Abstract
Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared with previously used methods. The synthesis of triazinyl-substituted benzene-sulfonamide conjugates with amino acids can be easily carried out using sodium carbonate-based water solution as a synthetic medium instead of N,N-Diisopropylethylamine/Dimethylformamide. The benefits of this synthetic procedure include: (i) high selectivity of the creation of disubstituted conjugates; (ii) several times higher yield (≥95%) than that achieved previously; (iii) elimination of organic solvents by the use of an environmental friendly water medium (green chemistry); (iv) simple and fast isolation of the product. The synthesis and resulting products were evaluated using TLC, IR, NMR, and MS methods. The present work demonstrates a significant advantage in providing shortened routes to target structures.
Highlights
Carbonic anhydrase (CA) IX and XII, as secondary tumor-related CAs, are found to be overexpressed in cervical, breast, bladder, and non-small cell lung cancers by instigating hypoxia and causing acidification in the extracellular region, which leads to metastatic spread of these tumor cells.the acidification can render classical cancer treatments ineffective, those utilizing basic antitumor drugs and radiotherapy
We studied the possibilities of effectivization of the synthetic procedure for the preparation of triazinyl-substituted benzene-sulfonamide conjugates with amino acids
Three synthetic procedures for a group of triazinyl-substituted benzene-sulfonamide conjugates with amino acids were designed and tested as alternatives to the already established procedure used for the preparation of these highly potent CA-inhibitors
Summary
Carbonic anhydrase (CA) IX and XII, as secondary tumor-related CAs, are found to be overexpressed in cervical, breast, bladder, and non-small cell lung cancers by instigating hypoxia and causing acidification in the extracellular region, which leads to metastatic spread of these tumor cells.the acidification can render classical cancer treatments ineffective, those utilizing basic antitumor drugs and radiotherapy. It was shown that sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II [4,5,6,7,8]. A reaction of triazinyl-substituted benzene-sulfonamide with amino acids afforded a new series of highly potent conjugates with enhanced polarity [4,5]. Declared yields for amino acid (glycine, β-alanine) conjugates ranged in the interval of 32–55%. These parameters indicate that there is a need to revise the established synthetic procedure with respect to the reaction yield and working conditions
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