Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation.,European Journal of Medicinal Chemistry

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Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-01-02 , DOI: 10.1016/j.ejmech.2019.112019
Mohamed A Said ₁ , Wagdy M Eldehna ₂ , Alessio Nocentini ₃ , Samar H Fahim ₄ , Alessandro Bonardi ₃ , Abdullah A Elgazar ₅ , Vladimír Kryštof ₆ , Dalia H Soliman ₇ , Hatem A Abdel-Aziz ₈ , Paola Gratteri ₉ , Sahar M Abou-Seri ₄ , Claudiu T Supuran ₁₀

Affiliation

Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
Laboratory of Growth Regulators, Palacky University & Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 78371, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinská 5, 77900, Olomouc, Czech Republic.
Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al Azhar University, Cairo, P.O. Box 11471, Egypt.
Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.

In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with KIs ranges 6-67.6 and 10.1-88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC50 = 6.4, 8.0 and 11.6 μM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.

中文翻译：

具有新的碳酸酐酶抑制剂的基于CAN的基于环酰胺类似物的CAN508具有抗肿瘤活性：设计，合成和体外生物学评估。

在本研究中，我们报告了新型基于CAN508磺酰胺的类似物（4、8a-e，9a-h和10a-e）的设计和合成，它们是具有潜在CDK抑制活性的新型碳酸酐酶（CA）抑制剂。采用生物等位取代方法，用氨磺酰基取代CAN508的酚羟基，得到化合物4。此后，采用环融合方法制备5/5稠合的咪唑并吡唑8a-e，随后将其扩容至6/5。吡唑并嘧啶9a-h和10a-e。评价所有合成的类似物对hCA I，II，IX和XII同工型的抑制活性。与靶肿瘤相关的同工型hCA IX和XII分别被KIs范围分别为6-67.6和10.1-88.6 nM抑制。此外，评估了所有化合物的潜在CDK2和9种抑制活性。吡唑并嘧啶9d，9e和10b表现出较弱的CDK2抑制活性（分别为IC50 = 6.4、8.0和11.6μM），以及已废除的CDK9抑制活性。该趋势表明吡唑并嘧啶衍生物值得进一步优化以提供更有效的CDK2抑制剂铅。由于它们对hCA IX和XII的优异活性和选择性，因此在高氧和低氧条件下，对吡唑并嘧啶10评估了它们对乳腺癌MCF-7和MDA-MB-468细胞系的抗增殖活性。最有效的抗增殖剂10a，10c和10d在sub-G1和G2-M期显着增加了细胞百分比，同时在经MCF-7处理的细胞中S期种群也随之减少。最后，

更新日期：2020-01-02

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