Nocentini Alessio, Bua Silvia, Lomelino Carrie L, McKenna Robert, Menicatti Marta, Bartolucci Gianluca, Tenci Barbara, Di Cesare Mannelli Lorenzo, Ghelardini Carla, Gratteri Paola, Supuran Claudiu T
Department of NEUROFARBA, Pharmaceutical and Nutraceutical section, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, Florida 32610, United States.
ACS Med Chem Lett. 2017 Nov 21;8(12):1314-1319. doi: 10.1021/acsmedchemlett.7b00399. eCollection 2017 Dec 14.
Incorporation of the purine/pyrimidine moieties as tails to classical benzenesulfonamide scaffolds afforded two series of human (h) carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The compounds were designed according to the molecular hybridization approach, in order to modulate the interaction with different CA isozymes and exploit the antitumor effect of uracil and adenine derivatives in parallel and synergic mode to the inhibition of the tumor-associated hCA IX. The sulfonamides were investigated as inhibitors of four isoforms, cytosolic hCA I/II and transmembrane hCA IV/IX. The inhibitory profiles were dependent on the length and positioning of the spacer connecting the two pharmacophores. X-ray crystallography demonstrated the binding mode of an inhibitor to hCA II and hCA IX-mimic. Compounds endowed with the best hCA IX inhibitory efficacy were evaluated for antiproliferative activity against HT-29 colon cancer cell lines. The results suggest multiple mechanisms of action are responsible for the compounds' cytotoxic efficacy.
将嘌呤/嘧啶部分作为尾巴引入经典的苯磺酰胺支架，得到了两个系列的人（h）碳酸酐酶（CA，EC 4.2.1.1）抑制剂。这些化合物是根据分子杂交方法设计的，目的是调节与不同CA同工酶的相互作用，并以平行和协同的方式利用尿嘧啶和腺嘌呤衍生物的抗肿瘤作用来抑制肿瘤相关的hCA IX。研究了这些磺酰胺作为四种同工型（胞质hCA I/II和跨膜hCA IV/IX）抑制剂的情况。抑制谱取决于连接两个药效基团的间隔基的长度和位置。X射线晶体学证明了一种抑制剂与hCA II和hCA IX模拟物的结合模式。对具有最佳hCA IX抑制效力的化合物进行了针对HT-29结肠癌细胞系的抗增殖活性评估。结果表明，多种作用机制导致了这些化合物的细胞毒性效力。
