer Res. 1992 Jul-Aug;12(4):1091-7.
The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.
成功合成了糖硼化胸苷核苷5'-O-[(三苯基膦-硼基)羰基]-3'-O-乙酰胸苷1和硼修饰的核苷磷酸三酯5'-(亚磷酸二乙酯-氰基硼烷)-3'-乙酰胸苷2。在针对8种细胞系进行测试时，这两种化合物均表现出不同的活性，对人Tmolt3白血病、结肠腺癌、HeLa S3子宫癌和骨肉瘤细胞的生长具有显著的细胞毒性活性。在体内研究中，发现这些药物以8mg/kg/天的腹腔注射剂量对艾氏腹水癌的生长有活性，对小鼠L1210和Lewis肺癌的生长有微弱活性。这些胸苷衍生物在Tmolt3细胞中的作用方式是抑制DNA和蛋白质合成。化合物2在抑制DNA聚合酶α以及mRNA、rRNA和tRNA聚合酶活性方面非常有效。两种化合物均抑制核糖核苷酸还原酶活性。从头嘌呤途径似乎是这些药物的主要抑制位点，肌苷酸脱氢酶、磷酸核糖焦磷酸酰胺转移酶和二氢叶酸还原酶的活性受到显著抑制。在嘧啶途径中，氨基甲酰磷酸合成酶和天冬氨酸转氨甲酰酶的活性被1抑制。正如预期的那样，用这些药物处理后，d[NTP]水平显著降低。在用这些药物将Tmolt3细胞孵育24小时后，DNA链断裂明显。
