Design, Synthesis, Pharmacological Screening And Molecular Mechanism Of Structurally Stable Analogues Of Curcumin

Curcumin,a main active component from the traditional Chinese herb Curcuma Longa,has been reported to possess various pharmacological activities,such as anti-tumor, anti-inflammation,cardio-protection and anti-virus.Unfortunately,curcumin has a poor stability in vitro and a weak pharmacokinetic profile in vivo,which significantly inhibits its clinical application.In this thesis,we present a series of mono-carbonyl analogues of curcumin by the deletion ofβ-diketone moiety that is considered to contribute to the stability and pharmacokinetic defects of curcumin.Firstly,we designed and synthesized 87 mono-carbonyl analogues of curcumin containing diverse substitutes and spacers,and determine their structures by ~1HNMR and ESI-MS,as well as single crystal X-ray diffraction of several representative compounds. The evidences from the detection of degradation degree in PH 7.4 buffer and pharmacokinetic study in vivo showed that our mono-carbonyl analogues have enhanced stability and improved pharmacokinetic profiles.Secondly,due to the pharmacological diversity of the leading curcumin,we evaluated several bioactivities of these analogues,such as anti-bacterial property against seven Gram+and Gram-bacteria,anti-tumor activity against seven human cancer cell lines by MTT method,and anti-inflammatory property by the inhibition of TNF-αand IL-6 release in LPS-induced macrophages.According to the screening results,the SAR conclusions in three kinds of pharmacological evaluations were analyzed and conducted,respectively. Some of mono-carbonyl analogues exhibited much higher bioactivities than curcumin.We also investigate the anti-inflammatory properties of several active analogues in dose-dependent mannar.In addition,the inhibition of the mRNA transcription of inflammatory factors,inflammatory enzymes such as COX-2,iNOS and PGDS, transcriptional factor NF--kB by active analogues reveals,partly,the cellular mechanism of analogues' anti-inflammatory activities.In the MTT assay,the significant difference of anti-tumor spectra between curcumin and analogues suggested that analogues may possess different molecular mechanism from the leading compounds.In this section,we found that compound B19,not like curcumin, exhibited a special anti-tumor mechanism by which B19 induced the apoptosis of human lung cancer H460 cells by ER stress.A series of molecular biological experiments showed that B19 increase the express of ER stress-related CHOP,XBP-1,ATF-4 both in dose-dependent and time-course manners,which revealed a different mechanism of B19 to induce cancer cell apoptosis from curcumin,and a perspective to develop a kind of anti-tumor drug with drug-resistant reverse.In summary,this thesis presents a kind of structurally stable analogues of curcumin through a lot of studies in drug design,synthesis,pharmacokinetics pharmacological evaluations,SARs and then molecular mechanisms.These studies are very helpful to develop new drugs from the natural curcumin.