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

Jinwoo Kim; Mikyung Park; Jiwon Choi; Dileep Kumar Singh; Ho Jeong Kwon; Seong Hwan Kim; Ikyon Kim

doi:10.1016/j.bmcl.2019.03.044

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

Jinwoo Kim, Mikyung Park, Jiwon Choi, Dileep Kumar Singh, Ho Jeong Kwon, Seong Hwan Kim, Ikyon Kim

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

17 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1350-1356
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2019.03.044
Publication status	Published - 2019 Jun 1

Bibliographical note

Funding Information:
We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, 2015M3A9B6027818 , and 2016K2A9A1A03904900 ) for generous financial support. MP and SHK were supported by project grants from Korea Research Institute of Chemical Technology ( KK1703-F02 , KK1803-F00 , and KK1932-20 ). We specially thank Prof. Nam Sook Kang ( Graduate School of New Drug Discovery and Development, Chungnam National University , Daejeon, Republic of Korea) for supporting cheminformatics and molecular docking simulation studies.

Funding Information:
We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, 2015M3A9B6027818, and 2016K2A9A1A03904900) for generous financial support. MP and SHK were supported by project grants from Korea Research Institute of Chemical Technology (KK1703-F02, KK1803-F00, and KK1932-20). We specially thank Prof. Nam Sook Kang (Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea) for supporting cheminformatics and molecular docking simulation studies.

Publisher Copyright:
© 2019 Elsevier Ltd

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2019.03.044

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@article{b161486933e9483a9cbdc309d3862d65,

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

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.",

author = "Jinwoo Kim and Mikyung Park and Jiwon Choi and Singh, {Dileep Kumar} and Kwon, {Ho Jeong} and Kim, {Seong Hwan} and Ikyon Kim",

note = "Funding Information: We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, 2015M3A9B6027818 , and 2016K2A9A1A03904900 ) for generous financial support. MP and SHK were supported by project grants from Korea Research Institute of Chemical Technology ( KK1703-F02 , KK1803-F00 , and KK1932-20 ). We specially thank Prof. Nam Sook Kang ( Graduate School of New Drug Discovery and Development, Chungnam National University , Daejeon, Republic of Korea) for supporting cheminformatics and molecular docking simulation studies. Funding Information: We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, 2015M3A9B6027818, and 2016K2A9A1A03904900) for generous financial support. MP and SHK were supported by project grants from Korea Research Institute of Chemical Technology (KK1703-F02, KK1803-F00, and KK1932-20). We specially thank Prof. Nam Sook Kang (Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea) for supporting cheminformatics and molecular docking simulation studies. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

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AU - Kim, Jinwoo

AU - Park, Mikyung

AU - Choi, Jiwon

AU - Singh, Dileep Kumar

AU - Kwon, Ho Jeong

AU - Kim, Seong Hwan

AU - Kim, Ikyon

N1 - Funding Information: We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, 2015M3A9B6027818 , and 2016K2A9A1A03904900 ) for generous financial support. MP and SHK were supported by project grants from Korea Research Institute of Chemical Technology ( KK1703-F02 , KK1803-F00 , and KK1932-20 ). We specially thank Prof. Nam Sook Kang ( Graduate School of New Drug Discovery and Development, Chungnam National University , Daejeon, Republic of Korea) for supporting cheminformatics and molecular docking simulation studies. Funding Information: We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, 2015M3A9B6027818, and 2016K2A9A1A03904900) for generous financial support. MP and SHK were supported by project grants from Korea Research Institute of Chemical Technology (KK1703-F02, KK1803-F00, and KK1932-20). We specially thank Prof. Nam Sook Kang (Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea) for supporting cheminformatics and molecular docking simulation studies. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/6/1

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N2 - 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.

AB - 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.

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ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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