1,3-Diaryl Triazenes Incorporating Disulfonamides Show Both Antiproliferative Activity and Effective Inhibition of Tumor-associated Carbonic Anhydrases IX and XII.

IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Anti-cancer agents in medicinal chemistry Pub Date : 2024-01-01 DOI:10.2174/0118715206285326240207045249
Nebih Lolak, Suleyman Akocak, Andrea Petreni, Yakup Budak, Esra Bozgeyik, Meliha Burcu Gurdere, Mustafa Ceylan, Claudiu Trandafir Supuran
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Abstract

Aim: The aim of this study was to synthesize a library of novel di-sulfa drugs containing 1,3- diaryltriazene derivatives TS (1-13) by conjugation of diazonium salts of primary sulfonamides with sulfa drugs to investigate the cytotoxic effect of these new compounds in different cancer types and to determine their inhibitory activity against tumor-associated carbonic anhydrases IX and XII.

Materials and methods: A carbonic anhydrase inhibitory activity of the obtained compounds was evaluated against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII) by a stoppedflow CO2 hydrase assay. In addition, in vitro, cytotoxicity studies were applied by using A549 (lung cancer), BEAS-2B (normal lung), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), CRL-4010 (normal breast epithelium), HT-29 (colon cancer), and HCT -116 (colon cancer) cell lines.

Results: As a result of the inhibition data, the 4-aminobenzenesulfonamide derivatives were more active than their 3-aminobenzenesulfonamide counterparts. More specifically, compounds TS-1 and TS-2, both of which have primary sulfonamides on both sides of the triazene linker, showed the best inhibitory activity against hCA IX with Ki values of 19.5 and 13.7 nM and also against hCA XII with Ki values of 6.6 and 8.3 nM, respectively. In addition, in vitro cytotoxic activity on the human breast cancer cell line MCF-7 showed that some derivatives of di-sulfa triazenes, such as TS-5 and TS-13, were more active than SLC-0111.

Conclusion: With the aim of developing more potent and isoform-selective CA inhibitors, these novel hybrid molecules containing sulfa drugs, triazene linkers, and the classical primary sulfonamide chemotype may be considered an interesting example of effective enzyme inhibitors and important anticancer agents.

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含有二磺酰胺的 1,3-二芳基三嗪类化合物既具有抗增殖活性,又能有效抑制肿瘤相关碳酸酐酶 IX 和 XII。
目的:本研究旨在通过将伯氨基磺胺的重氮盐与磺胺类药物共轭,合成含有 1,3- 二芳基三氮烯衍生物 TS(1-13)的新型二磺胺类药物库,以研究这些新化合物在不同癌症类型中的细胞毒性作用,并确定它们对肿瘤相关碳酸酐酶 IX 和 XII 的抑制活性:通过停流二氧化碳水合酶试验评估了所获化合物对四种选定的人类碳酸酐酶同工酶(hCA I、hCA II、hCA IX 和 hCA XII)的碳酸酐酶抑制活性。此外,还使用 A549(肺癌)、BEAS-2B(正常肺)、MCF-7(乳腺癌)、MDA-MB-231(乳腺癌)、CRL-4010(正常乳腺上皮细胞)、HT-29(结肠癌)和 HCT -116(结肠癌)细胞系进行了体外细胞毒性研究:抑制数据显示,4-氨基苯磺酰胺衍生物比 3-氨基苯磺酰胺衍生物更具活性。更具体地说,TS-1和TS-2化合物对hCA IX的抑制活性最好,Ki值分别为19.5和13.7 nM;对hCA XII的抑制活性也最好,Ki值分别为6.6和8.3 nM。此外,对人类乳腺癌细胞株 MCF-7 的体外细胞毒性活性表明,二磺胺三嗪的一些衍生物,如 TS-5 和 TS-13,比 SLC-0111 更具活性:为了开发更有效的同工酶选择性 CA 抑制剂,这些包含磺胺类药物、三氮茚连接体和经典的原基磺酰胺化学型的新型杂交分子可被视为有效酶抑制剂和重要抗癌剂的有趣范例。
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来源期刊
Anti-cancer agents in medicinal chemistry
Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL
CiteScore
5.10
自引率
3.60%
发文量
323
审稿时长
4-8 weeks
期刊介绍: Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.
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