Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, Telangana State, India.
Synergy Community Welfare Research Center (SCWRC), Head office, Panacea, Synergy India Foundation, 4th Floor TSWREIS building, Masab Tank Hyderabad 500028, India.
Anticancer Agents Med Chem. 2022;22(14):2647-2654. doi: 10.2174/1871520622666220304184525.
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and proton. Inhibition of isoforms IX and XII could aid in the amelioration of cancer.
A series of coumarin carboxamides (6a-j) were synthesized and were assayed against hCA isoforms I, II, IX, and XII.
Thin Layer Chromatography (TLC) analysis was done by utilizing Merck silica gel 60 F254 aluminum plates. Stuart Digital Melting Point Apparatus (SMP 30) was used in determining the melting points of the compounds, which are uncorrected. High Resolution Mass Spectra (HRMS) were determined by Agilent QTOF mass spectrometer 6540 series instrument and were performed using ESI techniques at 70eV.
All the compounds selectively inhibited isoforms IX and XII as against hCAs I and II. Compounds 6a-e exhibited the best inhibitory profiles against hCA IX (Ki < 25 nM). The isoform hCA XII was effectively inhibited by all compounds showing the Ki values less than 65 nM. The Compounds 6a, 6b, 6g, 6h, and 6j exhibited Ki values less than 10 nM. The binding interactions of the most potent compounds, 6a and 6b, were investigated through docking studies with hCAs IX and XII.
These compounds may be utilized as useful starting points for the design and development of selective and potent hCA IX and XII inhibitors.
碳酸酐酶（CA，EC 4.2.1.1）催化二氧化碳可逆水合为碳酸氢根和质子。抑制同工酶 IX 和 XII 可有助于改善癌症。
合成了一系列香豆素羧酰胺（6a-j），并对 hCA 同工酶 I、II、IX 和 XII 进行了测定。
采用 Merck 硅胶 60 F254 铝片进行薄层色谱（TLC）分析。采用 Stuart 数字熔点仪（SMP 30）测定化合物熔点，未经校正。高分辨率质谱（HRMS）由 Agilent QTOF 质谱仪 6540 系列仪器确定，并采用 ESI 技术在 70eV 下进行。
所有化合物均选择性抑制 hCAs I 和 II 同工酶，对 hCA IX 和 XII。化合物 6a-e 对 hCA IX 的抑制活性最佳（Ki < 25 nM）。所有化合物均能有效抑制 hCA XII，Ki 值均小于 65 nM。化合物 6a、6b、6g、6h 和 6j 的 Ki 值均小于 10 nM。通过与 hCA IX 和 XII 的对接研究，研究了最有效化合物 6a 和 6b 的结合相互作用。
这些化合物可用作设计和开发选择性和有效 hCA IX 和 XII 抑制剂的有用起点。
