Abstract
In our continuous search for new, relatively simple 2-alkylidene-1-oxoheterocycles as promising anticancer drug candidates, herein we report an efficient synthesis of 2,2,6-trisubstituted 5-methylidenetetrahydropyran-4-ones. These compounds were obtained in a four step reaction sequence, in which starting diethyl 2-oxopropylphosphonate was transformed into 2,2-disubstituted 5-diethoxyphosphoryldihydropyran-4-ones, followed by Michael addition of various Grignard reagents and Horner-Wadsworth-Emmons reaction of the obtained adducts with formaldehyde. Stereochemistry of the intermediate Michael adducts is also discussed. Final 5-methylidenetetrahydropyran-4-ones were tested for their possible antiproliferative effect against three cancer cell lines and 6-isopropyl-2,2-dimethyl-5-methylidenetetrahydropyran-4-one (11c), which showed very high cytotoxic activity against HL-60 human leukemia cells and was three times more active than known anticancer drug carboplatin, was selected for further biological evaluation, in order to disclose its mechanism of action. The obtained results indicated that 11c induced apoptosis in HL-60 cells and caused the arrest of the cell cycle in the G2/M phase, which may suggest its cytotoxic and cytostatic activity.
Highlights
In the continuation of our search for relatively simple structural motifs with anticancer potential [1,2,3], we turned our attention to 3-alkylidenetetrahydropyran-4-ones 1
We start our research from the synthesis of diethyl 4-hydroxy-2-oxoalkylphosphonates 7a–d using
The target 2,2,6-triisubstituted-5-methylidenetetrahydropyran-4-ones 11a–p were obtained by olefination of formaldehyde using 5-diethoxyphosphoryltetrahydropyran-4-ones were obtained by olefination of formaldehyde using 5-diethoxyphosphoryltetrahydropyran-4-ones
Summary
In the continuation of our search for relatively simple structural motifs with anticancer potential [1,2,3], we turned our attention to 3-alkylidenetetrahydropyran-4-ones 1. Compounds containing this skeleton are common in nature and display interesting biological activities. This compound shows in vivo activity against Ehrlich ascites carcinoma. Chrolactomycin 4 displays significant cytotoxicity in vitro against several human cancer. Chrolactomycin 4 displays significant cytotoxicity in vitro against several human cancer cell lines: ACHN, A431, MCF-7, and cell.
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