Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.Download high-res image (74KB)Download full-size image

•Cocaine intensively modified lipidome in NAc.•Cocaine mainly affected phospholipid and sphingolipid metabolism.•Ceramide was decreased in NAc after cocaine administration.•Cocaine increased long and polyunsaturated fatty acid phospholipids in NAc.Lipids are predominant components of the brain and key regulators for neural structure and function. The neuropsychopharmacological effect of cocaine has been intensively investigated; however, the impact of cocaine on brain lipid profiles is largely unknown. In this study, we used a LC-MS-based lipidomic approach to investigate the impact of cocaine on brain lipidome in two mouse models, cocaine-conditioned place preference (CPP) and hyperlocomotor models and the lipidome was profoundly modified in the nucleus accumbens (NAc) and striatum respectively. We comprehensively analyzed the lipids among 21 subclasses across 7 lipid classes and found that cocaine profoundly modified brain lipidome. Notably, the lipid metabolites significantly modified were sphingolipids and glycerophospholipids in the NAc, showing a decrease in ceramide and an increase in its up/downstream metabolites levels, and decrease lysophosphatidylcholine (LPC) and lysophosphoethanolamine (LPE) and increase phosphatidylcholine (PC) and phosphatidylethanolamines (PE) levels, respectively. Moreover, long and polyunsaturated fatty acid phospholipids were also markedly increased in the NAc. Our results show that cocaine can markedly modify brain lipidomic profiling. These findings reveal a link between the modified lipidome and psychopharmacological effect of cocaine, providing a new insight into the mechanism of cocaine addiction.

Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50 values of 1.4 and 1.7 nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem.2013, 56, 9496–9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study.

A precise and sensitive LC method was developed and further validated for the determination of enantiomeric purity of (S)-N-[2-(3-{trans-4-hydroxy-4-[5-(pyrimidin-2-yl)pyridin-2-yl] cyclohexylamino} pyrrolidin-1-yl)-2-oxoethyl]-3-(trifluoromethyl) benzamide (PF-04136309). Baseline separation with a resolution higher than 1.8 was accomplished within 40 min using a CHIRALPAK AD (250 × 4.6 mm; particle size 5 μm) column, with n-hexane:2-propanol (70:30 v/v) as mobile phase at a flow rate of 1 mL min−1. The eluted analytes were subsequently detected with a UV detector at 260 nm. The effects of mobile phase components and temperature on enantiomeric selectivity as well as the resolution of enantiomers were thoroughly investigated. The calibration curves were plotted within a concentration range between 0.01 and 1 mg mL−1 (n = 9), and recoveries between 98.17 and 101.28 % were obtained, with relative standard deviation (RSD) lower than 1.44 %. The LOD and LOQ for PF-04136309 were 3.59 and 11.54 μg mL−1 and for its enantiomer were 3.39 and 11.28 μg mL−1, respectively. The developed method was demonstrated to be accurate, robust and sensitive for the determination of enantiomeric purity of PF-04136309, especially for the analysis of bulk samples.

A series of novel benzamide derivatives were prepared and evaluated using cell-based measurements. Among these compounds, 10f significantly inhibited Hedgehog signaling and showed equivalent or more potency than GDC-0449 in different tests. Furthermore, compound 10f potently inhibited the proliferation of Daoy, a medulloblastoma cell line that is reported to be resistant to GDC-0449, which indicated a promising prospect in the treatment of Hedgehog signaling pathway related cancer in clinical trial.