Michael acceptor properties of 6-bicycloaryl substituted (R)-5,6-dihydro-2H-pyran-2-ones

Abstract

a b s t r a c tThe mechanism of action for a,b-unsaturated lactones can be explained by their Michael acceptor properties. They have the potential of being covalently binding inhibitors by accepting nucleophiles from target proteins. In this work, Michael addition reactions of ethanethiol with 6-bicycloaryl substituted 5,6-dihydro-2H-pyran-2-ones were studied to explore the existence of such interactions. Three of the Michael addition products were isolated and tested over PC3 (human prostate cancer) and MCF-7 (human breast adenocarcinoma) cancer cell lines and no cytotoxicity was observed. It was revealed that biological activity depends on the existence of a Michael acceptor, but potency probably depends upon the 3D structure of the substituent on lactone ring. The primary chemical-quantum properties of the lactones were also calculated using the Spartan'08 computer program.Ó 2010 Elsevier Inc. All rights reserved.Many biologically active natural compounds possess a,b-unsat- Fig. 1. Interestingly, compounds 1-5 were cytotoxic at submicromolar concentrations while compound 7 showed cytotoxicity at the nanomolar range whereas compound 6 was the most cytotoxic having an IC 50 of 50 nM for PC3 cell lines [5].Here, computer modeling software was used to help understand why, out of compounds 1-7, compounds 6 and 7 showed enhanced cytotoxicity. Michael addition reactions of ethanethiol to compounds 1-7 were studied to explore their relative reactivities with sulfhydryl based nucleophiles in biological systems.Energy minimization of compounds 1-7 has been calculated using the Spartan'08 [6] software via the semi-empirical AM1 method. The primary chemical-quantum properties of lactones were also calculated by the same method. Results of the calculations are summarized in Table 1.Compounds 1-7 were prepared as previously reported literature [5]. To carry out Michael addition reactions simply, 5-10 mg of compounds (1-7) was dissolved in DMSO-d 6 and then a blank 1 H NMR was acquired. Then one equivalent of ethanethiol was added with a syringe and mixed well. Ten minutes after the addition of ethanethiol, a subsequent 1 H NMR spectrum was taken. If the reactions were not complete within 10 min, then reactions were monitored by taking an 1 H NMR spectrum taken at continued appropriate intervals. The rate of the reactions were evaluated by the disappearance of signals belonging to protons attached to the a,b-unsaturated carbons as well as the signals from the appearance of new diastereomeric saturated protons.To determine the cytotoxicity of the compounds, MTT assay were performed under the same condition reported in literature at 0.1, 0.5, 1, 10, and 50 lM concentrations [5].The Corey-Pauling-Koltun (CPK) space-filling model volume and area for compounds 6 and 7 were approximately 20 units (Å 3 and Å 2 ) higher than for compounds 1-5. Log P values (measurement of permeability of the cell membrane) for compounds 6 and 7 were the same (3.87), but higher than the Log P values for compounds 2 and 4 (3.38). Log P values for th...

Antiproliferative activity of (R)-4′-methylklavuzon on hepatocellular carcinoma cells and EpCAM+/CD133+ cancer stem cells via SIRT1 and Exportin-1 (CRM1) inhibition

“…(R)-4 0 -methylklavuzon was previously synthesized by our group and its cytotoxic effects were demonstrated on prostate, colon, pancreatic, breast, ovary cancer cells [39,41,91,92]. (R)-4 0 -methylklavuzon was also found to irreversibly inhibit topoisomerase I enzyme [39].…”

Synthesis and Topoisomerase I inhibitory properties of klavuzon derivatives

“…Presence of a methyl substitution in the naphthalene-1-yl group (8 and 9) further increases its potency (Fig. 1) [16,17]. In this study, asymmetric and racemic preparations of novel derivatives of klavuzon (10)(11)(12)(13)(14)(15) and goniothalamin (16) were studied (Fig.…”

“…Asymmetric allylation of the 4-dimethylamino-1naphthaldehyde (17) was performed by allyltrimethoxysilane in the presence of R-Tol-BINAP.AgF complex at À20°C to produce R-homoallylic alcohol 18 with 69% yield [18]. Chiral HPLC studies with two separate chiral columns were performed to determine the ee% of the product and it showed a single peak, which might be the result of formation of a single enantiomer or poor resolution of enantiomers in the columns.…”

Perspectives on natural product epigenetic modulators in chemical biology and medicine

“…13,158,159 Such functionality oen endows these molecules with non-specicity and results in false positives or non-progressible hits. 160,161 Indeed, a variety of nucleophilic functionalities in biomolecules such as proteins and DNA have been shown to irreversibly bind to Michael acceptors through formation of a covalent bond. 162 Various natural product epigenetic modiers bearing a Michael acceptor have been reported.…”