College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
Org Biomol Chem. 2020 May 6;18(17):3324-3333. doi: 10.1039/d0ob00444h.
A new one-pot, sequential three-component access to 3,4-diacylpyrrolo[1,2-a]pyrazine was achieved from the reaction of an α-haloketone, azide, and N-substituted pyrrole-2-carboxaldehyde under mild reaction conditions, through which a polysubstitution pattern on the pyrazine moiety of the scaffold was realized. The formation of multiple bonds (one C-C and two C-N) was enabled by this domino process involving the in situ generation of α-iminoketones, intermolecular Mannich reaction, intramolecular imine formation, and aromatization. Construction of the relevant 3,4-diacylpyrazino[1,2-a]indole and further expansion of this chemical space via synthetic elaboration of the resulting products were demonstrated as well. Preliminary biological screening of the synthesized derivatives against oral adenosquamous carcinoma cells (CAL-27) and triple negative human breast cancer cells (MDA-MB-231) led us to identify a potent hit compound (7o) having ∼3 times stronger in vitro anticancer activity than that of the anticancer agent, capecitabine.
一种新的一锅法、顺序三组分方法被开发出来，用于从α-卤代酮、叠氮化物和 N-取代的吡咯-2-甲醛反应，得到 3,4-二酰基吡咯并[1,2-a]吡嗪，通过这种方法可以在支架的吡嗪部分上实现多取代模式。该多步反应通过原位生成α-亚氨基酮、分子间曼尼希反应、分子内亚胺形成和芳构化，实现了多个键（一个 C-C 和两个 C-N）的形成。还展示了相关的 3,4-二酰基吡嗪并[1,2-a]吲哚的构建，以及通过对所得产物的合成修饰进一步扩展这一化学空间。对合成衍生物对口腔鳞癌细胞（CAL-27）和三阴性人乳腺癌细胞（MDA-MB-231）的初步生物筛选使我们确定了一种有效的候选化合物（7o），其体外抗癌活性比抗癌药物卡培他滨强约 3 倍。
