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Semenova M.N.,Russian Academy of Sciences | Kiselyov A.S.,080 Center Drive | Tsyganov D.V.,RAS N. D. Zelinsky Institute of Organic Chemistry | Konyushkin L.D.,RAS N. D. Zelinsky Institute of Organic Chemistry | And 14 more authors.
Journal of Medicinal Chemistry

A series of 4-azapodophyllotoxin derivatives with modified rings B and E have been synthesized using allylpolyalkoxybenzenes from parsley seed oil. The targeted molecules were evaluated in vivo in a phenotypic sea urchin embryo assay for antimitotic and tubulin destabilizing activity. The most active compounds identified by the in vivo sea urchin embryo assay featured myristicin-derived ring E (4e, 6e, and 8e). These molecules were determined to be more potent than podophyllotoxin. Cytotoxic effects of selected molecules were further confirmed and evaluated by conventional assays with A549 and Jurkat human leukemic T-cell lines including cell growth inhibition, cell cycle arrest, cellular microtubule disruption, and induction of apoptosis. The ring B modification yielded 6-OMe substituted molecule 8e as the most active compound. Finally, in Jurkat cells, compound 8e induced caspase-dependent apoptosis mediated by the apical caspases-2 and -9 and not caspase-8, implying the involvement of the intrinsic caspase-9-dependent apoptotic pathway. © 2011 American Chemical Society. Source

Chernysheva N.B.,RAS N. D. Zelinsky Institute of Organic Chemistry | Tsyganov D.V.,RAS N. D. Zelinsky Institute of Organic Chemistry | Philchenkov A.A.,R.E. Kavetsky Institute of Experimental Pathology | Zavelevich M.P.,R.E. Kavetsky Institute of Experimental Pathology | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters

A series of novel 4-oxa-podophyllotoxin derivatives 7 featuring the intact lactone ring D and various substituents in rings B and E has been synthesized and evaluated in a phenotypic sea urchin embryo assay along with the representative 4-aza-analogs 5 for their antimitotic and microtubule destabilizing activity. The most active compounds exhibited myristicin-derived or a 3′,5′-dimethoxy substitution pattern in the ring E and a 6-methoxy moiety replacing the methylenedioxy ring A. Compounds 5xb, 5xe, 5yb, 7xa, 7xb, and 7xc showed potent antiproliferative effects in the NCI60 cytotoxicity screen. Notably, growth of the multi-drug resistant NCI/ADR-RES cells was more affected by these agents than the parent OVCAR-8 cell line. Although generally 4-oxa-podophyllotoxins were less potent than the respective 4-aza-derivatives in these assays, stability of the former series towards oxidation may prove to be of interest for the development of anticancer agents with in vivo activity. © 2011 Elsevier Ltd. All rights reserved. Source

Burli R.W.,BioFocus Chesterford Research Park | Thomas E.,BioFocus Chesterford Research Park | Beaumont V.,080 Center Drive
Topics in Medicinal Chemistry

Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided. © 2010 Springer-Verlag Berlin Heidelberg. Source

Orsatti L.,IRBM Science Park | Speziale R.,IRBM Science Park | Orsale M.V.,IRBM Science Park | Caretti F.,IRBM Science Park | And 11 more authors.
Journal of Pharmaceutical and Biomedical Analysis

Neuroactive metabolites in the kynurenine pathway of tryptophan catabolism are associated with neurodegenerative disorders. Tryptophan is transported across the blood-brain barrier and converted via the kynurenine pathway to N-formyl-. l-kynurenine, which is further degraded to l-kynurenine. This metabolite can then generate a group of metabolites called kynurenines, most of which have neuroactive properties. The association of tryptophan catabolic pathway alterations with various central nervous system (CNS) pathologies has raised interest in analytical methods to accurately quantify kynurenines in body fluids. We here describe a rapid and sensitive reverse-phase HPLC-MS/MS method to quantify l-kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxy-. l-kynurenine (3HK) and anthranilic acid (AA) in rat plasma. Our goal was to quantify these metabolites in a single run; given their different physico-chemical properties, major efforts were devoted to develop a chromatography suitable for all metabolites that involves plasma protein precipitation with acetonitrile followed by chromatographic separation by C18 RP chromatography, detected by electrospray mass spectrometry. Quantitation range was 0.098-100. ng/ml for 3HK, 9.8-20,000. ng/ml for KYN, 0.49-1000. ng/ml for KYNA and AA. The method was linear (r>. 0.9963) and validation parameters were within acceptance range (calibration standards and QC accuracy within ±30%). © 2015 Elsevier B.V. Source

Toledo-Sherman L.M.,080 Center Drive | Prime M.E.,Evotec | Mrzljak L.,CHDI Management CHDI Foundation | Beconi M.G.,080 Center Drive | And 30 more authors.
Journal of Medicinal Chemistry

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system. © 2015 American Chemical Society. Source

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