Yagamare Fall

Synthesis of seven-membered oxacycles. Part 2: The furan approach

We describe an efficient new approach for the synthesis of seven-membered oxacycles that is based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular Michael addition.

Vitamin D heterocyclic analogues. Part 1: A stereoselective route to CD systems with pyrazole rings in their side chains

Efficient preparation of two vitamin D CD ring system synthons with pyrazole rings in their side chains is based on the formation of the pyrazole ring from an α-acetylenic ketone.

Phenylpiperazine derivatives with strong affinity for 5HT1A, D2A and D3 receptors

Four 7-[3-(4-phenyl-1-piperazinyl)propoxy]coumarins were synthesized. The affinities of these compounds for DA (D2A, D3) and 5HT1A receptors were evaluated for their ability to displace [3H]-raclopride and [3H]-8-OH-DPAT respectively from their specific binding sites. The affinities of the target compounds were all in the nanomolar range and followed the order 5-HT1A > D2 > D3.

Synthesis and structure–activity relationships of new arylpiperazines: para substitution with electron-withdrawing groups decrease binding to 5-HT1A and D2A receptors

Abstract Compounds in which N -phenylpiperazines were linked by a propyloxy chain to position 6 or 7 of a coumarin ring were designed and synthesised, and their affinities for 5-HT 1A and D 2A receptors were determined by radioligand binding assays. The influence of para substitution in the phenyl ring, substitution at position 4 of the coumarin system, and the coumarin position at which the piperazinylalkyl chain is linked was explored. Electron-withdrawing phenyl ring substituents para to the piperazine strongly reduced activity at both receptors. Binding at 5HT 1A was influenced by the bulk of substituents at position 4 of the coumarin system, and binding at D 2A by their electronic properties. Neither binding affinity was significantly affected by whether the piperazinylalkyl chain was inserted at position 6 or 7 of the coumarin system.

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.

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. In this work, we revised different computational studies for a very large and heterogeneous series of GSK-3Is. First, we revised QSAR studies with conceptual parameters such as flexibility of rotation, probability of availability, etc. we then used the method of regression analysis and QSAR studies in order to understand the essential structural requirement for binding with receptor. Next, we reviewed 3D-QSAR, CoMFA and CoMSIA with different compounds to find out the structural requirements for GSK-3 inhibitory activity.

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. There are two main problems of the reported QSAR models: the homogeneous series of the compounds and the chirality of many candidates. In this work, we propose for the first time a QSAR model for a very large and heterogeneous series of HMGRIs. The model is based on the Topological Indices (TIs) of molecular structures. Using the predictions of this model as input, we construct the first complex network that describes the drug-drug similarity relationships for more than 1600 experimentally non-explored chiral HMGRIs isomers. We also presented a reduced version of this network (Giant Component) that contains the most representative set of chiral HMGRI candidates. The work suggests a new mixed application in the QSAR study of relevant aspects of structural diversity by using chiral/non-chiral TIs, combined with complex networks.

In silico studies using Radial Distribution Function approach for predicting affinity of 1α,25-dihydroxyvitamin D3 analogues for Vitamin D receptor

The Radial Distribution Function (RDF) approach has been applied to the study of the chick intestinal VDR affinity of 49 Vitamin D analogues. A model able to describe more than 77.5% of the variance in the experimental activity was developed with the use of the mentioned approach. In contrast, none of four different approaches, including the use of Topological, BCUT, Randić molecular profiles and Geometrical descriptors were able to explain more than 55% of the variance in the mentioned property, with the same number of variables in the equation.

METHOXYALLENE, A BUILDING BLOCK FOR THE SYNTHESIS OF SEVEN-MEMBERED OXACYCLES

Abstract An efficient new approach for the synthesis of seven-mem bered oxacycles is described.

An efficient stereoselective synthesis of 1α,24(R)-dihydroxyvitamin D3 by the dienyne route

Abstract 1 α ,24( R )-Dihydroxyvitamin D 3 ( 5e ) was synthesized. The key step in the preparation of the side-chain was opening of the chiral epoxide 10 by the α-anion of the nitrile 9 . The triene system was synthesized by the dienyne route.