High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design.

Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub µM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K b value of 2.87 × 108 M-1 which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.

Inhibition of the Replication of Different Strains of Chikungunya Virus by 3-Aryl-[1,2,3]triazolo[4,5- d]pyrimidin-7(6 H)-ones.

The re-emergence of chikungunya virus (CHIKV) is a serious global health threat. CHIKV is an alphavirus that is transmitted to humans by Aedes mosquitoes; therefore, their wide distribution significantly contributes to the globalization of the disease. Unfortunately, no effective antiviral drugs are available. We have identified a series of 3-aryl-[1,2,3]triazolo[4,5- d]pyrimidin-7(6 H)-ones as selective inhibitors of CHIKV replication. New series of compounds have now been synthesized with the aim to improve their physicochemical properties and to potentiate the inhibitory activity against different CHIKV strains. Among these newly synthesized compounds modified at position 3 of the aryl ring, tetrahydropyranyl and N- t-butylpiperidine carboxamide derivatives have shown to elicit potent antiviral activity against different clinically relevant CHIKV isolates with 50% effective concentration (EC50) values ranging from 0.30 to 4.5 µM in Vero cells, as well as anti-CHIKV activity in human skin fibroblasts (EC50 = 0.1 µM), a clinically relevant cell system for CHIKV infection.

Antiviral activity of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones against chikungunya virus targeting the viral capping nsP1.

Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted to humans by Aedes mosquitoes. Since 2005, CHIKV has been spreading worldwide resulting in epidemics in Africa, the Indian Ocean islands, Asia and more recently in the Americas. CHIKV is thus considered as a global health concern. There is no specific vaccine or drug available for the treatment of this incapacitating viral infection. We previously identified 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as selective inhibitors of CHIKV replication and proposed the viral capping enzyme nsP1 as a target. This work describes the synthesis of novel series of related compounds carrying at the aryl moiety a methylketone and related oximes combined with an ethyl or an ethyl-mimic at 5-position of the triazolopyrimidinone. These compounds have shown antiviral activity against different CHIKV isolates in the very low µM range based on both virus yield reduction and virus-induced cell-killing inhibition assays. Moreover, these antivirals inhibit the in vitro guanylylation of alphavirus nsP1, as determined by Western blot using an anti-cap antibody. Thus, the data obtained seem to indicate that the anti-CHIKV activity might be related to the inhibition of this crucial step in the viral RNA capping machinery.

General theory for multiple input-output perturbations in complex molecular systems. 1. Linear QSPR electronegativity models in physical, organic, and medicinal chemistry.

In general perturbation methods starts with a known exact solution of a problem and add "small" variation terms in order to approach to a solution for a related problem without known exact solution. Perturbation theory has been widely used in almost all areas of science. Bhor's quantum model, Heisenberg's matrix mechanincs, Feyman diagrams, and Poincare's chaos model or "butterfly effect" in complex systems are examples of perturbation theories. On the other hand, the study of Quantitative Structure-Property Relationships (QSPR) in molecular complex systems is an ideal area for the application of perturbation theory. There are several problems with exact experimental solutions (new chemical reactions, physicochemical properties, drug activity and distribution, metabolic networks, etc.) in public databases like CHEMBL. However, in all these cases, we have an even larger list of related problems without known solutions. We need to know the change in all these properties after a perturbation of initial boundary conditions. It means, when we test large sets of similar, but different, compounds and/or chemical reactions under the slightly different conditions (temperature, time, solvents, enzymes, assays, protein targets, tissues, partition systems, organisms, etc.). However, to the best of our knowledge, there is no QSPR general-purpose perturbation theory to solve this problem. In this work, firstly we review general aspects and applications of both perturbation theory and QSPR models. Secondly, we formulate a general-purpose perturbation theory for multiple-boundary QSPR problems. Last, we develop three new QSPR-Perturbation theory models. The first model classify correctly >100,000 pairs of intra-molecular carbolithiations with 75-95% of Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp). The model predicts probabilities of variations in the yield and enantiomeric excess of reactions due to at least one perturbation in boundary conditions (solvent, temperature, temperature of addition, or time of reaction). The model also account for changes in chemical structure (connectivity structure and/or chirality paterns in substrate, product, electrophile agent, organolithium, and ligand of the asymmetric catalyst). The second model classifies more than 150,000 cases with 85-100% of Ac, Sn, and Sp. The data contains experimental shifts in up to 18 different pharmacological parameters determined in >3000 assays of ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) properties and/or interactions between 31723 drugs and 100 targets (metabolizing enzymes, drug transporters, or organisms). The third model classifies more than 260,000 cases of perturbations in the self-aggregation of drugs and surfactants to form micelles with Ac, Sn, and Sp of 94-95%. The model predicts changes in 8 physicochemical and/or thermodynamics output parameters (critic micelle concentration, aggregation number, degree of ionization, surface area, enthalpy, free energy, entropy, heat capacity) of self-aggregation due to perturbations. The perturbations refers to changes in initial temperature, solvent, salt, salt concentration, solvent, and/or structure of the anion or cation of more than 150 different drugs and surfactants. QSPR-Perturbation Theory models may be useful for multi-objective optimization of organic synthesis, physicochemical properties, biological activity, metabolism, and distribution profiles towards the design of new drugs, surfactants, asymmetric ligands for catalysts, and other materials.

Inter- and intramolecular enantioselective carbolithiation reactions.

In this review we summarize recent developments in inter- and intramolecular enantioselective carbolithiation reactions carried out in the presence of a chiral ligand for lithium, such as (-)-sparteine, to promote facial selection on a C=C bond. This is an attractive approach for the construction of new carbon-carbon bonds in an asymmetric fashion, with the possibility of introducing further functionalization on the molecule by trapping the reactive organolithium intermediates with electrophiles.

Recent progress on fucosyltransferase inhibitors.

Fucosyltransferases (FucTs) are enzymes that transfer L-fucose from GDP-fucose to a glycoside or a peptide. They have important roles in a variety of diseases including cancer and autoimmune disorders, viral and bacterial infections and inflammatory processes, and thus they represent important drug targets for the development of agents for the treatment of such disorders. This review highlights recent developments regarding carbohydrate mimics as inhibitors of FucTs. The most recent and relevant synthetic strategies are described.