The Synthesis And Antitumor Activity Of Fluoroalkane Thioheterocyclic Derivatives

Cancer is an enormous global health burden, touching every region and socioeconomic level. Today, cancer accounts for one in every eight deaths worldwide-more than those due to combined HTV/AIDS, tuberculosis, and malaria ones. Therefore, the search and discovery of new anticancer drugs has been widely studied. Heterocyclic compounds, analogs and derivatives have attracted attention due to their diverse biological and pharmacological properties. Heterocycles such as benzothiazoles, benzimidazoles and benzoxazoles are constituents of many bioactive heterocyclic compounds, having a wide range of applications. When the heterocycles were introduced in fluorine atoms, sulfide, sulfoxide and sulfone, the biological activity can be enhanced.Two series of novel trifluorobutenyl derivatives of heterocyclic with convenient and efficient synthesis methods and their antitumor activities on three cell lines have been reported for the first time in the paper. In the first synthetic route, the nitrogen-containing heterocycles with sulfydry served as convenient starting materials were alkylated with 4-bromo-1,1,2-trifluorobutene-l-ene. The sulfide were selectively oxidized by hydrogen peroxide to product sulfoxide and sulfone or introduced chlorine atom by NCS. In the second synthetic route, the materials aromatic aldehyde or ketone was converted to the desired monosubstituted malononitrile through Rnoevenagel condensation and reduction reaction. The monosubstituted malononitrile reacted with 4-bromo-1,1,2-trifluorobutene-l-ene to furnish the corresponding compounds. In summary, thirty-seven trifluorobutenyl derivatives have been synthesized. Twenty-four new compounds were characterized by 1H-NMR,13C-NMR and HR-MS.Thirty-seven compounds were evaluated for the antitumor activity on three cancer cell lines (SH-SY5Y, MCF-7 and HepG2) using conventional MTT assay. The pharmacological results indicated that the benzothiazole and benzoxazole derivatives with sulfones and sulfoxides 3c,3h,4c,8,9,10 and 11 showed potent to moderate antitumor activity against three cancer cell lines, with IC50 values ranging between 0.4 μM and 41.5 μM. Comparing with reference compound taxol against MCF-7 and HepG2 lines, compounds 3c,3h,4c,8,9,10,11 present lower activities. However, their antitumor potencies against SH-SY5Y cells were far better than the reference compound noscapine. It’s worth noting that the antitumor activity of compound 3h (ICso= 0.4 μM) against SH-SY5Y cells was the best of all. It was likely to be a anti-cancer agent. The research lay certain basis for the research of nitrogen heterocyclic antitumor drugs. Compounds 3h,4c,8,10 present better selectivity than compounds 3c,9,11 among these three cells among the seven compounds, they have the potential to be leading compounds for anti-cancer agents and worthy further research.