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07-12-2022 | Breast Cancer | Original Paper

Rational design and structure–activity relationship studies reveal new esterified C₂₀-diterpenoid alkaloid analogues active against MCF-7 human breast cancer cells

Authors: Koji Wada, Akira Takaguri, Kyosuke Kaneda, Megumi Mizukami, Yuji Suzuki, Hiroshi Yamashita

Published in: Journal of Natural Medicines | Issue 2/2023

Abstract

Although various diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human tumor cell lines, little information is available regarding the antiproliferative effects of C₂₀-diterpenoid alkaloids against MCF-7 cells. Six new diterpenoid alkaloid derivatives (13, 14, 22, 23, 25, 26) were prepared by C-11 and 15 esterification of kobusine (6). The natural parent alkaloid 6 and all synthesized derivatives (7 − 27, 12a, 15a, 15b, 18a, 18b) were evaluated for antiproliferative activity against MCF-7 cells. The structure-based design strategy resulted in an initial lead derivative, 11,15-dibenzoylkobusine (7; IC₅₀ 8.6 µM). Subsequent synthesized 11,15-diacylkobusine derivatives (9, 16, 20, 21, 23, 25, and 26) showed substantially increased suppressive effects against the MCF-7 cell line (IC₅₀ 2.3−4.4 µM). In contrast, parent alkaloid 6, two 11-acylkobusine derivatives (15a, 18a), and two 15-acylkobusine derivatives (15b, 18b) showed no effect. 11,15-Diacylation appears to be critical for producing antiproliferative activity in this alkaloid class and could introduce a new avenue in overcoming breast cancer cell proliferation using natural product derivatives. In a preliminary mechanism of action study, representative derivatives (5, 8, 9, and 17) decreased cyclin D1 mRNA expression.

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Title: Rational design and structure–activity relationship studies reveal new esterified C20-diterpenoid alkaloid analogues active against MCF-7 human breast cancer cells
Authors: Koji Wada
Akira Takaguri
Kyosuke Kaneda
Megumi Mizukami
Yuji Suzuki
Hiroshi Yamashita
Publication date: 07-12-2022
Publisher: Springer Nature Singapore
Keywords: Breast Cancer
Alkaloids
Alkaloids
Breast Cancer
Published in: Journal of Natural Medicines / Issue 2/2023
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI: https://doi.org/10.1007/s11418-022-01667-6

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Rational design and structure–activity relationship studies reveal new esterified C₂₀-diterpenoid alkaloid analogues active against MCF-7 human breast cancer cells

Abstract

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Keynote webinar | Spotlight on medication adherence

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Abstract

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