Design,Synthesis And Antitumor Activity Of Isolongifolanone-Based Dihydropyrimidinethione And Thiazolo-Pyrimidine Derivatives

Natural products have various structures and are widely used,after chemical modifications and biological evaluations,these compounds may be developed as important drugs.Turpentine is an abundant and renewable resource whose main component is longifolene.Isolongifolanone can be obtained from longifolene by isomerization reaction and oxidation reaction.Isolongifolanone can also convert to other various derivatives which have many biological activities especially anti-tumor activity.In this paper,isolongifolanone-based dihypyrimidinethione and thiazolo-pyrimidine derivatives were synthesized by a series of reactions starting from isolongifolanone.The chemical structures of compounds obtained were characterized by ¹H NMR,¹³C NMR and High Resolution Mass Spectrometry（HRMS）.The antitumor activities of the target compounds were screened and the antitumor mechanisms of the selected compound were studied.In the first part of this article,twelve dihydropyrimidinethione derivatives have been synthesized from isolongifolanone by aldol and cyclization reactions.The chemical structures of compounds obtained were characterized by ¹H NMR,¹³C NMR and High Resolution Mass Spectrometry（HRMS）,and the structure of compound 3e was determined by X-ray single crystal diffraction.Their in vitro cytotoxicity against three cancer cell lines breast（MDA-MB-231）,cervix（He La）,liver（Hep G2）and one normal cell line mouse macrophages（RAW-264.7）were investigated.It was shown from the test results that these 12 compounds had good antitumor activity with IC₅₀values of 3.12⁴4.28μM.Among them,compounds 3j,3g,and 3k had the best antitumor activity against MDA-MB-231 cells(IC₅₀=3.12μM),He La cells(IC₅₀=4.04μM)and Hep G2 cells(IC₅₀=5.43μM),respectively.In addition,compound 3j arrested the cells in the G0/G1 phase of the MDA-MB-231 cell cycle and induced the early apoptosis of MDA-MB-231 cells in a dose-dependent manner.In the second part of this article,a series of novel thiazolo-pyrimidine derivatives（4a～4x）were synthesized from isolongifolanone according fragment-based design strategy,and their anticancer activity against human aortic smooth muscle cells（HASMC）,human breast cancer（MCF-7）cells,human cervical cancer（He La）cells,and human liver cancer（Hep G2）cells were investigated.Results of the anticancer activity illustrated that most of the compounds showed potent antitumor activity and compound 4i proved to be the most active derivative with IC₅₀values of 0.33±0.24（for MCF-7 cells）,0.52±0.13（for He La cells）and 3.09±0.11μM（for Hep G2 cells）,respectively.Moreover,we assessed the effects of 4i on cell apoptosis,cell cycle distribution,mitochondrial membrane potential and reactive oxygen species（ROS）generation.The results indicated that compound 4i altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of MCF-7 cells in a dose-dependent manner,however,without affecting cell cycle progression.These findings suggested that 4i was an effective compound and provided a promising candidate for anti-cancer drugs.In summary,isolongifolanone-based dihypyrimidinethione and thiazolo-pyrimidine derivatives had potent anticancer activity and its new application will be developed.