The potential of methioninase for cancer treatment.

Cancer cells are addicted to L-methionine (L-Met) and have a much greater requirement for L-Met than normal cells due to excess transmethylation, termed the Hoffman effect. By targeting this vulnerability through dietary restriction of L-Met, researchers have been able to achieve promising results in inhibiting tumor growth and eradicating cancer cells. Methioninase (EC 4.

Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.

A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay.

Antibacterial activity profile of miramistin in in vitro and in vivo models.

Background: Miramistin is a widely used antiseptic, disinfectant and preservative, and one of the most popular antimicrobial agents on pharmaceutical market of the Russian Federation (http://www.dsm.ru/en/news/385/).

Morphological and functional evaluation of the effect of novel pyrimidine derivatives on regeneration of the sciatic nerve in rats.

Two novel pyrimidine derivatives, RG2 and RG6, were studied using a rat's model of peripheral nerve injury. Toe-spreading reflex and skin sensitivity to pinch in the foot were monitored to follow recovery of motor and sensory functions in the treated animals. The remyelation rate in the distal segment of the damaged nerve was also studied using morphological analysis of cross-sections of the nerve stained with methylene blue.

Synthesis and in vitro antitumor activity of novel alkenyl derivatives of pyridoxine, bioisosteric analogs of feruloyl methane.

Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase.

In-vitro antitumor activity of new quaternary phosphonium salts, derivatives of 3-hydroxypyridine.

This work presents the results of in-vitro biological activity studies of three novel anticancer agents, phosphonium salts based on the 3-hydroxypyridine scaffold, including one derivative of 4-deoxypyridoxine. Proliferation and viability of cells treated with these compounds was assessed by the colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of the compounds on apoptosis and cell cycle were studied by flow cytometry using annexin V-FITC/propidium iodide and propidium iodide staining, respectively.

Author Correction: Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus.

Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%).

Synthesis and Antibacterial Activity of Quaternary Ammonium 4-Deoxypyridoxine Derivatives.

A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant strains with MICs in the range of 0.5-2 g/mL, exceeding the activity of miramistin.

Novel potent pyridoxine-based inhibitors of AChE and BChE, structural analogs of pyridostigmine, with improved in vivo safety profile.

We report a novel class of carbamate-type ChE inhibitors, structural analogs of pyridostigmine. A small library of congeneric pyridoxine-based compounds was designed, synthesized and evaluated for AChE and BChE enzymes inhibition in vitro. The most active compounds have potent enzyme inhibiting activity with IC50 values in the range of 0.

Nonlinear dimensionality reduction for visualizing toxicity data: distance-based versus topology-based approaches.

Over the years, a number of dimensionality reduction techniques have been proposed and used in chemoinformatics to perform nonlinear mappings. In this study, four representatives of nonlinear dimensionality reduction methods related to two different families were analyzed: distance-based approaches (Isomap and Diffusion Maps) and topology-based approaches (Generative Topographic Mapping (GTM) and Laplacian Eigenmaps). The considered methods were applied for the visualization of three toxicity datasets by using four sets of descriptors.

Computational mapping tools for drug discovery.

During the past decade, computational technologies have become well integrated in the modern drug design process and have gained in influence. They have dramatically revolutionized the way in which we approach drug discovery, leading to the explosive growth in the amount of chemical and biological data that are typically multidimensional in structure. As a result, the irresistible rush towards using computational approaches has focused on dimensionality reduction and the convenient representation of high-dimensional data sets.

CXCR4 receptor as a promising target for oncolytic drugs.

There has been considerable in vivo evidence that chemokine receptor CXCR4 and its endogenous ligand CXCL12 modulate some important physiological and pathophysiological processes, including cancer metastasis, angiogenesis, invasion, growth and progression. In this review we elucidate key aspects of CXCL12-CXCR4 signaling system with emphasis on peptide-based and small-molecule CXCR4 inhibitors.

Regulators of chemokine receptor activity as promising anticancer therapeutics.

Chemokines are a family of small proteins inducing directed cell migration via specific chemokine receptors, which play important roles in a variety of biological and pathological processes. Their respective ligands act as proinflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors, and also have a role in pathological conditions that require neovascularization. Therapeutic strategies based on modulation of chemokine receptor pathways were reported to be promising clinical strategies in the treatment of inflammatory diseases and viral infections.

Shape signatures: new descriptors for predicting cardiotoxicity in silico.

Shape Signatures is a new computational tool that is being evaluated for applications in computational toxicology and drug discovery. The method employs a customized ray-tracing algorithm to explore the volume enclosed by the surface of a molecule and then uses the output to construct compact histograms (i.e.

Caspase activity modulators as anticancer agents.

Proteolytic caspase enzymes play a central role in cell apoptosis, or programmed cell death, often as integrating elements of different stimuli leading to the cell death. Since blockade of apoptotic pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the activation of caspases is an attractive target for anticancer therapy. This review describes some of the druggable therapeutic targets thus far identified within the core apoptotic machinery, the corresponding drugs that have been developed, their effects on caspase-dependent apoptotic pathways and their potential impact on the therapy of cancer.

Novel mitotic targets and their small-molecule inhibitors.

With several successful anticancer drugs on the market and numerous compounds in clinical developments, antimitotic agents represent an important category of anticancer agents. However, clinical utility of the tubulin-binding agents is somewhat limited due to multiple drug resistance (MDR), poor pharmacokinetics and therapeutic index. There is ongoing need for the modulators of other intracellular targets that result in the same anti-mitotic effect without adverse effects of "traditional" tubulin binders.

Histone deacetylase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective.

Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. The latter mechanism includes dynamic acetylation and deacetylation of epsilon-amino groups of lysine residues present in the tail of the core histones. Enzymes responsible for the reversible acetylation/deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively.

Small-molecule modulators of Hh and Wnt signaling pathways.

Hedgehog (Hh) and Wnt signaling pathways play key roles in growth and patterning during embryonic development and in the postembryonic regulation of stem cell number in the epithelia. Numerous studies link aberrant modulation of these pathways to specific human diseases. This article focuses on general aspects of Hh and Wnt signal transduction and biologic molecules involved in the respective signaling cascades.

Recent progress in discovery and development of antimitotic agents.

This review highlights structural diversity of antimitotic agents. In particular, we emphasized current antimitotic therapies based on modulation of microtubule dynamics. With several successful anticancer drugs on the market and numerous compounds in clinical developments, tubulin-binding agents remain among the most important categories of anticancer agents.

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.

Insights for human ether-a-go-go-related gene potassium channel inhibition using recursive partitioning and Kohonen and Sammon mapping techniques.

The human ether-a-go-go related gene (hERG) can be inhibited by marketed drugs, and this inhibition may lead to QT prolongation and possibly fatal cardiac arrhythmia. We have collated literature data for 99 diverse hERG inhibitors to generate Kohonen maps, Sammon maps, and recursive partitioning models. Our aim was to investigate whether these computational models could be used either individually or together in a consensus approach to predict the binding of a prospectively selected test set of 35 diverse molecules and at the same time to offer further insights into hERG inhibition.

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.

Rational design approaches to chemical libraries for hit identification.

Sequencing of the human genome along with developments in combinatorial synthesis and high-throughput biological screening provide unparallel opportunities to drug discovery. It has been noted that the increased number of synthesized and annotated compounds did not yield the expected increase in number of viable drug candidates. To address this problem, several novel computation technologies have emerged for making combinatorial library design cost-effective.

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.