Abstract

The synthesis of novel 6-chloro/morpholino/amino/-9-sulfonylpurine derivatives was accomplished in two ways, either (i) involving the condensation reaction of 6-chloropurine with commercially available arylsulfonyl chlorides in acetone and the presence of aqueous KOH at 0 °C, followed by the substitution of C6-chlorine with morpholine, or (ii) employing a reversed synthetic approach where 6-morpholinopurine and commercially available adenine bases were reacted with the corresponding alkyl, 2-arylethene and arylsulfonyl chlorides giving the N9 sulfonylated products, the latter particularly used where prior nonselective sulfonylation was observed. In both approaches, the sulfonylation reaction occurred regioselectively at the purine N9 position lacking any concurrent N7 derivatives, except in the case of a smaller methyl substituent on SO₂ and the free amino group at C6 of the purine ring. The tautomeric features of initial N9 unsubstituted purines, as well as stability trends among the prepared N-9-sulfonylpurine derivates, were investigated using DFT calculations with an important conclusion that electron-donating C6 substituents are beneficial for the synthesis as they both promote the predominance of the desired N9 tautomers and help to assure the stability of the final products. The newly synthesized 6-morpholino and 6-amino-9-sulfonylpurine derivatives showed antiproliferative activity on human carcinoma, lymphoma, and leukemia cells. Among the tested compounds, 6-morpholino 17 and 6-amino 22 derivatives, with trans-β-styrenesulfonyl group attached at the N9 position of purine, proved to be the most effective antiproliferative agents, causing accumulation of leukemia cells in subG0 cell cycle phase.

摘要

新型 6-氯/吗啉/氨基/-9-磺酰基嘌呤衍生物的合成以两种方式完成，一种是 (i) 涉及 6-氯嘌呤与市售芳基磺酰氯在丙酮中的缩合反应，以及在 0 °C，然后用吗啉取代 C6-氯，或 (ii) 采用反向合成方法，其中 6-吗啉嘌呤和市售的腺嘌呤碱与相应的烷基、2-芳基乙烯和芳基磺酰氯反应，得到 N9 磺酰化产物，后者特别用于观察到先前的非选择性磺酰化。在这两种方法中，磺酰化反应在嘌呤 N9 位置区域选择性地发生，没有任何并发​​的 N7 衍生物，除了 SO 上较小的甲基取代基的情况₂和嘌呤环 C6 处的游离氨基。使用 DFT 计算研究了初始 N9 未取代嘌呤的互变异构特征，以及制备的N -9-磺酰基嘌呤衍生物之间的稳定性趋势，得出一个重要结论，即供电子 C6 取代基有利于合成，因为它们都促进了优势所需的 N9 互变异构体，并有助于确保最终产品的稳定性。新合成的 6-morpholino 和 6-amino-9-sulfonylpurine 衍生物对人类癌症、淋巴瘤和白血病细胞具有抗增殖活性。在测试的化合物中，6-吗啉代17和 6-氨基22衍生物，具有反式- β连接在嘌呤 N9 位的苯乙烯磺酰基，被证明是最有效的抗增殖剂，导致白血病细胞在亚 G0 细胞周期阶段积累。