Fawzia F. Albelwi, Mohamed S. Nafie, Nader R. Albujuq, Wafa Hourani, Ateyatallah Aljuhani, Khaled M. Darwish, Mohamed M. Tawfik, Nadjet Rezki and Mohamed Reda Aouad
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To this end, three focused bioactive series of mono- and -bis-1,2,3-triazoles were effectively synthesized <em>via</em> copper-assisted cycloaddition of mono- and/or di-alkyne chromenone derivatives <strong>2a</strong> and <strong>b</strong> and <strong>9</strong> with several sulfa drug azides <strong>4a–d</strong> and <strong>6</strong>. The resulting molecular derivatives were tested for cytotoxicity against prostate and breast cancer cells. Among the derivatives, <strong>10a</strong>, <strong>10c</strong>, and <strong>10e</strong> exhibited potent cytotoxicity against PC-3 cells with IC<small><sub>50</sub></small> values of 2.08, 7.57, and 5.52 μM compared to doxorubicin (IC<small><sub>50</sub></small> = 2.31 μM) with potent inhibition of CA IX with IC<small><sub>50</sub></small> values of 0.113, 0.134, and 0.214 μM. The most active compound, <strong>10a</strong>, was tested for apoptosis-induction; it induced apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound <strong>10a</strong> against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer†\",\"authors\":\"Fawzia F. Albelwi, Mohamed S. Nafie, Nader R. Albujuq, Wafa Hourani, Ateyatallah Aljuhani, Khaled M. Darwish, Mohamed M. 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引用次数: 0
摘要
考虑到近年来分子杂交在药物发现方面的良好效果,以及开发以 1,2,3-三唑为核心的生物活性支架的持续努力,本研究试图探讨 1,2,3-三唑连接的铬烯和苯磺酰胺核是否对人类乳腺癌细胞系 MCF-7 和前列腺癌细胞系 PC-3 具有活性。为此,通过铜辅助环加成法,将单和/或双炔铬烯酮衍生物 2a 和 b 以及 9 与几种磺胺类药物叠氮化物 4a-d 和 6 有效地合成了三个具有生物活性的单-和双-1,2,3-三唑系列。测试了所得分子衍生物对前列腺癌和乳腺癌细胞的细胞毒性。与多柔比星(IC50 = 2.31 μM)相比,10a、10c 和 10e 对 PC-3 细胞具有很强的细胞毒性,IC50 值分别为 2.08、7.57 和 5.52 μM,对 CA IX 具有很强的抑制作用,IC50 值分别为 0.113、0.134 和 0.214 μM。对活性最强的化合物 10a 进行了诱导细胞凋亡的测试,结果表明它能诱导细胞凋亡,使细胞周期在 G1 期停滞 31.9 倍。此外,分子建模方法突显了活性最高的化合物 10a 与作为 PC-3 前列腺癌相关生物靶点之一的 CA IX 的相关结合亲和力。
Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer†
Considering the promising effects of molecular hybridization on drug discovery in recent years and the ongoing endeavors to develop bioactive scaffolds tethering the 1,2,3-triazole core, the present study sought to investigate whether the 1,2,3-triazole-linked chromene and benzene sulfonamide nucleus could exhibit activity against the human breast cancer cell line MCF-7 and prostate cancer cell line PC-3. To this end, three focused bioactive series of mono- and -bis-1,2,3-triazoles were effectively synthesized via copper-assisted cycloaddition of mono- and/or di-alkyne chromenone derivatives 2a and b and 9 with several sulfa drug azides 4a–d and 6. The resulting molecular derivatives were tested for cytotoxicity against prostate and breast cancer cells. Among the derivatives, 10a, 10c, and 10e exhibited potent cytotoxicity against PC-3 cells with IC50 values of 2.08, 7.57, and 5.52 μM compared to doxorubicin (IC50 = 2.31 μM) with potent inhibition of CA IX with IC50 values of 0.113, 0.134, and 0.214 μM. The most active compound, 10a, was tested for apoptosis-induction; it induced apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound 10a against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.