Synthesis And Screening Anticancer Activity Of Novel Acyl Dihydropyrazole Derivatives Targeting Telomerase

Based on computer aided drug design，a series of12novel acyl dihydropyrazolederivatives were designed and synthesized with halogen-salicylic salicylaldehyde andacetone together. And the structures of these compounds were characterized with1HNMR and13C NMR, respectively. The crystal structures of three compounds weredetermined by single crystal X-Ray diffraction method. The synthesis condition of thesecompounds were explored and their anti-tumor activity and telomerase activity ofcompounds were seleted. Then the potent activity of the title compound was evaluatedby Discovery Studio2.1software based on molecular docking effect with telomerase(3DU6).(1)12novel acyl dihydropyrazole derivatives were firstly synthesized. Theα,β-unsaturated ketones were obtained from halogen-salicylic aldehyde andacetone as raw material. And the two dihydropyrazole moieties were synthesized bycyclization of α,β-unsaturated ketone with85%hydrazine hydrate. Finally, a series of12novel acyl dihydropyrazole derivatives were synthesized by the dihydropyrazolereacting with various amines.2) Among them,3compounds were determined by X-Ray diffraction.Compound5a-3belongs to orthorhombic and Pna2(1) space group,4b belongs totriclinic and P-1space group,and7a-2belongs to monoclinic and P2(1)/c space group.3) The compounds were evaluated for their antitumor activity and telomeraseactivity. It is obvious from the data that compound5a-3and4a exhibited high activity against SGC-7901cells and MGC-803cells with the IC50value of21.3±1.885μM and2.47±0.75μM respectively.It is clear that the anti-tumor activity of cyclic amines isbetter than that of direct-attached amines. Docking simulation was performed toposition compound4a into the telomerase (TERT) active site to determine the probablebinding model.In summary, a series of compounds were desiged and synthesized in this article andexhibited high anti-cancer activity,which enrich the structure of telomerase inhibitors.