Synthesis and Biochemical Evaluation of Δ²-Isoxazoline Derivatives as DNA Methyltransferase 1 Inhibitors

Abstract

A series of Δ(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.

Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents

“…[8][9][10][11] Numerous synthetic approaches for the construction of the isoxazole and 4,5-dihydroisoxazole framework have been reported. There are two main methodologies: The first approach involves the condensation of hydroxylamine with 1,3-dicarbonyl compounds, or their three-carbon 1,3-electrophilic variants, such as α,β-unsaturated ketones, enamino ketones, β-alkylthioenones and ynones.…”

Efficient synthesis of kainic acid analogues

“…In order to overcome the first drawback, we decided to investigate the feasibility of the cycloaddition reaction with the flow technology by using a procedure previously applied to similar pericyclic reactions. 33,34 As shown in scheme 2, an ethyl acetate solution of N-Boc-3,4-dehydro-L-proline methyl ester 1, prepared under flow conditions as previously reported, 35 and ethyl chlorooximinoacetate were mixed and delivered to a glass column filled with solid K 2 CO 3 heated at 90 °C. The desired cycloadducts were obtained in good yield (70%) in only 10 min and a slight excess of chloroxime.…”

Understanding the Regioselective and Molecular Mechanism of the TCE in Cycloaddtion Reaction (TCE+Cp) and Addition Reaction (TCE+HCl) using DFT calculation

“…They are also useful intermediates for synthesis of natural products and biologically active compounds [4][5][6][7][8][9][10]. A variety of synthetic methods has been developed for preparation of cyclic compounds, of which the most convenient and attractive route is probably the cycloaddition of diene or dipole to alkenes [10][11].…”