Design, synthesis, and biological evaluation of novel pyrrolo[1,2-a]pyrazine derivatives

• Published in: Bioorganic & medicinal chemistry letters 2019-06, Vol.29 (11), p.1350-1356
• Main Authors: Kim, Jinwoo, Park, Mikyung, Choi, Jiwon, Singh, Dileep Kumar, Kwon, Ho Jeong, Kim, Seong Hwan, Kim, Ikyon
• Format: Article
• Language: English
• Subjects: Biological activity; Chemical library; Chemical space; Diversity-oriented synthesis; Electrophilic acetylation; Pyrrolo[1,2-a]pyrazine; Vilsmeier-Haack formylation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.03.044

[Display omitted] •New pyrrolo[1,2-a]pyrazine-based chemical space via regiodivergent acetylation/formylation followed by aldol condensation.•Installation of a chalcone unit around the basic pyrrolo[1,2-a]pyrazine in a different orientation.•Anticancer screening of the synthesized pyrrolo[1,2-a]pyrazine-chalcone hybrids.•Identification of structural requirement of pyrrolo[1,2-a]pyrazine-chalcone skeleton to inhibit human lymphoma U937 cells.•Anticancer activity of 6x via the caspase-dependent apoptosis. A pyrrolo[1,2-a]pyrazine-based chemical territory was expanded via construction of new chemical library with distinctive substitution patterns, which was made possible by regiodivergent electrophilic acylation followed by aldol condensation. Biological screening of the compounds in this class revealed that the viability of human lymphoma U937 cells was strongly inhibited by 6b with a methoxy group at the o-position of the aromatic ring, but not by compounds 6t-w bearing a halogen at the o-position. Furthermore, 6x having a 2,4-dimethoxyphenyl group inhibited the survival of U937 cells more potently than 6b. In contrast, 6y possessing a 2,5-dimethoxyphenyl moiety did not show effective inhibition, implying the importance of orientation of the substituent(s) around the benzene ring. The anticancer action of 6x with safe therapeutic window could be associated with the FTase-p38 signaling axis.