Design, Synthesis, Biological Evaluation, and Structure−Activity Relationship (SAR) Discussion of Dipeptidyl Boronate Proteasome Inhibitors, Part I: Comprehensive Understanding of the SAR of α-Amino Acid Boronates

Abstract

New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC(50) values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC(50) values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC(50) value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.

Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA)

“…Thus far, there have been many kinds of proteasome inhibitors in the references, including peptide aldehydes, 10, 11 arecoline oxide tripeptides, 12, 13 retro hydrazino-azapeptoids, 14 proline- and arginine-rich peptides, 15 dipeptidyl boronates, 16 dipeptidyl boronic acids, 17-19 β-lactones, 20-22 epoxyketones, 23-26 vinyl sulfones, 27-29 substituted vinyl ketones, 30 α,β-unsaturated N-acylpyrrole peptidyl derivatives, 31 cyclic peptides, 32, 33 and so on. 34 According to their chemical properties, the proteasome inhibitors can be mainly grouped into several types, and each type has a unique binding mode with the active sites of proteasome.…”

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

“…Based on the built 3D-QSAR models, a series of novel dipeptide boronic acid proteaosme inhibitors were designed and synthesized [93]. Biological evaluation supported most results of the theoretical models, while for the SAR of substituents at P3 position, it is necessary to construct new 3D-QSAR models to guide the drug design.…”

Complementarity of electronic and vibrational circular dichroism based on stereochemical studies of vic-diols

“…However, in our hands, specific rotation of a (+)-pinanediol sample derived from Aldrich CAS Number 18680-27-8, under the same conditions as those used by Japanese authors [46], was +0.95. Much better agreement was observed in toluene, where the optical rotations of 7 were +8.5 to +7.9 [49][50][51]. In ethanol, in turn, these values vary between +2.8 and +3.3 [52][53][54].…”