Biomedical subjects

Sergey E Tkachenko

Publications and source records attributed to Sergey E Tkachenko.

15 recordsLinked to original sources

PubMed2007

VEGF/VEGFR signalling as a target for inhibiting angiogenesis.

VEGFs and a respective family of tyrosine kinases receptors (VEGFRs) are key proteins modulating angiogenesis, the formation of new vasculature from an existing vascular network. There has been considerable evidence in vivo, including clinical observations, that abnormal angiogenesis is implicated in a number of disease conditions, which include rheumatoid arthritis, inflammation, cancer, psoriasis, degenerative eye conditions and others. Antiangiogenic therapies based on inhibition of VEGF/VEGFR signalling were reported to be powerful clinical strategies in oncology and ophthalmology. Current efforts have yielded promising clinical data for several antiangiogenic therapeutics. In this review, the authors elucidate key aspects of VEGFR signalling, as well as clinically relevant strategies for the inhibition of VEGF-induced angiogenesis, with an emphasis on small-molecule VEGFR inhibitors.

Angiogenesis Inhibitors↗

PubMed2006

Natural products as templates for bioactive compound libraries: synthesis of biaryl derivatives of (+/-)-vasicine.

A reliable and high-yielding procedure for preparation of 7-aryl and 7-heteroaryl derivatives of (+/-)-vasicine in two steps from the naturally occurring material is described. This protocol broadens the chemical space for selective modifications of the vasicine tricyclic structure, thereby making it a valuable starting point for the development of novel compound libraries with potentially beneficial biological profiles.

Alkaloids↗

PubMed2006

One-step assembly of carbamoyl-substituted heteroannelated [1,4]thiazepines.

We present a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and 5-oxo-1,4-thiazepine-3-carboxamides using a modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.

Carbamates↗

PubMed2006

Virtual and biomolecular screening converge on a selective agonist for GPR30.

Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.

Animals↗

PubMed2006

Recent progress in development of non-ATP competitive small-molecule inhibitors of protein kinases.

The majority of marketed and late stage development kinase inhibitors are reported to be ATP-competitive. As a result, many promising drug candidates display non-specific activity that results in undesired physiological effects. There is growing interest towards non-ATP competitive kinase inhibitors, as they are expected to yield highly specific and efficacious molecules devoid of non-mechanistic toxicity. Recent developments in this area are summarized in our review.

Adenosine Triphosphate↗

PubMed2005

Synthesis and caspase-3 inhibitory activity of 8-sulfonyl-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines.

A convenient synthesis of novel 8-sulfonyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines is described. As key steps to assemble the target molecular scaffold, our method features (a) Pfitzinger reaction of isatin-5-sulfonate 1 with methyl 3-oxo-3-phenylpropanoate, (b) formation of 1-(1H-pyrazol-4-yl)-1H-pyrrole-2,5-dione intermediate 5, and (c) reaction of sulfinic acid 9 with acrylate or methylacrylate leading to the corresponding sulfonyl propionates. Two compounds, ester 11 and morpholide 13, have been identified as potent inhibitors of caspase-3 with IC50 = 6 nM. Our primary data suggest noncompetitive and reversible character of caspase-3 inhibition.

Caspase 3↗

PubMed2005

Pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors. Synthesis and SAR of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-pyrrolo[3,4-c]quinoline-1,3-diones.

Synthesis, biological evaluation and structure-activity relationships for a series of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several potent inhibitors with IC50 in the range of 3-10 nM have been identified. The most active compound within this series, 7{49} and 7{58}, inhibited caspase-3 with IC50=3 nM.

Caspase 3↗

PubMed2005

Synthesis and structure-activity relationship of 4-substituted 2-(2-acetyloxyethyl)-8-(morpholine-4-sulfonyl)pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors.

Synthesis, biological evaluation, and SAR dependencies for a series of novel 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline inhibitors of caspase-3 are described. The inhibitory activity of the synthesized compounds is highly dependent on the nature of 4-substituents on the core scaffold. 4-methyl-and 4-phenyl-substituted derivatives, which were the most active compounds within this series, inhibited caspase-3 with IC50 of 23 and 27 nM, respectively.

Apoptosis↗

PubMed2005

1,3-Dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines as potent caspase-3 inhibitors.

Synthesis, biological evaluation and structure-activity relationships for a series of novel nonpeptide small molecule inhibitors of caspase-3 are described. Among the studied compounds, 8-sulfamide derivatives of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines have been identified as potent inhibitors of caspases-3. The most active compound within this series (8f) inhibited caspase-3 with IC(50)=4 nM.

Caspase 3↗

PubMed2004

Exploring the chemogenomic knowledge space with annotated chemical libraries.

The recent human genome initiatives have led to the discovery of a multitude of genes that are potentially associated with various pathologic conditions and, thus, have opened new horizons in drug discovery. Simultaneously, annotated chemical libraries have emerged as information-rich databases to integrate biological and chemical data. They can be useful for the discovery of new pharmaceutical leads, the validation of new biotargets and the determination of the structural basis of ligand selectivity within target families. Annotated libraries provide a strong information basis for computational design of target-directed combinatorial libraries, which are a key component of modern drug discovery. Today, the rational design of chemical libraries enhanced with chemogenomics data is a new area of progressive research.

Combinatorial Chemistry Techniques↗

PubMed2004

Efficient optimization strategy for marginal hits active against abl tyrosine kinases.

Primary high-throughput screening of commercially available small molecules collections often results in hit compounds with unfavorable ADME/Tox properties and low IP potential. These issues are addressed empirically at follow-up lead development and optimization stages. In this work, we describe a rational approach to the optimization of hit compounds discovered during screening of a kinase focused library against abl tyrosine kinase. The optimization strategy involved application of modern chemoinformatics techniques, such as automatic bioisosteric transformation of the initial hits, efficient solution-phase combinatorial synthesis, and advanced methods of knowledge-based libraries design.

Algorithms↗

PubMedDate not supplied

A parallel solution-phase synthesis of substituted 3,7-diazabicyclo[3.3.1]nonanes.

The parallel solution-phase synthesis of a series of building blocks and combinatorial libraries based on natural bispidine scaffold has been accomplished. Key reactions include catalytic hydrogenation of the (-)-cytisine heterocyclic system, followed by alkali-mediated ring cleavage. Using this approach, a series of new bispidine core building blocks for combinatorial synthesis with three points of diversity were effectively synthesized. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation reactions. Obtained combinatorial libraries of 3,4,7-trisubstituted bispidines are potentially useful in the discovery of novel physiologically active compounds.

Journal Article↗

PubMedDate not supplied

Liquid-phase parallel synthesis of combinatorial libraries of substituted 6-carbamoyl-3,4-dihydro-2H-benzo[1,4]thiazines.

In this work, we explored several original combinatorial derivatization patterns for the 3,4-dihydro-2H-1,4-benzothiazine scaffold. The synthesis begins with commercially available 4-chloro- and 4-fluoro-3-nitrobenzoates and employs a sequence of moderate and high-yielding reactions that display a relatively high substituent tolerance. Simple manual techniques for parallel reactions were coupled with easy workup and purification procedures to give high-purity final products. The developed approach was easily adaptable for parallel synthesis of more than 2600 novel 2H-benzo[1,4]thiazine-6-carboxylic acid amides, which were efficiently prepared in a semiautomatic fashion using special CombiSyn synthesizers.

Chromatography, Liquid↗

PubMedDate not supplied

Property-based design of GPCR-targeted library.

The design of a GPCR-targeted library, based on a scoring scheme for the classification of molecules into "GPCR-ligand-like" and "non-GPCR-ligand-like", is outlined. The methodology is a valuable tool that can aid in the selection and prioritization of potential GPCR ligands for bioscreening from large collections of compounds. It is based on the distillation of knowledge from large databases of GPCR and non-GPCR active agents. The method employed a set of descriptors for encoding the molecular structures and by training of a neural network for classifying the molecules. The molecular requirements were profiled and validated by using available databases of GPCR- and non-GPCR-active agents [5736 diverse GPCR-active molecules and 7506 diverse non-GPCR-active molecules from the Ensemble Database (Prous Science, 2002)]. The method enables efficient qualification or disqualification of a molecule as a potential GPCR ligand and represents a useful tool for constraining the size of GPCR-targeted libraries that will help speed up the development of new GPCR-active drugs.

Databases, Factual↗

PubMedDate not supplied

Structure-based versus property-based approaches in the design of G-protein-coupled receptor-targeted libraries.

In this work, two alternative approaches to the design of small-molecule libraries targeted for several G-protein-coupled receptor (GPCR) classes were explored. The first approach relies on the selection of structural analogues of known active compounds using a substructural similarity method. The second approach, based on an artificial neural network classification procedure, searches for compounds that possess physicochemical properties typical of the GPCR-specific agents. As a reference base, 3365 GPCR-active agents belonging to nine different GPCR classes were used. General rules were developed which enabled us to assess possible areas where both approaches would be useful. The predictability of the neural network algorithm based on 14 physicochemical descriptors was found to exceed the predictability of the similarity-based approach. The structural diversity of high-scored subsets obtained with the neural network-based method exceeded the diversity obtained with the similarity-based approach. In addition, the descriptor distributions of the compounds selected by the neural network algorithm more closely approximate the corresponding distributions of the real, active compounds than did those selected using the alternative method.

Algorithms↗