【文章名】Morpholino, Piperidino, and Pyrrolidino Derivatives of Pyrimidine Nucleosides as Inhibitors of Ribonuclease A: Synthesis, Biochemical, and Crystallographic Evaluation,.
Morpholino, Piperidino, and Pyrrolidino Derivatives of Pyrimidine Nucleosides as Inhibitors of Ribonuclease A: Synthesis, Biochemical, and Crystallographic Evaluation,.
[摘要]：Six 5'-deoxy-5'-morpholine, piperidine, and pyrrolidine of pyrimidine nucleosides, e.g. I, have been synthesized and characterized. Their inhibitory action to RNase A has been studied by biochem. anal. and X-ray crystallog. These compds. are moderate inhibitors of RNase A with mid-to-upper micromolar inhibition consts. (Ki). The high resoln. X-ray crystal structures of the RNase A-inhibitor complexes have shown that all inhibitors bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B1R2 subsites while the 5' group binds away from the main subsite P1, where P-O5' bond cleavage occurs, toward the solvent close to subsite P. Structure-activity relationship anal. has demonstrated that the compds. with the larger group in the 5' position are more potent. Comparative structural anal. of these RNase A complexes with other similar RNase A-ligand complexes provides a structural explanation of their potency and suggests ways to improve their efficiency and selectivity. These inhibitors can be the starting point for the development of compds. that can be used as pharmaceuticals against pathologies assocd. with RNase A homologues such as human angiogenin, which is implicated in tumor induced neovascularization.
