Studies On The Synthesis And Antitumor Activities Of Mulity-substituted Pyrrolidine Compounds Based On Ar-tumerone Structure

Ar-tumerone is main constituent of essential oils isloated from traditional Chinese medicine Curcuma longa.According to modern medicine research,it exhibits many activities including anti-cancer,anti-bacterial,fungicidal,and antivenom,etc.At present research of Curcuma longa is forcused on curcumin over the world,but Few researchs show the synthesis of a series of novel skelectons based on ar-tumerone seen as lead compond and the evaluation of anti-cancer activities on these compounds.3,3?-pyrrolidinl-spirooxindole unit are important bioactive core existing in a broad range of natural pruducts and bioactive compound,which received much attention.As one of efficient and atom-economic method for the synthesis of pyrrolidine derivatives,1,3-dipolar cycloaddition of azomethine ylides to alkene has attracted much interest in recent years.The molecular hybridization has been well employed as an effective strategy for designing new drugs based on pharmacophoric sub-units of two or more known bioactive derrivatives.In this paper,we show a facile construction of novel ar-turmerone motif-fused spiropyrrolidine oxindoles via a multicomponent1,3-dipolar cycloaddition reaction,their bioloical activities against human leukemia cells K562 have been evaluated.After optimizing reaction conditions,we synthesize a series of desired products.This reaction syetem displayed broad substrate scope and gave 45 ar-turmerone motif-fused spiropyrrolidine oxindole derivatives in high yield?61%-93%?and with high diastereoselectivities?up to>20:1?.anti-cancer activity of total 45 componds has been measured using the microculture tetrazolium method?MTT?in vitro against human leukemia cells K562 and Cisplatin was a positive control.The IC₅₀0 of the compounds 3le,3la,4da,5oa,5pa and Cisplatin were 43.5?M,33.8?M,38.5.5?M,22.3?M,27.6?M and 21.3?Mrespectively,which revealed some of ar-turmerone motif-fused spiropyrrolidine oxindoles exhibited considerable antitumor activities.The second part:the study on the synthesis and aititumor of spirooxindole tetrahydropyranones.spirooxindole tetrahydropyranones frameworks are common in bioactive natural products and pharmaceutical leads and are crucial intermediates.At the same time Many natural products and pharmaceuticals share a common propan-2-ether molecular unit.The relative researches suggested that a propan-2-ether moiety located in the natural skeleton is an important functionality for activity,the possible mechanism could be ascribed to the lipophilicity enhancement of this core structure by the propan-2-ether moiety,which leads to the better penetration through the membranes to reach the targets.In this paper,we have firstly synthesized a series of spirooxindole tetrahydropyranones frameworks containing propan-2-ether unit through one-pot knoevenagel condensation/Michael cycloaddition.We investigate the reaction with sample substrates istains and 4-methylpent-3-en-2-one.the reaction demonstrated high function group tolerance and achieved the synthesis of final componds in moderate yields?32%-55%?.anti-cancer activity of total 15 componds has been measured using the microculture tetrazolium method?MTT?in vitro against human leukemia cells K562,however all componds dispayed bad potency.