The Research Of Novel Monocarbonyl Curcumin Analogues

To make further researches on the novel Curcumin analogues with a goodstability, stronger anticancer activity and higher bioavailability, several series of novelmonocarbonyl Curcumin analogues A^-substituted arylmethyl-3?5-bis(benzylid-4-pipeirdones were designed and synthesized,and the structures were confirmed by lHNMR, IR，MS and elemental analysis. The structural formulas of compounds are asfollows respectively: All the forty eight new analogues were evaluated for their anticancer activityagainst ten human cancer cell lines (K562，Jurkat, U937，THP-1, ECA-109, EC-9706,SMMC-7721, H0-8910，MCF-7，PC-3) in vitro, and the higher cytotoxicity of theseanalogues against leukemic K562cells was observed. Preliminary bioassays showedthat most of the title analogues exhibited godd antiproliferative activities against allhuman cancer cell lines examined. Among them, the analogues2c (IC5o=0.045^M),3e (IC5o=0.043(xM) and4b (IC5o=0.04|xM) have better antiproliferative activities thanthe anticancer drug imatinib (IC50=0.074|iM) against leukemic K562cells.Further, the acirdine orange fluorescence, the flow cytometric analysis, and thecell cycle analysis, as well as the DNA fragmentation assay indicatated that theanalogue3e induced leukemic K562cell death by apoptosis, and it arrested the cellcycle in the G2/M phase.In addition, the analogue3e had good metabolic stability in rat liver microsome,and exhibited no direct inhibition and competitive inhibition on the catalytic activitiesof ifve main drug metabolism enzymes (CYP3A4, CYP2D6，CYP2C9, CYP1A2，CYP2C19) in human liver microsome. The pharmacokinetics and absolutebioavailability of analogue3e in rats were determined, and the results suggested thatanalogue3e (BA=5.2%)had better bioavailability than the standard Curcumin(BA=4.13%)，the half-life (Tl/2z) of3e were217.76土56.48min and511.68士258.53min atfer i.v and i.g administration, respectively. The CLz (L/min/kg)and Vdss (L/kg)of3e were0.22土0.06L/min/kg and38.61士24.61L/kg atfer i.v administration.Even more，analogue3e was well tolerated in mice whereby five daily doses up to andincluding2000mg/kg did not cause mortalities. All the results implied that ourdesigned mono-carbonyl Curcumin analogues were both practical and feasible.For reducing the toxicity of A^-substitutedtetrahydropyirdyl indole deritives andTetrahydropyridine deritives to normal bone marrow cells, two series of novelantibody-deritives were designed and synthesized. They were purified by membrane dialysis method and detected by UV. Preliminary bioassays indicated that bothcompounds and conjugates exhibited good antiproliferative activities against leukemiccells. Atfer conjugating with Monoclonal Antibody (McAb)，the conjugates showedlower toxicity to normal mice bone marrow cells than compounds. The results impliedthat our designed mono-carbonyl Curcumin analogues conjugates were both practicaland feasible.