Design, Synthesis And Anticancer Activity Of Paclitaxel-benzoxazoles Hybrid Molecules

Paclitaxel is a tetracyclic diterpenes extracted from the genus taxus.As a famous natural antitumor drug,paclitaxel and its derivatives Docetaxel and Cabazitaxel have been approved by the U.S.FDA for clinical treatment of breast cancer,ovarian cancer and non-small cell lung cancer.However,the neurotoxicity and multi-drug resistance of paclitaxel have gradually emerged accompanying with the clinical application.On the other side,paclitaxel is faced with poor water solubility and low content of natural sources,which makes it difficult to meet the increasing clinical demands.In order to find some compound molecules that may have similar activity to paclitaxel,we screened a number of compounds by using a molecular docking simulation withβ-tubulin.The results showed that the paclitaxel-benzoxazoles hybrid molecules have a good binding effect with β-tubulin.Besides,benzoxazole and its derivatives,important structural units in many bioactive natural products and some drugs,can be used as the cytotoxin,the anticancer agent,cathepsin inhibitor,HIV reverse transcriptase inhibitor and so on.While,there are no reports on the study of paclitaxel-benzoxazoles hybrid molecules at present.Based on the assumption of "combination principle" applied in the design of new drugs and the results of molecular docking simulation screening,we have designed to synthesize a series of 2-arylbenzoxazole compounds by the metal-catalyzed synthesis method developed by our research group previously to replace the complex diterpenoid nucleus of paclitaxel and obtain the paclitaxel-benzoxazoles hybrid molecules,then we test the anticancer activity of these compounds in vitro.In this study,we designed a feasible synthetic route through a series of conditions.Finally,we obtained 26 new paclitaxel-benzoxazoles hybrid molecules and characterized their NMR and MS data.Then we tested their anticancer activity against human breast cancer cell lines MDA-MB-231 and human liver cancer cell lines HepG2 in vitro.The experimental results showed that most of the compounds had higher inhibition rate than paclitaxel at the concentration of 50μM.Among them,the inhibition rates of compound 3k,3H and 4A were more than 90%,while the inhibitory rates of compound 3G,3J and 3M on these two kinds of cancer cells were significantly lower than those of the positive control.In the concentration-dependent screening experiment,the IC50 values of the compounds were higher than paclitaxel.It was considered that the inhibitory effect of these compounds was better at the high concentration,but weakened with the decrease of the concentration.