Design, Synthesis, and Biological Evaluation of New Type of Gemini Analogues with a Cyclopropane Moiety in Their Side Chain.

We synthesized two new gemini analogues, and , that incorporate a modified longer side chain containing a cyclopropane group. The evaluation of the bioactivities of the two gemini analogues indicated that the 17,20 threo (20) compound, , is the most active one and is as active as 1,25(OH)D. Docking and molecular dynamics (MD) data showed that the compounds bind efficiently to vitamin D receptor (VDR) with to form an energetically more favorable interaction with His397.

Structural analysis and biological activities of C25-amino and C25-nitro vitamin D analogs.

Intense synthetic efforts have been directed towards the development of noncalcemic analogs of 1,25-dihydroxyvitamin D. We describe here the structural analysis and biological evaluation of two derivatives of 1,25-dihydroxyvitamin D with modifications limited to the replacement of the 25-hydroxyl group by a 25-amino or 25-nitro groups. Both compounds are agonists of the vitamin D receptor.

On the mechanism of the dyotropic expansion of hydrindanes into decalins.

A combined computational/experimental approach has revealed key mechanistic aspects in a recently reported dyotropic expansion of hydrindanes into decalins. While computer simulations had already anticipated the need for acid catalysis for making this reaction feasible under the mild conditions used in the laboratory, this work places the dyotropic step not into the reaction flask but at a later step, during the work up instead. With this information in hand the reaction has been optimized by exploring the performance of different activating agents and shown to be versatile, particularly in steroid related chemistry due to the two scaffolds that this reaction connects.

Easy Access to Polyfunctionalized Chiral Decalins.

An unexpected ring expansion that converts hydrindanes into decalins via an unprecedented dyotropic reaction involving a mesylate group has been observed, and this paved the way for easy access to polyfunctionalized chiral decalins. These polyfunctionalized chiral decalins can be very useful building blocks for the synthesis of the thia analogues of many natural compounds. They can also be used in asymmetric catalysis and also in the synthesis of the new analogues of vitamin D with a modified D ring and side chain.

Synthesis, Characterization and Antimicrobial Activities of 1,4- Disubstituted 1,2,3-Triazole Compounds.

Background: 1,2,3-triazoles are five-membered heterocyclic scaffold; their broad-spectrum biological activities are known. Researchers around the world are increasingly being interested in this emerging area, owing to its immense pharmacological scope.

Objective: This work summarizes the synthesis of 1,2,3-triazoles and the significance of this pattern as a lead structure for new drug molecules discovery.

Access to a Library of 1,3-disubstituted-1,2,3-triazenes and Evaluation of their Antimicrobial Properties.

Background: Due to the rapid development of microbial resistance, finding new molecules became urgent to counteract this problem.

Objective: The objective of this work is to access 1,2,3-triazene-1,3-disubstituted, a class of molecule with high therapeutic potential.

Methods: Here we describe the access to 17 new triazene including six with an imidazole-1,2,3-triazene moiety and eleven with an alkyl-1,2,3-triazene moiety and their evaluation against five strains: two gram (-): Escherichia coli ATCC 25921 and Pseudomonas aeruginosa ATCC 27253; two gram (+) : Staphylococcus aureus ATCC 38213 and Enterococcus faecalis ATCC 29212; and one fungi: Candida albicans ATCC 24433.

Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies.

The active form of vitamin D , calcitriol, is a potent antiproliferative compound. However, when effective antitumor doses of calcitriol are used, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim of retaining or even increasing the antitumor effects while decreasing its calcemic activity.

Synthesis of a novel analog of calcitriol and its biological evaluation as antitumor agent.

Calcitriol analogs have shown promising potential as compounds to be used in cancer chemotherapy. This report presents the synthesis of a novel vitamin D derivative with an amide and a carboxyl group in its side chain, called ML-344. In addition, we report its in vitro antitumor activity and its in vivo calcemic effects.

From Hydrindane to Decalin: A Mild Transformation through a Dyotropic Ring Expansion.

An unexpected ring expansion converting hydrindane cores into decalins has been observed. The process occurs under very mild conditions and with exquisite transfer of chiral information. The ring expansion provides access to decorated decalins with complete stereocontrol.

Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.

Synthetic analogs of 1α,25-dihydroxyvitamin D (1,25(OH)D) have been developed with the goal of improving the biological profile of the natural hormone for therapeutic applications. Derivatives of 1,25(OH)D with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, we describe the synthesis and biological evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2″-hydroxy-2″-propyl)-tetrahydrofuryl]-22,23,24,25,26,27-hexanor-1α-hydroxyvitamin D3, with different stereochemistry at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S).

Use of surface plasmon resonance in the binding study of vitamin D, metabolites and analogues with vitamin D binding protein.

Vitamin D and its metabolites are lipophilic molecules with low aqueous solubility and must be transported bound to plasma carrier proteins, primarily to vitamin D binding protein (DBP). The biological functions of vitamin D metabolites are intimately dependent on the protein, hence the importance of determining their affinity for DBP. In this study, we developed a novel procedure for measuring the kinetic and equilibrium constants of human-DBP with vitamin D and three metabolites: 1,25-dihydroxyvitamin D [1,25(OH)D], 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D [24,25(OH)D] by surface plasmon resonance (SPR).

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.

Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression.

Vitamin D analogue: potent antiproliferative effects on cancer cell lines and lack of hypercalcemic activity.

The active form of vitamin D3, 1α,25(OH)2D3, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and pro-differentiating agent. Unfortunately, it usually causes hypercalcemia in vivo when effective antitumour doses are used.

Synthesis and biological evaluation of a new vitamin D2 analogue.

A new vitamin D(2) analogue was synthesized using the Julia-Kocienski olefination. It has antiproliferative effects on cell lines from squamous cell carcinomas of colon and head and neck, but is also as hypercalcaemic as calcitriol in vivo.

Review of synthesis, biological assay, and QSAR studies of HMGR inhibitors.

Effective as statin drugs or acids are inhibitors mevinic limiting enzyme in cholesterol biosynthesis, 3-hydroxy- 3-methyl-glutaryl coenzyme A-3-hydroxy-3-reductase (HMGR), an enzyme responsible for the reduction the double methyl-glutaryl coenzyme A. These compounds promoted the synthesis and evaluation of new inhibitors of HMGR, called HMGRIs. The high number of potential candidates need to create models of quantitative structure-activity relationship in order to guide the HMGRI (3-hydroxy-3-methyl-glutarylcoenzyme A inhibitor) synthesis.

Review of QSAR for DNA polymerase inhibitors and new models for heterogeneous series of compounds.

DNA polymerases are essential enzymes for DNA replication, repair and recombination. The high number of possible candidates creates the necessity of Quantitative Structure-Activity Relationship models in order to guide the DNA polymerase inhibitors. In this work, we revised different computational studies for a very large and heterogeneous series of DNA polymerase inhibitors.

An application of two MIFs-based tools (Volsurf+ and Pentacle) to binary QSAR: the case of a palinurin-related data set of non-ATP competitive glycogen synthase kinase 3β (GSK-3β) inhibitors.

VolSurf+ and GRIND descriptors extract the information present in MIFs calculated by GRID: the first are simpler to interpret and generally applied to ADME-Tox topics, whereas the latter are more sophisticated and thus more suited for pharmacodynamics events. Here we present a study which compares binary QSAR models obtained with VolSurf+ descriptors and GRIND for a data set of non-ATP competitive GSK-3β inhibitors chemically related to palinurin for which the biological activity is expressed in binary format. Results suggest not only that the simpler Volsurf+ descriptors are good enough to predict and chemically interpret the investigated phenomenon but also a bioactive conformation of palinurin which may guide future design of ATP non-competitive GSK-3 inhibitors.

First computational chemistry multi-target model for anti-Alzheimer, anti-parasitic, anti-fungi, and anti-bacterial activity of GSK-3 inhibitors in vitro, in vivo, and in different cellular lines.

In the work described here, we developed the first multi-target quantitative structure-activity relationship (QSAR) model able to predict the results of 42 different experimental tests for GSK-3 inhibitors with heterogeneous structural patterns. GSK-3β inhibitors are interesting candidates for developing anti-Alzheimer compounds. GSK-3β are also of interest as anti-parasitic compounds active against Plasmodium falciparum, Trypanosoma brucei, and Leishmania donovani; the causative agents for Malaria, African Trypanosomiasis and Leishmaniosis.

Using topological indices to predict anti-Alzheimer and anti-parasitic GSK-3 inhibitors by multi-target QSAR in silico screening.

Plasmodium falciparum, Leishmania, Trypanosomes, are the causers of diseases such as malaria, leishmaniasis and African trypanosomiasis that nowadays are the most serious parasitic health problems worldwide. The great number of deaths and the few drugs available against these parasites, make necessary the search for new drugs. Some of these antiparasitic drugs also are GSK-3 inhibitors.

QSAR, docking, and CoMFA studies of GSK3 inhibitors.

GSK-3 inhibitors are interesting candidates to develop Anti-Alzheimer compounds. GSK-3β are also interesting as Anti-parasitic compounds active against Plasmodium falciparum, Trypanosoma brucei, and Leishmania donovani; the causative agents for Malaria, African Trypanosomiasis and Leishmaniosis. The high number of possible candidates creates the necessity of Quantitative Structure-Activity Relationship models in order to guide the GSK3 (glycogen synthase kinase 3 inhibitor) synthesis.

QSAR & complex network study of the HMGR inhibitors structural diversity.

Efficient drugs such as statins or mevinic acids are inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), an enzyme responsible for the double reduction of 3-hydroxy-3-methyl-glutaryl coenzyme A. These compounds promoted the synthesis and evaluation of new inhibitors for HMGR, named HMGRIs. The high number of possible candidates creates the necessity of Quantitative Structure-Activity Relationship models in order to guide the HMGRI (3-hydroxy-3-methyl-glutaryl coenzyme A inhibitor) synthesis.

The first enantioselective synthesis of palinurin.

The first enantioselective synthesis of palinurin has been accomplished starting from commercially available furaldehyde and (R)-methyl-3-hydroxy-2-methylpropionate; the key steps of the synthesis include the use of a chiral pyrrolidine to create the chiral tetronic moiety, and Horner-Wadsworth-Emmons, Wittig and Wittig-Horner reactions to construct the alkene units.

QSAR and complex network study of the chiral HMGR inhibitor structural diversity.

Efficient drugs such as statins or mevinic acids are inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), an enzyme responsible for the double reduction of 3-hydroxy-3-methyl-glutaryl coenzyme A into mevalonic acid. These compounds promoted the synthesis and evaluation of new inhibitors for HMGR, named HMGRIs. The high number of possible candidates creates the necessity of Quantitative Structure-Activity Relationship models in order to guide the HMGRI synthesis.