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

Abstract

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.

Development of Novel Selective Peptidomimetics Containing a Boronic Acid Moiety, Targeting the 20S Proteasome as Anticancer Agents

“…cently reported. [14,15] In this context, boronic acids 3 c and 3 d showed K i values of 17 and 20 nm, respectively, against ChT-L activity, which are quite comparable to the K i value of bortezomib (9.8 nm), which was tested under the same experimental conditions.…”

“…Additional structural modifications were the incorporation of different sterically hindered residues at the P2 position, such as phenylalanine in analogy to the structure of bortezomib and b-alanine, taking into consideration that several dipeptidyl boronic acids constructed from b-amino acids are endowed with a good profile in terms of proteasome inhibition, cytotoxic activity versus hematologic tumor cell lines, and pharmacokinetic properties. [14,15] The Leu-boronic electrophilic moiety was maintained as a warhead for its ability to reversibly interact with the N-terminal catalytic active site T1O…”

In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: Identifying sinensetin as a novel antiangiogenesis agent

“…These assays provide no information about hidden toxicity or any side effect due to interaction with other molecular targets and cell types and, more importantly, leading to overall toxicity to the whole organism. Recently, in vivo SAR analysis of active compounds that takes bioavailability and ADME (absorption, distribution, metabolism, and excretion) properties of the screened compound into account, has been realized in a zebrafish model []. However, there is no reported study on content screen for both activity and toxicity in zebrafish.…”

Inhibitors of Proteinases as Potential Anti-Cancer Agents

“…Alongside with physiologic studies synthesis and evaluation of inhibitory activity of its analogues have been carried out. Although in some cases inhibitors of similar potency were obtained (Aubin et al, 2005;Vivier et al, 2005;Zhu et al, 2010) none of them was found to be better than bortezomib.…”