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Abstract
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.
Highlights
The incidence of oncological diseases has been constantly growing over recent years, while they have been ranked among the leading causes of death globally
New derivatives of 4-[((40,60 -dichloro-10,30,50 -triazine-20 -yl)amino)methyl/-2amino)ethyl]benzenesulfonamide possessing a pair of identical amino acid with a nonpolar (Ala, Tyr, Trp) and a polar side chain (Gln, Asn, Ser, Thr) were synthesized using a two-step nucleophilic substitution of chlorine atoms of cyanuric chloride
The present work focused on the synthesis, isolation, purification, identification, and human carbonic anhydrase (hCA)
Summary
The incidence of oncological diseases has been constantly growing over recent years, while they have been ranked among the leading causes of death globally. The structural modification and development of novel small-molecule- or monoclonal-antibody-based compounds, with affinity and selectivity towards tumorspecific receptors/markers, belong to the most prospective approaches in the diagnosis, imaging, and therapy of hypoxic tumors, and so for personalized care of oncological patients [5]. A mechanism of the catalytic activity of tumor-associated hCA isozymes in hypoxic tumors and its inhibition has been a promising target over a long period in many studies by Supuran [6,7,8,9], Pastorek and Pastorekova [10,11,12,13] working groups and in other very recently published papers [14,15,16,17,18]. Anyway, considering a broader extent of disease ( involving non-oncological ones), the inhibition of other hCA isozymes is useful, e.g., hCA I is related to retinal and cerebral edema, hCA II to glaucoma, bone and renal diseases, edema, epilepsy, or acute high-altitude illness, and hCA IV to glaucoma, stroke, and retinitis [19]
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