2016
DOI: 10.1016/j.bmc.2016.04.005
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Substituted quinolines as noncovalent proteasome inhibitors

Abstract: Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity … Show more

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Cited by 30 publications
(20 citation statements)
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References 51 publications
(57 reference statements)
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“…These compounds became widely used chemical probes and, subsequently, a few were approved for the treatment of multiple myeloma patients 53 , where they seem to exploit the need of cancer cells for high protein turnover. More recently, other strategies have been developed to create inhibitors with different mechanisms 62 . Activators of the proteasome, in contrast, have received less attention; as mentioned above, such molecules would ideally bind to the unbound 20S and open its pore, acting as “artificial activators” to compensate for the loss of natural PAs and proteasome activity during ageing (Fig 3).…”
Section: Pharmacological Activators Of the 20s Proteasomementioning
confidence: 99%
“…These compounds became widely used chemical probes and, subsequently, a few were approved for the treatment of multiple myeloma patients 53 , where they seem to exploit the need of cancer cells for high protein turnover. More recently, other strategies have been developed to create inhibitors with different mechanisms 62 . Activators of the proteasome, in contrast, have received less attention; as mentioned above, such molecules would ideally bind to the unbound 20S and open its pore, acting as “artificial activators” to compensate for the loss of natural PAs and proteasome activity during ageing (Fig 3).…”
Section: Pharmacological Activators Of the 20s Proteasomementioning
confidence: 99%
“…Quinoline is one of the privileged scaffolds due to its wide abundance in biologically active natural products . Compounds containing quinoline scaffolds play a significant role in a wide range of therapeutic areas including antimalarial, antimicrobial, CNS, anti-inflammatory, anticancer agents, and potentially recent SARS-CoV-2 treatment . Substituted quinoline derivatives have also been used as building blocks and catalysts .…”
Section: Introductionmentioning
confidence: 99%
“…Relatively few noncompetitive/allosteric small molecule regulators of the CP activities have been described so far. Among them are several compounds with a quinoline or imidazoline scaffold (inhibitors), derivatives of rapamycin (inhibitors), chlorpromazine (activators), or betulinic acid (inhibitors/activators). A promising direction in the design of proteasome modulators could be peptidic structures, since peptides and peptidomimetics can offer higher specificity and lower toxicity than low molecular weight compounds . Peptide modulators can be derived from the binding regions of proteins which are natural proteasome regulators.…”
Section: Introductionmentioning
confidence: 99%