Design, synthesis and biological evaluation of indanone-chalcone hybrids as potent and selective hCES2A inhibitors.

Human carboxylesterase 2 (hCES2A), one of the major serine hydrolases distributed in the small intestine, plays a crucial role in hydrolysis of ester-bearing drugs. Accumulating evidence has indicated that hCES2A inhibitor therapy can modulate the pharmacokinetic and toxicological profiles of some important hCES2A-substrate drugs, such as the anticancer agent CPT-11. Herein, a series of indanone-chalcone hybrids are designed and synthesized to find potent and highly selective hCES2A inhibitors. Inhibition assays demonstrated that most indanone-chalcone hybrids displayed strong to moderate hCES2A inhibition activities. Structure-hCES2A inhibition activity relationship studies showed that introduction of a hydroxyl at the C4' site and introduction of an N-alkyl group at the C6 site were beneficial for hCES2A inhibition. Particularly, B7 (an N-alkylated 1-indanone-chalcone hybrid) exhibited the most potent inhibition on hCES2A and excellent specificity (this agent could not inhibit other human esterases including hCES1A and butyrylcholinesterase). Inhibition kinetic analyses demonstrated that B7 potently inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a calculated Ki value of 0.068 µM. Furthermore, B7 was capable of inhibiting intracellular hCES2A in living cells and displayed good metabolic stability. Collectively, our findings show that indanone-chalcone hybrids are good choices for the development of hCES2A inhibitors, while B7 is a promising candidate for the development of novel anti-diarrhea agents to ameliorate irinotecan-induced intestinal toxicity.

[The effect of newcastle disease virus on the biological behavior of tumor cells].

AIM: To investigate the anti-tumor effect of newcastle disease virus (NDV). METHODS: Plaque formation test was used to investigate the effect of NDV on chicken embryofibroblasts(CEF). Cell suppression test, agarose gel electrophoresis, cytoskeleton staining, fluorescence staining, TUNEL staining, and sialic acid content determination were used to observe the influence of NDV on several human tumor cells. RESULTS: The Plaque formation was observed in chicken embryo fibroblasts.NDV could lead to the apparent cytopathy of BHK, Hela and Hep-2 tumor cells, but has no apparent effect on Wish cells. The strong suppressive effect of NDV on the growth of these tumor cells was found without dose dependence. The optimal dose of NDV could induce the death of tumor cells which was mainly apoptosis, as showed by the classical DNA ladder in DNA gel electrophoresis. NDV also resulted in the changes of cytoskeleton and decreased the level of sialic acid contents on tumor cells. CONCLUSION: NDV may be a potential anti-tumor agent.