Study Of Synthesis And Biological Activity Of ?,?-Diamino-Acid Ester Derivatives Based On Alkynylamide Ylide Trapping With Electrophile

Alkyne moieties widely exist in natural products and some pharmaceuticals as important pharmacophores,especially anticancerogens,which attributes to the primary reason that alkyne group can covalently interact with the cysteine residue of protein targets via addition reaction and enhance the interaction between drugs.and targets.The high energy and unsaturated structure makes alkynes possess goodreactivity to amino,hydroxyl,imine,diazo and other functional groups.Hence,there initiates a great challenge to directly introduce an alkynyl group into a complex molecule with poly functional groups.Based on Multi-component reactions(MCRs)trapping carbamate ammonium ylide with imines,we successfully constructed alkynylamide-substituted ?,?-diamino-acid ester derivatives 4 with poly functional groups and structural diversity from simple starting materials through "one-pot".Meanwhile,we explored the biological activity of the resulting products 4 and initially achieved the structure-activity relationship study.There introduces the important part of alkyne moieties for anticancer medicines and it's synthetic strategies in the chapter one,and we propose our research conception and project goals according to the current study levels.In the chapter two,the initial exploration was carried out by reacting aryldiazoacetates 1,propiolamide 2 and imines 3 as substrates and Rh2(OAc)4 as a catalyst to smoothly construct alkynylamide-substituted ?,?-diamino-acid ester derivatives 4 with good yield and high diastereoselectivity by "one-pot".In the chapter three,the value of our practically synthesized novel products 4 for hit hunting has been demonstrated in exploring biological activity,and discovered the resulting products exhibited significant inhibitory activity with IC50 values in the low micromolar range in human colon cancer and human liver cancer cells.After that,carrying on the structure-activity relationship study,we found that the alkynylamide-substituted ?,?-diamino-acid ester derivatives 4,lack of the hydroxyl group,revealed strong activity and IC50 values were up to the nanomolar,especially the IC50 value in SJSA-1 cells was 9.56 nM,which indicated that the hydroxyl is unnecessary group;some prodcuts bearing alkenyl and alkyl instead of terminal alkynyl or benzo-oxazolopyrazinone derivative 7 were completely inactive,which indicated that alkynyl group is necessary for anticancer activity.Thus,our designed and synthesized alkynylamide-substituted ?,?-diamino-acid ester derivatives 4 may be a new potential class of anticancer drugs,which provides the material basis for the subsequent pharmacology research,and the possibility of potential druggability.