Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic.
J Med Chem. 2010 Jan 14;53(1):460-70. doi: 10.1021/jm901428k.
A series of novel 7-deazapurine ribonucleosides bearing an alkyl, aryl, or hetaryl group in position 6 and H, F, or Cl atom in position 7 has been prepared either by Pd-catalyzed cross-coupling reactions of the corresponding protected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with alkyl- or (het)arylorganometallics followed by deprotection, or by single-step aqueous phase cross-coupling reactions of unprotected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with (het)arylboronic acids. Significant cytostatic effect was detected with a substantial proportion of the prepared compounds. The most potent were 7-H or 7-F derivatives of 6-furyl- or 6-thienyl-7-deazapurines displaying cytostatic activity in multiple cancer cell lines with a geometric mean of 50% growth inhibition concentration ranging from 16 to 96 nM, a potency comparable to or better than that of the nucleoside analogue clofarabine. Intracellular phosphorylation to mono- and triphosphates and the inhibition of total RNA synthesis was demonstrated in preliminary study of metabolism and mechanism of action studies.
已经制备了一系列在 6 位带有烷基、芳基或杂芳基的新型 7-脱氮嘌呤核苷，在 7 位带有 H、F 或 Cl 原子，或者通过 Pd 催化的相应保护的 6-氯-（7-卤代-）7-脱氮嘌呤核苷与烷基-或（杂）芳基有机金属试剂的交叉偶联反应，然后脱保护，或者通过未保护的 6-氯-（7-卤代-）7-脱氮嘌呤核苷与（杂）芳基硼酸的单步水相交叉偶联反应来制备。所制备的化合物中有相当一部分表现出显著的细胞抑制作用。最有效的是 6-呋喃基或 6-噻吩基-7-脱氮嘌呤的 7-H 或 7-F 衍生物，在多种癌细胞系中具有细胞抑制活性，半数生长抑制浓度的几何平均值范围为 16 至 96 nM，与核苷类似物克拉屈滨相当或更好。在代谢和作用机制研究的初步研究中，证明了细胞内磷酸化为单磷酸和三磷酸以及总 RNA 合成的抑制。
