Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia.
Department of Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, Osijek, Croatia.
Nucleosides Nucleotides Nucleic Acids. 2021;40(4):470-503. doi: 10.1080/15257770.2021.1896001. Epub 2021 Mar 12.
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 SO 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 -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 and 6-amino derivatives, with --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.
新型 6-氯/吗啉基/氨基/-9-磺酰基嘌呤衍生物的合成都采用了两种方法，或者（i）在 0°C 下，将 6-氯嘌呤与商业上可获得的芳基磺酰氯在丙酮和水性 KOH 中进行缩合反应，然后用吗啉取代 C6-氯，或者（ii）采用反向合成方法，其中 6-吗啉基嘌呤和商业上可获得的腺嘌呤碱基与相应的烷基、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非选择性磺酰化的情况。在这两种方法中，磺酰化反应都在嘌呤 N9 位置上发生区域选择性，没有任何同时存在的 N7 衍生物，除了在 SO 上的较小甲基取代基和嘌呤环的 C6 上的游离氨基的情况下。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所制备的-9-磺酰基嘌呤衍生物之间的稳定性趋势，得出了一个重要结论，即给电子的 C6 取代基有利于合成，因为它们既促进了所需的 N9 互变异构体的优势，又有助于确保最终产物的稳定性。新合成的 6-吗啉基和 6-氨基-9-磺酰基嘌呤衍生物对人癌、淋巴瘤和白血病细胞表现出抗增殖活性。在所测试的化合物中，带有--苯乙烯磺酰基的 6-吗啉基和 6-氨基衍生物在嘌呤的 N9 位置上，被证明是最有效的抗增殖剂，导致白血病细胞在 subG0 细胞周期阶段积累。
