Design,Synthesis,Antitumor Activities And Radioprotective Effects Evaluation Of Aryl Benzyl Sulfoxide/Sulfone Derivatives

Malignant tumors threaten human health and life.Conventional treatments for cancer have significantly improved the prognosis and survival of cancer patients.However,several disadvantages,such as severe surgical trauma and severe damage to normal tissue cells,have stunted their therapeutic uses.Therefore,development of more specific drugs than existing ones is becoming a hot research topic supported by many governments.Targeted therapy is a new approach for cancer treatment.It has some advantages,such as specificity,and few side effects,which traditional methods do not have.Exposure to ionizing radiation could cause serious body injuries,such as acute radiation syndrome(ARS),or long-term health effects like cancer or pulmonary fibrosis.Ex-RAD,also known as ON 01210.Na(4-carboxystyryl-4-chlorobenzyl sulfone,sodium salt),is a chlorobenzyl sulfone derivative developed by Onconova Therapeutics(Newtown,PA,USA)and the Armed Forces Radiobiology Research Institute as a radioprotector and mitigator,it acts on ATM-p53 signaling pathway.Unlike most radioprotectors,Ex-RAD is not a free-radical scavenger or responsible for cell cycle arrest.Available data suggest that Ex-RAD has a novel mechanism for radiation protection involving DNA repair pathways.It exhibits potent radioprotective properties both in vitro and in vivo.Rigosertib(ON 01910 Na)is synthetic benzyl styryl sulfone((E)-2-{2-methoxy-5-[(20,40,60-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate)developed by Onconova Therapeutics as an antitumor agents.Rigosertib is a small molecule non-ATP-competitive inhibitor,which simultaneously inhibits PI3K and PLK signaling pathways.The structures of Ex-RAD and Rigosertib are similar and they both belong to benzyl styryl sulfone derivatives.In our previous work,we designed and synthesized 102 benzyl aryl sulfoxide/sulfone derivatives using Ex-RAD as the lead compound and found that they have a certain tyrosine kinase inhibitory activity.Based on these findings and the literature about Rigosertib,the structure of those active compounds were optimized and66 novel compounds were synthesized.The protein tyrosine kinase inhibitory activity,the antiproliferative effects on cancer cells and the radioprotective effects of these compounds were then further evaluated.The research contents and results were listed as follows:1.The protein tyrosine kinase inhibitory activities of the 102 compounds synthesized earlier were rescreened and the antiproliferative effects on cancer cells of these compounds were further evaluated.The results indicated that the benzyl-2-indolinone sulfoxide/sulfone derivatives(TL001-TL056)have strong protein tyrosine kinase inhibitory activity,The IC50 values of most compounds are lower than10μM.However,only the benzyl-2-indolinone sulfoxide derivatives showed potent antiproliferative effects on tumor cells,among which TL019(6j)and TL029(6o)are the two most active compounds.2.Based on the structure of the active compounds synthesized previously and combined with the pharmacophore features of the positive compound,we optimized the structure of these compounds.66 novel compounds were finally synthesized,including50 benzyl sulphur-containing 2-indolinone derivatives and 16 benzyl sulphur-containing2-naphthyl derivatives.The structures of target compounds were characterized by ~1H NMR spectra analyses.3.The protein tyrosine kinase inhibitory activity and the antiproliferative effects on tumor cells of the novel 66 compounds were evaluated.The results indicated that the benzyl-2-indolinone sulfide derivatives(10a-10p)did not show significant protein tyrosine kinase inhibitory activity,but strong antiproliferative effects on tumor cells.The benzyl-2-indolinone sulfone derivatives(12a-12r)did not show obvious protein tyrosine kinase inhibitory activity and antiproliferative effects on tumor cells.Only the benzyl-2-indolinone sulfoxide derivatives(11a-11q)have the both biological activities.Most of the benzyl-2-naphthyl sulfur-containing compounds(17-22)exhibited potent antiproliferative effects on tumor cells.Among them,compound 22a-1 showed better antiproliferative effects against HeLa and Hep G2 cells than Rigosertib,and compound22d-1 exhibited better antiproliferative effects against SCC-15 cells than Rigosertib.These two compounds are valuable for further research as promising anticancer agents.4.The anti-radiation activites of the target compounds were evaluated.The results indicated that some benzyl-2-naphthyl sulfoxide/sulfone derivatives(TLN07,TLN13,TLN19,TLN31,TLN32,TLN35,TLN38,TLN39 and TLN48)exhibited potent radioprotective effects.Among them,compound TLN35 is the most active one.In vivo,TLN35 could significantly increase the survival rate of irradiated cells and reduce the radiation-induced DNA damage;In vitro,TLN35 could not only significantly improve the 30-day survival rate after irradiation in mice,but also remarkably improve the peripheral blood cells counts after irradiation in mice.Compound TLN35 is a benzyl2-naphthyl sulfoxide derivative with potent anti-radiation activity.The results both in vitro and in vivo studies demonstrated that the radioprotective effect of TLN35 is significantly better than that of Ex-RAD.Moreover,TLN35 even exhibited better radioprotective effect than Ex-RAD by improving the peripheral blood cells counts after irradiation more effectively in mice.Compound TLN35 is valuable for further research as promising radioprotector.In this study,a total of 168 aryl benzyl sulfoxide/sulfone derivatives were screened.The results demonstrated that the antitumor activity of the two new compounds was comparable to that of Rigosertib at the cellular level,and the radioprotective effect of TLN35 is significantly better than that of Ex-RAD both in vitro and in vivo.The laws of anti-tumor and anti-radiation effects were systematically discussed and the structure activity relationships of these compounds were preliminary analyzed.This study has great application value and theoretical significance and has laid an experimental foundation for the development of anti-tumor drugs and radioprotectors.