A series of beta-carbolin-2-ones and 3,10-dihydro-2H-azepino[3,4-b]indol-1-ones have been designed, synthesized, and evaluated as RET protein kinase inhibitors oil the basis Of their Structural similarity with the prototype indolin-2-one RPI-1. Some beta-carbolin-2-ones (structure 2) showed ail ability to inhibit RET enzymatic activity in vitro and proliferation of RETC634R oncogene-transformed NIH3T3 cells comparable to that of the reference compound. The docking analysis of the interaction of these compounds with the crystallographic structure of RET tyrosine kinase domain suggested a new binding interaction scheme different from the one proposed during their design. The rigid structure of the compounds of this series represents a new scaffold with potential advantages in the design of RET protein kinase inhibitors.
Synthesis, Modeling, and RET Protein Kinase Inhibitory Activity of 3- and 4-Substituted β-Carbolin-1-ones / R. Cincinelli, G. Cassinelli, S. Dallavalle, C. Lanzi, L. Merlini, M. Botta, T. Tuccinardi, A. Martinelli, S. Penco, F. Zunino. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 51:24(2008 Dec 25), pp. 7777-7787.
Synthesis, Modeling, and RET Protein Kinase Inhibitory Activity of 3- and 4-Substituted β-Carbolin-1-ones
R. CincinelliPrimo
;S. Dallavalle;L. Merlini;
2008
Abstract
A series of beta-carbolin-2-ones and 3,10-dihydro-2H-azepino[3,4-b]indol-1-ones have been designed, synthesized, and evaluated as RET protein kinase inhibitors oil the basis Of their Structural similarity with the prototype indolin-2-one RPI-1. Some beta-carbolin-2-ones (structure 2) showed ail ability to inhibit RET enzymatic activity in vitro and proliferation of RETC634R oncogene-transformed NIH3T3 cells comparable to that of the reference compound. The docking analysis of the interaction of these compounds with the crystallographic structure of RET tyrosine kinase domain suggested a new binding interaction scheme different from the one proposed during their design. The rigid structure of the compounds of this series represents a new scaffold with potential advantages in the design of RET protein kinase inhibitors.Pubblicazioni consigliate
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