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

Yohan Seo; Jeong Hwa Lee; So hyeon Park; Wan Namkung; Ikyon Kim

doi:10.1016/j.ejmech.2019.111988

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

Yohan Seo, Jeong Hwa Lee, So hyeon Park, Wan Namkung, Ikyon Kim

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Article number	111988
Journal	European Journal of Medicinal Chemistry
Volume	188
DOIs	https://doi.org/10.1016/j.ejmech.2019.111988
Publication status	Published - 2020 Feb 15

Bibliographical note

Funding Information:
We thank the National Research Foundation of Korea ( NRF-2017R1A2A2A05069364 , NRF-2018R1A6A1A03023718 , and NRF-2019R1I1A1A01061117 ) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019-12-0013 ). Appendix A

Funding Information:
We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, and NRF-2019R1I1A1A01061117) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019-12-0013).

Publisher Copyright:
© 2019 Elsevier Masson SAS

All Science Journal Classification (ASJC) codes

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2019.111988

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title = "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",

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.",

author = "Yohan Seo and Lee, {Jeong Hwa} and Park, {So hyeon} and Wan Namkung and Ikyon Kim",

note = "Funding Information: We thank the National Research Foundation of Korea ( NRF-2017R1A2A2A05069364 , NRF-2018R1A6A1A03023718 , and NRF-2019R1I1A1A01061117 ) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019-12-0013 ). Appendix A Funding Information: We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, and NRF-2019R1I1A1A01061117) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019-12-0013). Publisher Copyright: {\textcopyright} 2019 Elsevier Masson SAS",

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AU - Park, So hyeon

AU - Namkung, Wan

AU - Kim, Ikyon

N1 - Funding Information: We thank the National Research Foundation of Korea ( NRF-2017R1A2A2A05069364 , NRF-2018R1A6A1A03023718 , and NRF-2019R1I1A1A01061117 ) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019-12-0013 ). Appendix A Funding Information: We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, and NRF-2019R1I1A1A01061117) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019-12-0013). Publisher Copyright: © 2019 Elsevier Masson SAS

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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

Abstract

Bibliographical note

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UN SDGs

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