A class of compounds with a common thiazolo[3,2-a]pyrimidinone motif has been developed as general inhibitors of Bcl-2 family proteins. The lead compound was originally identified in a random screening of a small compound library using a fluorescence polarization-based competitive binding assay. Its binding to the Bcl-x(L) protein was further confirmed by (15) N-HSQC NMR experiments. Structural modifications on the lead compound were guided by the outcomes of molecular modeling studies. Among the 42 compounds obtained, a number of them exhibited much improved binding affinities to Bcl-2 family proteins as compared to the lead compound. The most potent compound, BCL-LZH-40, inhibited the binding of BH3 peptides to Bcl-x(L), Bcl-2, and Mcl-1 with inhibition constants (K(i)) of 17, 534, and 200 nM, respectively.
Fluorinated peptidomimetic foldamers are still in their infancy. We report here the easy access to fluorinated triazolamers based on 2-amino-3,3,3-trifluoropropyl-1,4-triazolyl acetic acid (CF 3 À 1,4-Tz) and on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-TzÀ CF 2). Both CF 3 À 1,4-Tz and 1,4-TzÀ CF 2 amino acids were efficiently prepared by copper(I)-catalyzed Huisgen 1,3dipolar cycloaddition. Their conformational preferences were studied by 2D NMR analyses and molecular dynamic simulations. Foldamers based on CF 3 À 1,4-Tz amino acids are capable of adopting short multi-stranded β-sheet-like structures that are maintained by electrostatic interactions between the triazole proton and N2 atom of neighboring subunits. On the contrary, foldamers based on 1,4-TzÀ CF 2 units adopt elongated β-strandlike structures, stabilized by electrostatic interaction between fluorine atoms and their neighboring protons.
In a previous study we reported a class of compounds with a 2H-thiazolo[3,2-a]pyrimidine core structure as general inhibitors of anti-apoptotic Bcl-2 family proteins. However, the absolute stereochemical configuration of one carbon atom on the core structure remained unsolved, and its potential impact on the binding affinities of compounds in this class was unknown. In this study, we obtained pure R and S enantiomers of four selected compounds by HPLC separation and chiral synthesis. The absolute configurations of these enantiomers were determined by comparing their circular dichroism spectra to that of an appropriate reference compound. In addition, a crystal structure of one selected compound revealed the exocyclic double bond in these compounds to be in the Z configuration. The binding affinities of all four pairs of enantiomers to Bcl-xL , Bcl-2, and Mcl-1 proteins were measured in a fluorescence-polarization-based binding assay, yielding inhibition constants (Ki values) ranging from 0.24 to 2.20 μM. Interestingly, our results indicate that most R and S enantiomers exhibit similar binding affinities for the three tested proteins. A binding mode for this compound class was derived by molecular docking and molecular dynamics simulations to provide a reasonable interpretation of this observation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.