6-Bicycloaryl substituted (S)- and (R)-5,6-dihydro-2H-pyran-2-ones: Asymmetric synthesis, and anti-proliferative properties

Abstract

a b s t r a c t (R)-Goniothalamin, is a member of styryl lactones, possesses selective cytotoxicity against cancer cell lines. In this work, replacement of styryl substituent with 2-naphthyl and 3-quinoyl gave new analogues which may have less conformational changes compared to the lead compound. Anti-proliferative tests indicated that 2-naphthyl substituted (R)-5,6-dihydro-2H-pyran-2-one has slightly better cytotoxicity than (R)-goniothalamin. To clarify the effect of 2-naphthyl substituent additional aryl substituted (R)-5,6-dihydro-2H-pyran-2-ones have been synthesized enantioselectively and tested against PC-3 and MCF-7 cell lines.

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

“…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.…”

“…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].…”

“…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.…”

“…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).…”

“…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.…”