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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Further lead optimization on Bax activators: Design, synthesis and pharmacological evaluation of 2-fluoro-fluorene derivatives for the treatment of breast cancer
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Further lead optimization on Bax activators: Design, synthesis and pharmacological evaluation of 2-fluoro-fluorene derivatives for the treatment of breast cancer

机译：Bax活化剂的进一步优化：2-氟 - 芴衍生物治疗乳腺癌的设计，合成和药理评价

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摘要

To further pursue potent Bax activators with better safety profiles for the treatment of breast cancer, structural optimization was conducted based on lead compound CYD-4-61 through several strategies, including scaffold hopping on the 2-nitro-fluorene ring, replacement of the nitro group with bioisosteres to avoid potential toxicity, and further optimization on the upper pyridine by exploring diverse alkylamine linkers as a tail or replacing the pyridine with bioisosteric heterocycles. F-containing compound 22d (GL0388) exhibited a good balance between the activity and toxicity, displaying submicromolar activities against a variety of cancer cell lines with 5.8-10.7-fold selectivity of decreased activity to MCF-10A human mammary epithelial cell line. Compound 22d dose-dependently blocked colony formation of breast cancer cells and prevented the migration and invasion of MDA-MB-231 cells. Mechanism of action studies indicate that 22d activated Bax, rendering its insertion into mitochondrial membrane, thereby leading to cytochrome c release from the mitochondria into the cytoplasm, subsequently inducing release of apoptotic biomarkers. Further in vivo efficacy studies of 22d in human breast cancer xenografts arisen from MDA-MB-231 cells demonstrated that this drug candidate significantly suppressed tumor growth, indicating the therapeutic promise of this class of compounds for the treatment of breast cancer as well as the potential for developing F-radiolabeled imaging ligands as anticancer chemical probes. (C) 2021 Elsevier Masson SAS. All rights reserved.
机译：为了进一步寻求具有更好安全性的有效Bax激活剂治疗乳腺癌，基于先导化合物CYD-4-61，通过多种策略进行了结构优化，包括在2-硝基芴环上跳跃支架，用生物异构体替换硝基以避免潜在毒性，通过探索不同的烷基胺连接物作为尾部或用生物同构杂环取代吡啶，进一步优化上吡啶。含F化合物22d（GL0388）在活性和毒性之间表现出良好的平衡，对多种癌细胞系显示出亚微摩尔活性，对MCF-10A人乳腺上皮细胞系的活性降低的选择性为5.8-10.7倍。化合物22d剂量依赖性地阻断乳腺癌细胞的集落形成，并阻止MDA-MB-231细胞的迁移和侵袭。作用机制研究表明，22d激活Bax，使其插入线粒体膜，从而导致细胞色素c从线粒体释放到细胞质中，随后诱导凋亡生物标记物的释放。进一步对MDA-MB-231细胞产生的人乳腺癌异种移植物进行22d的体内药效研究表明，该候选药物显著抑制肿瘤生长，表明这类化合物在治疗乳腺癌方面的治疗前景，以及开发F-放射性标记成像配体作为抗癌化学探针的潜力。（c）2021爱思唯尔马松SAS。版权所有。

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