Show simple item record

dc.contributor.authorPerchellet, Jean-Pierre H.
dc.contributor.authorPerchellet, Elisabeth M.
dc.contributor.authorCrow, Kyle R.
dc.contributor.authorBuszek, Keith R.
dc.contributor.authorBrown, Neil
dc.contributor.authorEllappan, Sampathkumar
dc.contributor.authorGao, Ge
dc.contributor.authorLuo, Diheng
dc.contributor.authorMinatoya, Machiko
dc.contributor.authorLushington, Gerald H.
dc.identifier.citationPERCHELLET, J.-P. H., PERCHELLET, E. M., CROW, K. R., BUSZEK, K. R., BROWN, N., ELLAPPAN, S., … LUSHINGTON, G. H. (2009). Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins. International Journal of Molecular Medicine, 24(5), 633–643.en_US
dc.description.abstractPilot-scale libraries of eight-membered medium ring lactams (MRLs) and related tricyclic compounds (either seven-membered lactams, thiolactams or amines) were screened for their ability to inhibit the catalytic activity of human recombinant 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. A dozen of the synthetic compounds mimic the inhibition of purified HMG-CoA reductase activity caused by pravastatin, fluvastatin and sodium salts of lovastatin, mevastatin and simvastatin in this cell-free assay, suggesting direct interaction with the rate-limiting enzyme of cholesterol biosynthesis. Moreover, several MRLs inhibit the metabolic activity of L1210 tumor cells in vitro to a greater degree than fluvastatin, lovastatin, mevastatin and simvastatin, whereas pravastatin is inactive. Although the correlation between the concentration-dependent inhibitions of HMG-CoA reductase activity over 10 min in the cell-free assay and L1210 tumor cell proliferation over 4 days in culture is unclear, some bioactive MRLs elicit interesting combinations of statin-like (IC50: 7.4-8.0 µM) and anti-tumor (IC50: 1.4-2.3 µM) activities. The HMG-CoA reductase-inhibiting activities of pravastatin and an MRL persist in the presence of increasing concentrations of NADPH. But increasing concentrations of HMG-CoA block the HMG-CoA reductase-inhibiting activity of pravastatin without altering that of an MRL, suggesting that MRLs and existing statins may have different mechanisms of enzyme interaction and inhibition. When tested together, suboptimal concentrations of synthetic MRLs and existing statins have additive inhibitory effects on HMG-CoA reductase activity. Preliminary molecular docking studies with MRL-based inhibitors indicate that these ligands fit sterically well into the HMG-CoA reductase statin-binding receptor model and, in contrast to mevastatin, may occupy a narrow channel housing the pyridinium moiety on NADP+.en_US
dc.publisherSpandidos Publicationsen_US
dc.titleNovel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statinsen_US
kusw.kuauthorBrown, Neil
kusw.kuauthorLushington, Gerald H.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO 6/28/2017: hor's Pre-print: cross author cannot archive pre-print (ie pre-refereeing) Author's Post-print: cross author cannot archive post-print (ie final draft post-refereeing) Publisher's Version/PDF: grey tick subject to Restrictions below, author can archive publisher's version/PDF Restrictions:

6 months embargo

General Conditions:

Publisher's version/PDF must be used On Institutional Repository or Funder's repository Must link to publisher version Published source must be acknowledged with full citation Publisher will automatically deposit authors post-print in PubMed Central or Europe PMC after 6 months or 12 months as required by funding agency
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

Files in this item


This item appears in the following Collection(s)

Show simple item record