具有各种杂环的伯磺酰胺衍生物代表了最广泛的潜在人类碳酸酐酶(hCA)抑制剂,对hCA家族的特定同工酶具有高亲和力和选择性。在这项工作中,新的4-氨基甲基和氨基乙基-苯磺酰胺衍生物,其1,3,5-三嗪被一对相同的氨基酸双取代,拥有一个极地(Ser,Thr,Asn,Gln)和非极性(Ala,Tyr,Trp)侧链,已经合成了。优化的合成,净化,和分离程序提供了几个明显的好处,如短的反应时间(在碳酸氢钠水性介质),大多数新产品的收率令人满意(20.6-91.8%,平均60.4%),一个有效的,明确定义的半制备RP-C18液相色谱(LC)分离高纯度(>97%)的所需产物,以及绿色化学原理的保存。这些新合成的结合物,加上先前制备的4-氨基苯磺酰胺类似物,已经在对HCAI的体外抑制研究中进行了研究,II,IV和肿瘤相关同工酶IX和XII。实验结果表明,对于具有非极性侧链的氨基酸的衍生物(7.5-9.6nM),hCAXII的抑制作用最强,具有低纳摩尔抑制常数(Kis)。各种衍生物也有希望用于一些其他同工酶。
Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a pair of identical amino acids, possessing a polar (Ser, Thr, Asn, Gln) and non-polar (Ala, Tyr, Trp) side chain, have been synthesized. The optimized synthetic, purification, and isolation procedures provided several pronounced benefits such as a short reaction time (in sodium bicarbonate aqueous medium), satisfactory yields for the majority of new products (20.6-91.8%, average 60.4%), an effective, well defined semi-preparative RP-C18 liquid chromatography (LC) isolation of desired products with a high purity (>97%), as well as preservation of green chemistry principles. These newly synthesized conjugates, plus their 4-aminobenzenesulfonamide analogues prepared previously, have been investigated in in vitro inhibition studies towards hCA I, II, IV and tumor-associated isozymes IX and XII. The experimental results revealed the strongest inhibition of hCA XII with low nanomolar inhibitory constants (Kis) for the derivatives with amino acids possessing non-polar side chains (7.5-9.6 nM). Various derivatives were also promising for some other isozymes.