María del Carmen Cruz

Design, synthesis, and docking of highly hypolipidemic agents: Schizosaccharomyces pombe as a new model for evaluating α-asarone-based HMG-CoA reductase inhibitors

A series of alpha-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of alpha-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.

Conjugate systems in the construction of heterocycles and quaternary stereocenters

The synthetic application of 4,5-bis-alkylidene-1,3-oxazolidin-2-ones led to the efficient and regioselective synthesis of 2-(3H)-benzoxazolones and diarylamines with a short methodology. They were also valuable synthons in a total synthesis of naturally occurring carbazoles. New enantiopure 4-oxazoline-2-one and 4-methylene-2-oxazolidinone were prepared via a one-pot microwave (MW)-promoted condensation of α-ketols and an enantiopure isocyanate. These enamides were efficient nucleophiles when added to Michael acceptors to give a series of compounds with quaternary stereocenters in fairly good stereoisomeric ratios. The novel approach for the synthesis of benzofurans and indoles by intramolecular cyclization of enaminones has been applied in the preparation of furobenzofurans starting from benzo-bis-enaminones.

A New Synthetic Route of 2-Aroyl- and 2-Benzyl-Benzofurans and their Application in the Total Synthesis of a Metabolite Isolated from Dorstenia gigas

The Lewis acid-catalyzed cyclization of the (Z)-3-(dimethylamino)-2-aryloxy-1-arylprop-2-en-1-ones 4a–h leads to a regioselective and short synthesis of 2-aroylbenzofurans 2a–h. The Wolff–Kishner reduction of the latter yielded a series of substituted 2-benzylbenzofurans 3a–h. This methodology was applied in the first total synthesis of the metabolite 2-(4-hydroxybenzyl)-6-methoxybenzofuran 1, which was isolated from the tropical plant Dorstenia gigas, and obtained through a six-step route and in a 24% overall yield.

Synthesis and highly potent hypolipidemic activity of alpha-asarone- and fibrate-based 2-acyl and 2-alkyl phenols as HMG-CoA reductase inhibitors

In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase.