The Synthesis And Antitumor Activity Study Of Selenium-/Sulfur- Or Piperazine-/Aminopiperidine-Containing Indole Derivatives

Combretastatin A-4(CA-4),a good leading compound,is a powerful inhibitor of tubulin polymerization that displays cytotoxic and antivascular activities by binding at the colchicine site of tubulin.The structure-activity relationships(SAR)of CA-4 indicate that a cis-configuration of the olefinic bridge,the presence of 3,4,5-trimethoxy groups on ring A and a non-coplanar B ring with apara-methoxy group are required for anti-tubulin activity.Recently,many indole group-containing compounds replacing the cis-double bond of CA-4 with one-atom bridges(e.g.carbonyl,methylene,sulfur and amino,et al)have been reported as CA-4 analogues with potent antitubulin and antiproliferative activities.In our case,using bioisosterism,combination principles and computer aided drug design(CADD)strategies,the bridges of these indole derivatives were replaced with selenium/sulfur or piperazine/amino-piperidine,respectively,and indole ring was treated as ringA/B to design our target compounds.Compounds ?/? were synthesized from diselenide/disulfide and indoles via 3-selenylation/3-sulfuration,followed by oxidation and O-deallylation,and compounds ? were obtained via condensation,sulfonylation and Buchwald-Hartwig cross-coupling reaction.Microwave(MW)was used for the synthesis of target compounds I,which significantly improved both the rates and yields of 3-selenylation reaction.While 3'-OH containing target compounds ? could be furnished via a mild ultrasound(US)-promoted two-step process involving 3-selenylation/3-sulfuration followed by O-deallylation at room temperature.A comparison of the reaction rates of O-deallylation and ester reduction demonstrated that O-deallylation was more sensitive to US irradiation,as O-deallylation could be significantly improved while the ester reduction could hardly be effected,and these significant reaction rate differences made it possible to selective synthesis of compounds with O-deallylation or O-deallylation and ester reduction.The evaluation of antiproliferative activity of target compounds against three human cancer cell lines was performed using MTT assay,and most of them exhibited moderate to potent activity.Fourteen of the synthesized compounds showed the nanomolar IC50 values,which were very close to that of CA-4,and worthy of further evaluation as promising new antitumor agent.The results of tubulin polymerization studies,immunofluorescence studies and docking studies indicated that their antitubulin activities were very close to that of CA-4 and the molecular target of these synthesized compounds is most likely tubulin.