Expansion of chemical space based on a pyrrolo[1,2-a]pyrazine core: Synthesis and its anticancer activity in prostate cancer and breast cancer cells

  • Eur J Med Chem. 2020 Feb 15;188:111988. doi: 10.1016/j.ejmech.2019.111988.
Yohan Seo  1 ,  Jeong Hwa Lee  1 ,  So-Hyeon Park  2 ,  Wan Namkung  3 ,  Ikyon Kim  4
Affiliations
  • 1. College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85, Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
  • 2. Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, 21983, Republic of Korea.
  • 3. College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85, Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea; Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School, Yonsei University, Seoul, 03722, Republic of Korea. Electronic address: [email protected].
  • 4. College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85, Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea. Electronic address: [email protected].
PMID: 31901746 DOI: 10.1016/j.ejmech.2019.111988
Abstract

In connection with our continued research to generate new aza-fused heteroaromatic chemical scaffolds, we developed a highly atom-economical three-component route to novel 3,4-dihydropyrrolo[1,2-a]pyrazine ring skeleton multi-functionalized on the pyrazine unit. This [4+1+1] annulation approach led us to gain access to a new N-fused bicyclic chemical space having two distinctive functional groups (heteroaryl and aroyl) in a trans manner. Investigation of Anticancer activity of the synthesized compounds and their derivatives revealed that (3R*,4S*)-3-(4-bromophenyl)-4-(4-fluorobenzoyl)-2-(2-oxo-2-phenylethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-ium bromide (3h) has potent Anticancer activity. 3h significantly inhibited cell viability in prostate Cancer cells (PC-3) and breast Cancer cells (MCF-7) with IC50 value of 1.18 ± 0.05 μM and 1.95 ± 0.04 μM, respectively. In addition, 3h strongly reduced cell migration in a dose dependent manner, and induced Apoptosis via Caspase-3 activation and cleavage of PARP in PC-3 and MCF-7 cells. Our results in this study imply that 3h can be a potential Anticancer agent against prostate Cancer and breast Cancer.

Keywords
3,4-Dihydropyrrolo[1,2-a]pyrazine; Annulation; Anticancer activity; Apoptosis; Chemical space; Diversity-oriented synthesis; Three-component reaction.
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