Identification of a new series of amides as non-covalent proteasome inhibitors

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

doi:10.1016/j.ejmech.2014.01.022

Cited by 25 publications

(18 citation statements)

References 44 publications

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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

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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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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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“…[3,19,[30][31][32][33][34] Alternative conformations of the Arg120, Tyr355,G lu 524, and Ser 530 side chains have been previously observedi nC OX crystal structures complexed with several inhibitors,h ighlighting the innate plasticity of the active site. [26,35,36] Accordingly,t he Arg 120, Tyr355, Glu 524, and Ser 530 side chains were allowedt om ove during the docking experiments.…”

Section: Dockingstudiesmentioning

confidence: 85%

Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

et al. 2016

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A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N-(9-{2-[(4-{2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetamido}butyl)carbamoyl]phenyl-6-(ethylamino)-2,7-dimethyl-3H-xanthen-3-ylidene}ethanaminium chloride] was found to be a selective COX-1 inhibitor, whereas 17 (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]ethanone) was found to be a sub-micromolar selective COX-2 inhibitor. However, both were shown to interact with P-glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.

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“…by covalent binding with the threonine nucleophile or by non-covalent binding at the proteolytic sites. Examples of the former include epoxomicin, bortezomib and carfilzomib [70] while examples of the latter are TMC-95 and various amides [73]. Both neutral and cationic copper(II) species seem to be stable within 48 h, and the ROS-generating and proteasome inhibition properties can be attributed to these species.…”

Section: S Proteasome Inhibitionmentioning

confidence: 98%