Discovery of small-molecule inhibitors of RUVBL1/2 ATPase.

RUVBL1 and RUVBL2 are highly conserved AAA ATPases (ATPases Associated with various cellular Activities) and highly relevant to the progression of cancer, which makes them attractive targets for novel therapeutic anticancer drugs. In this work, docking-based virtual screening was performed to identify compounds with activity against the RUVBL1/2 complex. Seven compounds showed inhibitory activity against the complex in both enzymatic and cellular assays.

Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity.

Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C-C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1 activity over previously reported bivalent ligands.

Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry.

A bivalent compound featuring both a mu opioid receptor (MOR) and a CXCR4 antagonist pharmacophore (naltrexone and IT1t) was designed and synthesized. Further binding and functional studies demonstrated acting as a MOR and a CXCR4 dual antagonist with reasonable binding affinities at both receptors. Furthermore, compound seemed more effective than a combination of IT1t and naltrexone in inhibiting HIV entry at the presence of morphine.

One-pot synthesis of 1,3,5-triazine-2,4-dithione derivatives via three-component reactions.

A catalyst-free one-pot synthetic methodology was developed for the preparation of 1,3,5-triazine-2,4-dithione derivatives through three-component reactions of arylaldehydes, thiourea, and orthoformates. The procedure tolerated a diverse range of arylaldehydes and orthoformates and provided a rapid entry to a variety of 4-aryl-6-(alkylthio)-3,4-dihydro-1,3,5-triazine-2(1)-thiones (29 examples). The synthetic strategy relies on the dual role of thiourea in the cyclization with the aldehydes and the alkylation via an intermediate imidate formation.

Novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) with high anti-tumor activity and low side reaction.

To discover whether novel anti-tumor platinum agents are capable of selectively accumulating in tumor tissue, three novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) were prepared. At a dose of 1.67 μmol kg(-1) the in vivo anti-tumor potencies of two of the compounds were higher than that of oxaliplatin.

A new platinum-complex showing easy preparation, promising anti-tumor activity, and better efficacy and distribution properties than oxaliplatin.

Current clinically used chemotherapeutic platinum drugs can trigger severe toxic effects. To develop a model system for the evaluation of the therapeutic efficacy and the toxic effects of new platinum agents, we have synthesized a new compound N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-hydroxyproline dichloroplatinum(ii) (PHDP), compared its in vitro anti-proliferation activity, in vivo anti-tumor activity and safety to those of oxaliplatin, and correlated all these biological actions with the platinum occurring in the spleen, kidney, heart, brain, blood, tumor tissue, urine and faeces of the treated mice. We explored the atomic absorption based determinations of the platinum which occurred in the spleen, kidney, heart, brain, blood, tumor tissue, urine and faeces and constitute a model system that can be generally used in the investigation of the novel platinum agents.

One single HPLC-PDA/(-)ESI-MS/MS analysis to simultaneously determine 30 components of the aqueous extract of Rabdosia rubescens.

In China the leaves of Rabdosia rubescens have been cooked in water and widely drank to treat inflammatory and pain related diseases. To explore the components that were possibly absorbed by people the aqueous extract of the leaves was prepared, and one single HPLC-PDA/(-)ESI-MS/MS analysis was developed to simultaneously determine the components. Using the HPLC-PDA analysis 39 peaks were found in the aqueous extract, while using the (-)ESI-MS/MS analysis we were able to identify 30 peaks represented components, including 5 nucleic acids, 21 phenolic acids and 4 diterpenoids.

HPLC-MS aided PC12 cell systems: to quantitatively monitor the conversion of nitronyl nitroxide in biological systems with and without NO.

Nitronyl nitroxides are capable of preventing cells, tissues, and organs from radical-induced damage through scavenging NO˙, ˙O(2)(-) and ˙OH. In order to explore the conversions of nitronyl nitroxides in biological systems with and without NO˙, HPLC-MS aided PC12 cell systems were developed, and the conversions of 2-(3'-nitrophenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl -3-oxide (3-nitro-PTIO), 1-oxyl-2-(3'-nitrophenyl)-4,4,5,5-tetramethylimidazoline (3-nitro-PTI), and 1-hydroxyl-2-(3'-nitrophenyl)-4,4,5,5-tetramethylimidazoline (3-nitro-PTIH) were quantitatively monitored. In these systems 3-nitro-PTIO and 3-nitro-PTI were time-dependently converted to 3-nitro-PTIH, while no conversion of 3-nitro-PTIH was detected.

Novel Cu(II)-RGD-octapeptides: Synthesis, coordination mode, in vitro anti-platelet aggregation/in vivo anti-thrombotic evaluation and correlation of sequence with nano-structure.

Unlabelled: The synthesis, bioassays and nano-structure characterization of Cu(II)-RGD-octapeptide complexes Cu(II)-Arg-Gly-Asp-Ser-Arg-Gly-Asp-Ser [Cu(II)-4a], Cu(II)-Arg-Gly-Asp-Val-Arg-Gly-Asp-Val [Cu(II)-4b] and Cu(II)-Arg-Gly-Asp-Phe-Arg-Gly-Asp-Phe [Cu(II)-4c] were investigated. UV-vis, CD and CD/ESI-MS spectra suggested that the coordination of Cu(II)-4a-c met a 3 N mode. In the in vitro anti-platelet aggregation assay the IC(50) values of Cu(II)-RGD-octapeptide complexes were 10 - 110 folds lower than that of RGD-octapeptides.

{2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM): its anti-cancer efficacy and intercalation mechanism identified via multi-model systems.

{2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) was provided as a DNA-intercalator. For the comprehensive evaluation of this new intercalator, an assay system consisting of cell, S180 mouse, healthy mouse, spectrum, non-spectrum, and gel electrophoresis models was constructed. On the cell (S180, K562, MCF-7, HeLa and HepG2) models, MIAM selectively inhibited the viability of HeLa.

N-[2-chloro-9H-purin-6-yl]-N-cyclopropylglycylamino acids and derivatives: synthesis, evaluation as a class of novel analgesics, and 3D QSAR analysis.

Via a five-step-reaction procedure for the preparation of 19 known N-[2-chloro-9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycylamino acid benzylesters (6a-s) and successive removal of 9-(tetrahydropyran-2-yl) and benzylester groups 19 novel N-[2-chloro-9H-purin-6-yl]-N-cyclopropylglycylamino acid benzylesters (7a-s) and 19 novel N-[2-chloro-9H-purin-6-yl]-N-cyclopropylglycylamino acids (8a-s) were provided. On tail-flick mouse model the in vivo analgesic activities of these 38 novel compounds were measured and most of them were defined as good analgesics. Based on Molecular Field Analysis of the pain threshold variations of the mice receiving 48 compounds in terms of the descriptors proton and methyl an equation was established.

A class of novel conjugates of substituted purine and Gly-AA-OBzl: synthesis and evaluation of orally analgesic activity.

Aimed at the chemotherapy of chronic pain two kinds of analgesic pharmacophores, substituted purine and Gly-AA-OBzl, were coupled via a five-step-reaction procedure and 19 novel conjugates N-[2-chloro-9-(tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycylamino acid benzylesters were provided. On mouse-tail flick model their in vivo analgesic activities were assayed. The results indicate that introducing Gly-OC(2)H(5) into the 6-position of the substituted purine leads to ambiguous increase of the analgesic activity, while introducing Gly-AA-OBzl into this position leads to significant increase of the analgesic activity.