Development of peptidomimetic boronates as proteasome inhibitors

Micale, Nicola; Ettari, Roberta; Lavecchia, Antonio; Giovanni, Carmen Di; Scarbaci, Kety; Troiano, Valeria; Grasso, Silvana; Novellino, Ettore; Schirmeister, Tanja; Zappalà, Maria

doi:10.1016/j.ejmech.2013.03.032

Cited by 35 publications

(37 citation statements)

References 24 publications

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“…The binding mode of 3 c, 3 d, and 4 a was similar to that of previously published proteasome inhibitor 1 [6] and bortezomib. [13] As depicted in Figure 2, the inhibitors were found to adopt a b conformation and to fill the gap between strands S2 and S4 by forming H-bonds with residues T21 and G47, and for 4 a only, A49 of the b5 subunit.…”

Section: Docking Studiessupporting

confidence: 63%

“…Coupling reactions between corresponding acids 13 a-p, obtained by alkaline hydrolysis, and pinanediol leucine boronate (14) [6] in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), hydroxybenzotriazole (HOBt), and N,Ndiisopropylethylamine (DIPEA) afforded pinanediol esters 15 ap (Scheme 2), which were employed without any further purification in the transesterification reaction with isobutylboronic acid under acid conditions to provide desired boronic acids 2-4.…”

Section: Chemistrymentioning

confidence: 99%

“…[6] A variety of secondary and tertiary amino groups (e.g., phenylamino, 3-ethylphenylamino, 4-methoxyphenylamino, benzylamino, piperidin-1-yl, and 4-methylpiperazin-1-yl) were introduced in that position with the aim to establish a trend of reactivity. At the same time, 3-amino-substituted pyridone analogues were developed to compare their binding mode and their ability to interact with b6-D114.…”

Section: Introductionmentioning

confidence: 99%

“…ment of natural amino acids with unnatural amino acids or by the introduction of a rigid scaffold into peptide sequences in such a way as to lock a defined conformation of the peptide. [10][11][12] In this context, we recently developed conformationally constrained pseudopeptide boronates [6] by using bortezomib as a lead compound that are characterized by a 1H-pyridin-2-one ring at P3 as a constrained motif. Overall, this new class of peptidomimetics showed a promising inhibitory profile by blocking two out of three proteolytic activities of the proteasome with preference for b5 subunits.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT-L activity of 20S proteasome. Compounds bearing a β-alanine residue at the P2 position were the most active, that is, 3-ethylphenylamino and 4-methoxyphenylamino (R)-1-{3-[4-(substituted)-2-oxopyridin-1(2H)-yl]propanamido}-3-methylbutylboronic acids (3 c and 3 d, respectively), and these derivatives showed inhibition constants (Ki ) of 17 and 20 nM, respectively. In addition, they co-inhibited post glutamyl peptide hydrolase activity (3 c, Ki=2.57 μM; 3 d, Ki=3.81 μM). No inhibition was recorded against the bovine pancreatic α-chymotrypsin, which thus confirms the selectivity towards the target enzyme. Docking studies of 3 c and related inhibitors into the yeast proteasome revealed the structural basis for specificity. The evaluation of growth inhibitory effects against 60 human tumor cell lines was performed at the US National Cancer Institute. Among the selected compounds, 3 c showed 50% growth inhibition (GI50) values at the sub-micromolar level on all cell lines.

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Section: Docking Studiessupporting

confidence: 63%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…GOLD allows a user-definable number of GA runs per ligand, each of which starts from a different orientation. For these experiments, the number of GA runs was set to 200 without the option of early termination, and scoring of the docked poses was performed with the original ChemPLP scoring function followed by rescoring with ChemScore [36][37][38][39][40]. The final receptor-ligand complex for each ligand was chosen interactively by selecting the highest scoring pose that was consistent with experimentally-derived information about the binding mode of the ligand.…”

Section: Docking Simulationsmentioning

confidence: 99%

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Zurlo

Ziccardi

Votino

et al. 2016

Biochemical Pharmacology

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a b s t r a c tCladosporols are secondary metabolites from Cladosporium tenuissimum characterized for their ability to control cell proliferation. We previously showed that cladosporol A inhibits proliferation of human colon cancer cells through a PPARc-mediated modulation of gene expression. In this work, we investigated cladosporol B, an oxidate form of cladosporol A, and demonstrate that it is more efficient in inhibiting HT-29 cell proliferation due to a robust G0/G1-phase arrest and p21 waf1/cip1 overexpression. Cladosporol B acts as a PPARc partial agonist with lower affinity and reduced transactivation potential in transient transfections as compared to the full agonists cladosporol A and rosiglitazone. Site-specific PPARc mutants and surface plasmon resonance (SPR) experiments confirm these conclusions. Cladosporol B in addition displays a sustained proapoptotic activity also validated by p21 waf1/cip1 expression analysis in the presence of the selective PPARc inhibitor GW9662. In the DMSO/H 2 O system, cladosporols A and B are unstable and convert to the ring-opened compounds 2A and 2B. Finally, docking experiments provide the structural basis for full and partial PPARc agonism of 2A and 2B, respectively. In summary, we report here, for the first time, the structural characteristics of the binding of cladosporols, two natural molecules, to PPARc. The binding of compound 2B is endowed with a lower transactivation potential, higher antiproliferative and proapoptotic activity than the two full agonists as compound 2A and rosiglitazone (RGZ).

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Organocatalyzed Enantioselective Michael Addition of 2‐Hydroxypyridines and α,β‐Unsaturated 1,4‐Dicarbonyl Compounds

Jhong

Lin

et al. 2019

Adv Synth Catal

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The framework of 2-pyridones is prevalent in biologically and medicinally important molecules. Here we report that chiral N-substituted 2-pyridones were prepared by enantioselective, organocatalytic aza-Michael additions of halogenated 2-hydroxypyridines (pyridin-2(1H)-ones) to α,β-unsaturated-1,4-dketones or 1,4-ketoesters. The reactions were optimized by the choice of solvents and systematic screening of Cinchona alkaloid-based bifunctional catalysts to achieve excellent yields and enantioselectivities (up to 98% yield and > 99% ee). Density functional theory calculations provided rationales for the observed enantioselectivity. Formal synthesis of a human rhinovirus protease inhibitor was achieved using the chiral Michael adduct generated by this method.

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Development of peptidomimetic boronates as proteasome inhibitors

Cited by 35 publications

References 24 publications

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

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

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Organocatalyzed Enantioselective Michael Addition of 2‐Hydroxypyridines and α,β‐Unsaturated 1,4‐Dicarbonyl Compounds

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