Structure Optimization And Intestinal Absorption Study Of The Active Halophenol Compound LM49

Objective:In order to find new candidate compounds, we designed and synthesized a series of chlorinated polyhydroxy benzophenone compounds with LM49as a lead compound, and several activities of the obtained halophenols were evaluated in vitro. Then the intestinal absorption in rats of LM49and another new compound with a high activity against H2O2-induced injury in human umbilical vein endothelial cell (HUVEC) was performed to explain the relationship between intestinal absorption and bioavailability.Methods and Results:A series of novel chlorinated polyhydroxy benzophenone derivatives were prepared from methoxy and halogen substituted benzoic acids, followed by acylation of carboxylic acid, Friedel-Crafts acylation, halogenation reaction and demethylation. The structures were confirmed by ESI-MS, HRMS,1H NMR, and13C NMR spectra. Then the target compounds were evaluated for their in vitro bioactivities, including cytoprotective activity against H2O2-induced injury in human umbilical vein endothelial cell (HUVEC), inhibitory activity against protein tyrosine kinase (PTK), and antiproliferative activity against cancer cell.Twelve new compounds were prepared, including eight new target compounds. The results showed that some chlorophenols displayed potent cytoprotective activity. Two chlorophenols,2,3’,5-trichloro-3,4,6’-trihydroxydiphenylmethanone (2b1) and2,3’-dichloro-4,5,6’-trihydroxydiphenylmethanone (9a1), exhibited high protective activity against H2O2-induced injury in HUVEC with EC50values of5.2μM and6.2μM, compared with the positive control group, quercetin (5.8μM) and LM49(3.5μM). In addition,2b’also exhibited higher inhibitory activity against PTK with an IC50of3.1μM than the positive control genistein13.6μM.The absorptions of LM49with three concentrations (20,40,80μg·mL-1)in different intestinal segments were studied by in situ rats single pass perfusion model, then a new derivative having high endothelial cell protective activity and being obtained easily was compared with LM49to evaluate the extent of the whole intestinal absorption, with the concentration of40μg·mL-1was selected.Studies suggested that9a1and LM49were easy to be absorbed, and LM49could be well absorbed at all segments of intestine in rats.Conclusions:The study found two new candidate compounds with a strong cytoprotective activity against H2O2-induced injury in HUVEC. Meanwhile the study demonstrated that LM49exhibited high absorption in intestinal, which inspired us that the low bioavailability of LM49maybe caused by the First Pass Effect.