Yongqiang Zhu

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

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.

3D-QSAR studies of boron-containing dipeptides as proteasome inhibitors with CoMFA and CoMSIA methods

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of dipeptide boronate proteasome inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 46 molecules served to establish the models. The optimum CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q(2)) of 0.676 and 0.630 and conventional coefficients (r(2)) of 0.989 and 0.956, respectively. The predictive capacities of both models were successfully validated by calculating a test set of 13 molecules that were not included in the training set. The predicted correlation coefficients (r(2)(pred)) of CoMFA and CoMSIA are 0.963 and 0.919, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of beta5 subunit of 20S proteasome, which suggests that the 3D-QSAR models constructed in this paper can be used to guide the development of novel dipeptide boronate inhibitors of 20S proteasome.

Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure—Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of β-Amino Acids

A series of novel dipeptidyl boronic acid proteasome inhibitors composed of beta-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i was the most active. The IC(50) value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC(50) values nearly less than 5 microM against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in a similar way as bortezomib.

Synthesis, in vitro and in vivo biological evaluation, and comprehensive understanding of structure-activity relationships of dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids.

An extensive structure-activity relationship (SAR) study of 72 dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids is reported. SAR analysis revealed that bicyclic groups at the R¹ position, 3-F substituents at the R² position, and bulky aliphatic groups at the R³ position were favorable to the activities. Enzymatic screening results showed that compound 78, comprising all of these features, was the most active inhibitor against the 20S human proteasome at less than a 2 nM level, as active as the marketed drug bortezomib. Cellular assays confirmed that compound 78 was the most potent against two hematologic and some solid tumor cells with IC₅₀ values less than 1 μM. Pharmacokinetic profiles suggested that 78 showed higher plasma exposure and a longer half-life than bortezomib.

Pharmacophore Modeling, Docking Studies, and Synthesis of Novel Dipeptide Proteasome Inhibitors Containing Boron Atoms

A 3D pharmacophore model had been generated for a series of dipeptide proteasome inhibitors containing boron atoms using Catalyst. A data set consisting of 24 inhibitors was selected on the basis of the information content of the structures and activity data as required by the Catalyst/HypoGen program. The built model was able to predict the activity of other known proteasome inhibitors not included in the model generation. Based on the analysis of the best hypotheses, some novel proteasome inhibitors were designed and predicted. Three dipeptide boronic acid inhibitors SMNT 1, SMNT 2, and SMNT 3, were synthesized and biologically assayed. It turned out that the three designed molecules were all more potent than the marketed MG341, and the experimental values were consistent with the predicted ones, indicating that the theoretical model was reliable enough to predict and design novel proteasome inhibitors. The covalent interaction mode between the boron atom of the inhibitor and O(gamma)-Thr1 residue of the 20S proteasome was studied for the first time by employing the most potent inhibitor SMNT 2 with the Insight II 2005/Affinity program. The docking results agreed well with the experimental ones.

Progress of computer-aided drug design (CADD) of proteasome inhibitors.

The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer-aided drug design (CADD) plays a more and more important role in todays drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteasome were visualized with these new technologies.