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. 2025 Oct 10;101(8):510-518.
doi: 10.2183/pjab.101.029. Epub 2025 Jul 18.

Syntheses and biological evaluation of M-COPA analogs derived from pentadienoic Weinreb amide

Hisazumi Tsutsui  1 , Daiki Usukura  1 , Fumiya Watabe  1 , Hiroki Okano  1 , Ryo Hirata  1 , Ryunosuke Shiogama  1 , Yamato Kanai  1 , Saki Kato  1 , Yuki Asahara  1 , Sayaka Chogi  1 , Yingjia Lu  1 , Haruka Hirai  1 , Mai Kitamoto  1 , Miho Kojima  1 , Yuuki Obata  2 , Motoyuki Shimonaka  1 , Takatsugu Murata  1 , Isamu Shiina  1
Affiliations

Syntheses and biological evaluation of M-COPA analogs derived from pentadienoic Weinreb amide

Hisazumi Tsutsui et al. Proc Jpn Acad Ser B Phys Biol Sci. .

Abstract

M-COPA (1), which contains diene and 3-picolylamine moieties in its side chain and seven stereogenic centers in a multisubstituted octalin skeleton, strongly inhibits the growth of several cancer cell lines. Expecting the improvement of conformational flexibility of basic and coordinating 3-pyridylmethylamino group on M-COPA and its physical properties, we efficiently synthesized its amine analogs by replacing its amide group with an amino group through the Weinreb amide-type Horner-Wadsworth-Emmons reaction. The cytotoxic properties of 1 and its analogs were evaluated against NCI-H226, a lung cancer cell line, HeLa, a cervical cancer cell line, and GIST-T1, a gastrointestinal stromal tumor cell line. The evaluation results indicated that the structural alteration from amide moiety to amine moiety lowered the pharmacological activity but remained strong cytotoxicity.

Keywords: Horner–Wadsworth–Emmons reaction; M-COPA; cytotoxicity.

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Figures

Figure 1.
Figure 1.
Structures of M-COPA and trichodermic acid (TDA).
Figure 2.
Figure 2.
Structure–activity relationship (SAR) of imatinib (3) and indole derivative (5).
Figure 3.
Figure 3.
Amine analogs 7–9 of M-COPA (1).
Figure 4.
Figure 4.
Retrosynthetic analysis of amines 7–9.
Scheme 1.
Scheme 1.
Syntheses of secondary amine 7 and tertiary amines 17 and 8.
Scheme 2.
Scheme 2.
Synthesis of secondary amine 9.
Scheme 3.
Scheme 3.
Syntheses of amide derivatives 22 and 23.
See this image and copyright information in PMC

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