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

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

  • Bioorg Med Chem Lett. 2019 Jun 1;29(11):1350-1356. doi: 10.1016/j.bmcl.2019.03.044.
Jinwoo Kim 1,  Mikyung Park 2,  Jiwon Choi 1,  Dileep Kumar Singh 1,  Ho Jeong Kwon 3,  Seong Hwan Kim 4,  Ikyon Kim 5
Affiliations

Affiliations

  • 1 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
  • 2 Chemical Genomics GRL, Department of Biotechnology, Yonsei University, Seoul, Republic of Korea; Innovative Target Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
  • 3 Chemical Genomics GRL, Department of Biotechnology, Yonsei University, Seoul, Republic of Korea. Electronic address: kwonhj@yonsei.ac.kr.
  • 4 Innovative Target Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. Electronic address: hwan@krict.re.kr.
  • 5 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea. Electronic address: ikyonkim@yonsei.ac.kr.
PMID: 30954427 DOI: 10.1016/j.bmcl.2019.03.044
Abstract

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.

Keywords

Biological activity; Chemical library; Chemical space; Diversity-oriented synthesis; Electrophilic acetylation; Pyrrolo[1,2-a]pyrazine; Vilsmeier-Haack formylation.

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