Ribonuclease A Inhibition by Carboxymethylsulfonyl‐Modified Xylo‐ and Arabinopyrimidines

Abstract

A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hydroxy groups in inhibiting RNase A activity. Uridines and cytidines modified with SO2 CH2 COOH groups at the 2'- and 3'-positions show good inhibitory properties with low inhibition constant (Ki ) values in the range of 109-17 μM. The present work resulted in a set of inhibitors that undergo more effective interactions with the RNase A active site, as visualized by docking studies.

Carboxymethylsulfonylated Ribopyrimidines: Rational Design of Ribonuclease A Inhibitors Employing Chemical Logic

“…The inhibition constantv alues obtained from this kinetic experiment are in agreement with the preliminary results obtained from the agarose gel based electrophoresis andp recipitation assays (Table 1). [30] Circular dichroism (CD) spectroscopy also confirmedt hat inhibitor 2 (ribo-C3'SO 2 CH 2 COOH) induced perturbationo ft he secondary structure, which probablyr esulted in reducedc atalytic activity of RNase A. [30] Circular dichroism (CD) spectroscopy also confirmedt hat inhibitor 2 (ribo-C3'SO 2 CH 2 COOH) induced perturbationo ft he secondary structure, which probablyr esulted in reducedc atalytic activity of RNase A.…”

“…The best result so far was obtained by employing the carboxymethylsulfonyl group. [30] To increase the efficiency of binding of this class of molecules further,w eargued that if the otherg roups remained the same, the configurationo ft he 2'-hydroxy group could be altered to synthesize corresponding ribose derivatives 1 (ribo-U3'SO 2 CH 2 COOH)a nd 2 (ribo-C3'SO 2 CH 2 COOH) ( Figure 5), which more closely mimic the natural ribose configuration. Interestingly,i tw as observed during ac omparatives tudy that an increase in the number of acidic groups only produced an inhibitory efficiency similar to that elicited by 2'-hydroxy-group-bearing Y(a) and Y(b).A dditional experiments also established that these compounds were much less polar if measured against the natural substrate or analogous nucleotides.…”

“…[30] Severalo ther factors such as the acidity and additional hydrogen-bondingc apacities of the sulfone oxygen atoms of the carboxymethylsulfonyl group were found to contribute to the overall inhibitory properties of theses ynthetic nucleosides. Qualitative and quantitative bioassays led us to conclude that apart from the presenceo fthe acidic functionality,t he other crucial factor for effective inhibition is the configuration of the 2'-OH group in the sugar ring of the nucleoside.…”

“…[30,43] Accurately weighed (0.50, 1.00, 2.00, and 4.00 mg) portions of 3'-CMP and inhibitors 1 and 2 were individually dissolved in 5.0 mL of pH 7.4, 0.01 m phosphate buffer in volumetric flasks. [30,43] Accurately weighed (0.50, 1.00, 2.00, and 4.00 mg) portions of 3'-CMP and inhibitors 1 and 2 were individually dissolved in 5.0 mL of pH 7.4, 0.01 m phosphate buffer in volumetric flasks.…”

Interplay between intergrin-linked kinase and ribonuclease inhibitor affects growth and metastasis of bladder cancer through signaling ILK pathways

“…However, the protein at a higher concentration causes cell damage by resisting protein synthesis through increased ribonucleolytic activity. And this phenomenon aroused great interest of scientists in designing ribonuclease inhibitors [12–14]. Ribonuclease inhibitor (RI) is a 50 kDa horseshoe-shaped protein.…”