香豆素与哌嗪衍生物作为肿瘤相关碳酸酐酶 IX 和 XII 同工型的选择性抑制剂。
Coumarin and Piperazine Conjugates as Selective Inhibitors of the Tumor-associated Carbonic Anhydrase IX and XII Isoforms.
机构信息
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research, Hyderabad, Balanagar, India.
Department of Chemistry, Directorate of Distance Education, Maulana Azad National Urdu University, Gachibowli, Hyderabad, 500032, T.S. India.
出版信息
Anticancer Agents Med Chem. 2023;23(10):1184-1191. doi: 10.2174/1871520623666230202123535.
BACKGROUND
Carbonic Anhydrases (CAs) are a family of metalloenzymes that catalyze the reversible interconversion of CO and water to bicarbonate and proton. CA isoforms I, II, IX, and XII are considered physiologically and pharmacologically relevant.
OBJECTIVE
The objective of this study is to synthesize potent and selective tumor-associated CA IX and XII inhibitors.
METHODS
A library of 17 coumarin derivatives clubbed with piperazine and benzyl moiety was designed, synthesized and evaluated for its inhibitory effects and selectivity profile towards physiologically and pharmacologically relevant CA isoforms I, II, IX, and XII.
RESULTS
All the derivatives were found to be active against the tumor-associated isoforms IX and XII. The most active compound against hCA (human Carbonic Anhydrase) IX was found to possess a K of 229 nM, while the one against hCA XII had a K of 294.2 nM. Additionally, two of the compounds were found to have exquisite selectivity towards the off-target hCA I and II isoforms. Moreover, they were found to be approximately 20-fold more selective towards hCA IX than XII. The selectivity of the compounds was further investigated molecular modeling techniques.
CONCLUSION
Coumarin-piperazine hybrids were identified as potent and selective CA IX and XII inhibitors. Molecular modeling techniques provided interesting cues pertaining to observed selectivity.
背景
碳酸酐酶（CA）是一类金属酶，可催化 CO 和水可逆地相互转化为碳酸氢根和质子。CA 同工酶 I、II、IX 和 XII 被认为具有生理和药理学相关性。
目的
本研究旨在合成有效的、对肿瘤相关的 CAIX 和 CAXII 具有选择性的抑制剂。
方法
设计、合成了一个包含香豆素衍生物和哌嗪及苄基部分的 17 个化合物库，并对其抑制作用和对生理和药理学相关的 CA 同工酶 I、II、IX 和 XII 的选择性进行了评估。
结果
所有衍生物均对肿瘤相关同工酶 IX 和 XII 表现出活性。对 hCA（人碳酸酐酶）IX 活性最强的化合物的 K 值为 229 nM，而对 hCA XII 的 K 值为 294.2 nM。此外，有两种化合物对靶标 hCA I 和 II 同工酶具有极高的选择性。此外，它们对 hCA IX 的选择性比 XII 高约 20 倍。进一步通过分子建模技术对化合物的选择性进行了研究。
结论
香豆素-哌嗪杂合体被鉴定为有效的、对 CAIX 和 CAXII 具有选择性的抑制剂。分子建模技术提供了与观察到的选择性相关的有趣线索。
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