PTEN inhibition leads to the development of resistance to novel isoquinoline derivative TNBG-5602 in human liver cancer cells.

TNBG-5602, a new synthesized derivative of tetrazanbigen, is a potential chemotherapeutic agent against cancer. However, its underlying mechanism is complex and still unknown. In this investigation, the anticancer effects of TNBG-5602 were determined in vitro and in vivo. Small RNA retroviral library plasmids that overexpress 19-bp fragments were used to generate TNBG-5602-resistant cells. After validation, the overexpressed 19-bp fragments were sequenced using next-generation sequencing (NGS) in the drug-resistant cells. Furthermore, the relationship of TNBG-5602, phosphatase and tensin homolog deleted on Chromosome 10 (PTEN), and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway was explored. The results showed that TNBG-5602 can effectively inhibit cancer cell proliferation and induce apoptosis in vitro and in vivo. Drug-resistant cells were screened using the small RNA library. Compared with naïve cells, drug-resistant cells were more resistant to TNBG-5602 in vitro and in vivo. NGS results revealed that the second highest overexpressed 19-bp fragment perfectly matched the PTEN gene, so the expression of PTEN in various cells and tissues was verified. Further research showed that exogenous overexpression of PTEN strengthened the anticancer effects of TNBG-5602 on p-Akt expression, whereas silencing of PTEN weakened these effects in naïve cells. Taken together, by using this library, we confirmed that PTEN is the target gene to the anticancer effects of TNBG-5602 via the PI3K/Akt pathway.

Synthesis and characterization of four process impurities in pazopanib.

Pazopanib (trade name Votrient®) is a potent and selective multi-targeted tyrosine kinase inhibitor that blocks tumor growth and inhibits angiogenesis. Based on a recently reported procedure, we herein report the first synthesis of four potential process impurities generated in the production of pazopanib. The structure of these impurities were synthesized and characterized by 1H NMR, 13C NMR and HRMS data. The possible formation mechanisms of these impurities were also elucidated. These findings should be useful for the quality control of pazopanib in manufacture.

Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists.

A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.