Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

New dihydro-pyrrol-2-one
compounds, featuring dual sulfonamide
groups, were synthesized through a one-pot, three-component approach
utilizing trifluoroacetic acid as a catalyst. Computational analysis
using density functional theory (DFT) and condensed Fukui function
explored the structure–reactivity relationship. Evaluation
against human carbonic anhydrase isoforms (hCA I, II, IX, XII) revealed
potent inhibition. The widely expressed cytosolic hCA I was inhibited
across a range of concentrations (KI 3.9–870.9 nM). hCA II, also cytosolic, exhibited good
inhibition as well. Notably, all compounds effectively inhibited tumor-associated
hCA IX (KI 1.9–211.2
nM) and hCA XII (low nanomolar). Biological assessments on MCF7 cancer
cells highlighted the compounds’ ability, in conjunction with
doxorubicin, to significantly impact tumor cell viability. These findings
underscore the potential therapeutic relevance of the synthesized
compounds in cancer treatment.

本研究通过以三氟乙酸为催化剂的一锅法三组分合成策略，制备了一类带有双磺酰胺基团的新型二氢吡咯-2-酮（dihydro-pyrrol-2-one）类化合物。采用密度泛函理论（DFT）与凝聚福井函数开展计算分析，探究了该类化合物的构效关系。针对人类碳酸酐酶同工型（hCA I、II、IX、XII）的活性测试结果显示，此类化合物具有强效抑制活性：在广泛组织中表达的胞质型hCA I在多个浓度梯度下均被抑制，其抑制常数KI为3.9~870.9纳摩尔；同为胞质型的hCA II也展现出良好的抑制效果。值得注意的是，所有化合物均可有效抑制肿瘤相关的hCA IX（KI 1.9~211.2纳摩尔）与hCA XII（可在低纳摩尔浓度下实现抑制）。对MCF7癌细胞的生物学评估表明，该类化合物与多柔比星（doxorubicin）联用时，可显著降低肿瘤细胞存活率。上述研究结果凸显了本研究合成的这类化合物在癌症治疗领域的潜在治疗价值。