Design of a structure-activity relationship model of vitamin K epoxide reductase (VKORC1) inhibitors combining chemical synthesis of new compounds, enzymatic assays and molecular modelling.

Vitamin K antagonists (VKAs) anticoagulants have been used since the 1950s as medicines and rodenticides. These molecules are mainly 4-hydroxycoumarin derivatives and act by inhibiting the vitamin K epoxide reductase (VKORC1), an endoplasmic reticulum membrane resident enzyme. However, many VKORC1 mutations have been reported over the last decade, inducing VKAs resistances and thus treatments failures. Although studies have reported experimental and computational investigations of VKAs based on VKORC1 structural homology models, the development of new effective anticoagulants has been quite complex due to the lack of structural data and reliable structure-activity relationships. However, the recent publication of VKORC1 crystal structure provides new information for further studies. Based on these findings, we combined chemical synthesis, enzymatic assays and molecular modelling methods to design a structure-activity relationship (SAR) model. Our results proved that the lipophilicity, the membrane permeability of inhibitors and their affinity towards human VKORC1 enzyme are the main characteristics for potent anticoagulants. Our SAR model managed to rank compounds according to their ability to inhibit the human VKORC1. Such a tool might constitute an alternative to evaluate new molecules potency before their chemical synthesis and biological assessment and might assist the development of new VKAs.

Synthesis and biological evaluation of C-3 aliphatic coumarins as vitamin K antagonists.

Since the discovery of Warfarin in the 1940s, the design of new warfarin-derived anticoagulants for rodent management has been challenging, with mainly structural modifications performed on the C3 position of the coumarin skeleton. In order to better understand the pharmacomodulation of such derivatives, we have synthesized a family of C3 (linear and branched) alkyl-4-hydroxycoumarins, which led to the identification of compounds 5e and 5f as potential short-term active anticoagulants.

Homogeneous acylation of Cellulose diacetate: Towards bioplastics with tuneable thermal and water transport properties.

In this study, we report a simple, non-degrading and efficient homogeneous acylation of cellulose diacetate (CDA) by using a large panel of commercially available acylating aliphatic moieties, differing in their structure (fatty, ramified, bulky, cycloaliphatic, aromatic, more or less spaced from the cellulose backbone), in view of generating a library of well-defined cellulose mixed esters with enhanced thermoplasticity. As reflected by a lowering of the glass temperature (Tg), the covalent grafting confers an improved mobility to the cellulose chains, by disrupting the initial H-bonds. In particular, it appears that the gain in free volume is tailored by the substituent structure and that acylating reagents consisting in a terminal bulky moieties spaced from CDA chains by a linear chain efficiently separate macromolecular chains without generating detrimental stiffening interactions (low Tg around 125 °C). Moreover, free-standing films easily prepared by solvent casting exhibit relevant water transport properties, which are closely dictated and tuned by the water solubility of the cellulose mixed ester.

Comparative inhibitory effect of prenylated coumarins, ferulenol and ferprenin, contained in the 'poisonous chemotype' of Ferula communis on mammal liver microsomal VKORC1 activity.

Two distinguishable chemotypes of Ferula communis have been described: the 'nonpoisonous' chemotype, containing as main constituents the daucane esters; and the 'poisonous' chemotype containing prenylated coumarins, such as ferulenol and ferprenin. Ferulenol and ferprenin are 4-oxygenated molecules such as dicoumarol and warfarin, the first developed antivitamin K molecules. Antivitamin K molecules specifically inhibit VKORC1, an enzyme essential for recycling vitamin K. This latest is involved in the activation of clotting factors II, VII, IX, X. The inhibiting effect of ferulenol on VKORC1 was shown in rat, but not for species exposed to F. communis while in vivo studies suggest differences between animal susceptibility to ferulenol. The inhibiting effect of ferprenin on VKORC1 was never demonstrated. The aim of this study was to compare the inhibiting effect of both compounds on VKORC1 of different species exposed to F. communis. Vitamin K epoxide activity was evaluated for each species from liver microsomes and inhibiting effect of ferulenol and ferprenin was characterized. Ferulenol and ferprenin were shown to be able to inhibit VKORC1 from all analyzed species. Nevertheless, susceptibility to ferulenol and ferprenin presented differences between species, suggesting a different susceptibility to 'poisonous' chemotypes of F. communis.