Carboxymethyl tethered poly(disubstituted)triazoles built on nucleoside skeletons: A unique class of ribonuclease A inhibitors designed using chemical logic. (15th December 2022)

• Record Type: Journal Article
• Authors: Mondal, Pampa; Dasgupta, Swagata; Pathak, Tanmaya
• Is Part Of: Bioorganic & medicinal chemistry. Volume 76(2022)
• Publication Date: 2022-12-15
• Subjects: RNA hydrolysis, hyperbolic partial competitive inhibitors -- 1, 4-disubstituted 1, 2, 3-triazole -- Click chemistry -- Polytriazolylated pyrimidines -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117065
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Molecular docking studies indentified monotriazolylated pyrimidine nucleosides and their poly(disubstituted)triazole congener as inhibitors of ribonuclease A (RNase A). Thus several carboxymethyl tethered poly(disubstituted)triazoles on nucleoside skeleton were prepared by easy synthetic routes using the well-established CuAAC mediated 1, 4-DT formation. These poly-heterocyclic compounds were screened as RNase A inhibitors by biochemical studies. Kinetic studies revealed that the nature and efficiency of inhibition were significantly altered by the functional groups present at different positions of the nucleosides. Abstract: Molecular docking of N -1, 4-disubstituted-1, 2, 3-triazole tethered carboxymethylated thymidine and uridine with ribonuclease A, indicated their possible binding with the P1, B1 and P2 subsites with varied efficiencies. This theoretical study in combination of our earlier experimental observations was used as the guiding principles for designing a range of 1, 4-disubstituted 1, 2, 3- triazole tethered carboxymethylated pyrimidine nucleosides. Triazoles are biologically important molecules and at the same time easily accessible through less complicated synthetic routes as reported about two decades back in the context of "click" reactions. Regioselective propargylation of the nucleosides under controlled conditions followed by the use of CuAAC strategy afforded mono-, bis-, tris- and tetratriazolyl pyrimidine nucleosides. Although the characteristics of nucleosides were lost in these densely functionalized polyheterocycles, the catalytic efficiency of ribonuclease A was significantly reduced by these molecules which were investigated experimentally and by docking studies. Triazoles as linkers helped one or more acidic groups to reach the P1 subsite of ribonuclease A. Enzyme kinetics showed that the efficiency of inhibition reached the highest point with an optimum number of functional groups and were not linearly dependent on the number of triazole tethered carboxymethyl groups. The location of the triazole ring in the molecule affected the efficiency and nature of inhibition which were the result of the overall structure of the modified nucleosides. Thus, the tris-triazolylated thymidine derivative (T-3′, 5′, N -tris-CH2 TzCH2 COOH) as opposed to tetra-triazolylated uridine (U-2′, 3′, 5′, N -tetrakis-CH2 TzCH2 COOH) emerged as the best inhibitor with an inhibition constant value of 2.3 ± 0.05 µM.