吡啶基 4-(2-氧代烷基咪唑烷-1-基)苯磺酸盐及其盐酸盐作为新型水溶性抗肿瘤原药在乳腺癌细胞中被细胞色素 P450 1A1 生物活化

IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics
MedChemComm Pub Date : 2024-08-27 DOI:10.1039/D4MD00476K
Vincent Ouellette, Chahrazed Bouzriba, Atziri Corin Chavez Alvarez, Quentin Bruxelles, Geneviève Hamel-Côté and Sébastien Fortin
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引用次数: 0

摘要

我们开发出了由细胞色素 P450 (CYP) 1A1 生物活化的第一类抗乳腺癌原药 4-(2-氧代-烷基咪唑烷-1-基)苯磺酸苯酯(PAIB-SOs),该原药对多种乳腺癌细胞具有高度选择性。然而,它们的水溶性很差。因此,我们用一个取代的吡啶基取代了它们的苯环 B,制备出了新型吡啶基 4-(2-氧代-3-烷基咪唑烷-1-基)苯磺酸盐(PYRAIB-SOs)及其盐酸盐。我们的研究结果表明,PYRAIB-SO 盐酸盐的水溶性比其中性盐和 PAIB-SO 盐高出 625 倍。PYRAIB-SO的氮原子位于吡啶基环的第3位,对敏感的CYP1A1阳性乳腺癌细胞和稳定转染CYP1A1的细胞具有很强的抗增殖活性(IC50:0.03-3.3 μM)和高选择性(8->1250)。它们能诱导细胞周期停滞在 G2/M 期,并破坏微管的动态组装。酶测定证实,CYP1A1 可将PYRAIB-SOs 代谢为其活性形式,在啮齿动物和人类肝脏微粒体中的体外肝半衰期为 55-120 分钟。总之,这将有助于提高体内研究的药物浓度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl)benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells†

Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl)benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells†

Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl)benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells†

We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC50: 0.03–3.3 μM) and high selectivity (8–>1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with in vitro hepatic half-lives (55–120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for in vivo studies.

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来源期刊
MedChemComm
MedChemComm BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
4.70
自引率
0.00%
发文量
0
审稿时长
2.2 months
期刊介绍: Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry. In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.
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