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

Abstract

Abstract. Pilot-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 ratelimiting 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 concentrationdependent 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 (IC 50 : 7.4-8.0 μM) and anti-tumor (IC 50 : 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 + .

In VitroScreening forβ-Hydroxy-β-methylglutaryl-CoA Reductase Inhibitory and Antioxidant Activity of Sequentially Extracted Fractions ofFicus palmataForsk

“…For the standardization of the protocol, preliminary screening of pravastatin was done against HMG-COA reductase activity and observed 50% inhibition at 70.25 nM, which was in concordance with other studies [43]. From the data presented in Table 2 and Figure 3(a), it is evident that FPBA (IC 50 = 9.1 ± 0.61  μ g/mL), FPLE (IC 50 = 27 ± 1.21  μ g/mL), FPBD (IC 50 = 30 ± 1.51  μ g/mL), FPBE (IC 50 = 35 ± 1.84  μ g/mL), FPLH (IC 50 = 38 ± 1.86  μ g/mL), FPBM (IC 50 = 45 ± 2.13  μ g/mL), FPLD (IC 50 = 58 ± 3.21  μ g/mL), and FPLM (IC 50 = 65 ± 3.42  μ g/mL) extracts exhibited significant inhibition of HMG-CoA reductase activity, while other extracts were found to be nonsignificant.…”

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

“…Currently, generic statins offer several cost benefits. These inhibitors of the posttranscriptional lipid modifications of RAS are likely to be effective, because they have been shown to exert antitumoral action in different cancer cells with mutations on RAS (125,126). Indeed, statins reduced cardiac hypertrophy in a transgenic model of HCM (127,128).…”

Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent

“…Many researches focused on the ability of MVN and other statins to sensitize tumor cells for conventional chemotherapeutics 11 . Some experimental reports manifested a potential anti-cancer activity of MVN and other HMGCo-A reductase inhibitors per se 12 . However, the exact signaling mechanism of MVNinduced cell death remain controversial.…”