目的:制备了一系列异香豆素-查尔酮杂种,并测定了抑制人碳酸酐酶(hCA;EC4.2.1.1)的四种同工型,HCAI,II,九和十二。材料和方法:通过将乙酰基-异香豆素与芳香醛缩合合成异香豆素-查尔酮杂化物。它们没有显著抑制脱靶胞质同工型hCAI和II(KI>100μM),但充当肿瘤相关同工型hCAIX和XII的低微摩尔或亚微摩尔抑制剂。结果和结论:我们的工作提供了一种新的和几乎没有研究的化学型的见解,提供了有趣的肿瘤相关CA抑制剂,考虑到一些此类衍生物,如磺胺SLC-0111,正在进行治疗转移性晚期实体瘤的高级临床试验。
制备了一系列异香豆素-查尔酮杂种,并测定了金属酶碳酸酐酶的四种同工型(CA;EC4.2.1.1),即,人(h)同工型hCAI,II,九和十二。异香豆素作为该酶的抑制剂的研究较少。在这里,我们显示异香豆素-查尔酮杂种不显著抑制脱靶胞质同工型hCAI和II(KIs>100μM),但充当肿瘤相关同工型hCAIX和XII的低微摩尔抑制剂。因此,我们的工作提供了一种新的,几乎没有研究的化学型的见解,可能提供有趣的肿瘤相关CA抑制剂,因为一些这样的化合物,例如,磺胺SLC-0111目前正在进行治疗转移性晚期实体瘤的高级临床试验。
Aim: A series of isocoumarin-
chalcone hybrids were prepared and assays for the inhibition of four isoforms of human carbonic anhydrase (hCA; EC 4.2.1.1), hCA I, II, IX and XII. Materials & methods: Isocoumarin-
chalcone hybrids were synthesized by condensing acetyl-isocoumarin with aromatic aldehydes. They did not significantly inhibit off-target cytosolic isoforms hCA I and II (KI >100 μM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Results & conclusion: Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors.
A series of isocoumarin–
chalcone hybrids was prepared and assays for the inhibition of four isoforms of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1), i.e., human (h) isoforms hCA I, II, IX and XII. Isocoumarins were less investigated as inhibitors of this enzyme. Here we show that the isocoumarin–
chalcone hybrids do not significantly inhibit the off-target cytosolic isoforms hCA I and II (KIs >100 μM) but act as low micromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Our work thus provides insights into a new and scarcely investigated chemotype which may provide interesting tumor-associated CA inhibitors, because some such compounds, e.g., the sulfonamide SLC-0111, are presently in advanced clinical trials for the management of metastatic advanced solid tumors.