Synthesis Of Poly-Substituted Five-Membered Ring Parallelly-Fused Oxindole And Evaluation Of Its Antitumor Activity

This thesis is composed of three parts:the first part sums up the progress of researches on 1-indanol derivatives and antineoplastic drugs screening techniques;the second part lists the research results related to Michael/Aldol cascade reaction of poly-substituted five-membered ring parallelly-fused oxindole compounds;the third part describes the researches on in-vitro anti-tumor cytotoxic activity of poly-substituted five-membered ring parallelly-fused oxindole compounds.1-indanol exists as the basic skeleton structure in a large number of natural products and compounds with biological activity,and is present in first-line anti-AIDS drug Crixivan and compounds including Tetrapetalone A.Owing to its excellent pharmacological activity,it has been concerned and studied by researchers in recent years.Upon a lot of literature research,we can see that there are currently many synthetic methods for preparing 1-indanol derivatives.However,there is few research on regioselectivity of Michael/Aldol cascade reaction.In the first part of this paper,1-indanol derivatives are summarized from bioactivity,existing synthetic methods,etc.,and the current research progress of antineoplastic drugs screening techniques are described.In the second part,research results related to Michael/Aldol cascade reaction of poly-substituted five-membered ring parallelly-fused oxindole compounds are described.In this part,1-indanol-fused 3-oxindole compound is firstly established using polycomponents.In particular,it should be noted that the product has obvious regioselectivity.Firstly,the Sandmeyer method is used to compound the initial isatin substrate and further obtain the poly-substituted 2-oxindole derivative,which reacts?Knoevenagel condensation reaction?with o-Phthalaldehyde upon the catalyst to produce the key reaction intermediate.Finally,the intermediate is reacted with malononitrile or ethyl cyanoacetate?Michael/Aldol cascade reaction?upon the catalyst to produce different substituted five-membered ring parallelly-fused oxindole compounds,which have continuous three-dimensional centers.Meanwhile,we also observe influence of a variety of tertiary amine,quaternary ammonium salt,inorganic base and various organic solvents on the reaction products,among which under the optimal reaction condition that phase transfer catalyst?TBAB?and inorganic base?K₂CO₃?are used as catalysts and DCM is used as the reactive solvent,moderate to high yields are obtained at room temperature?up to 92%?,with good diastereoselecti-vity?up to 20:1?.There are a total of 16 target compounds acquired,of which regioselectivity mechanism is then studied.In the third part,the researches on in-vitro anti-tumor cytotoxic activity of poly-substituted five-membered ring parallelly-fused oxindole compounds are described.This paper adopts MTT method and takes clinical commonly used anticancer drug Cisplatin as positive control,as well as selects 10 compounds for research on in-vitro anti-tumor cytotoxic activity.It targets at checking the cytotoxic activity over K562?human's chronic myeloid leukemia cell?.Among them,3aa,3ba,3da and 3ea have good cytotoxic activity.3aa(IC₅₀=58.99?M),3ba(IC₅₀=55.22?M),3da(IC₅₀=47.92?M)and 3ea(IC₅₀=64.42?M)are relatively close to the IC₅₀0 value of the positive control drug Cisplatin(IC₅₀=29.8?M).Within 6.25-100?moL/L,the drug presents enhanced capacity in suspressing K562 cell proliferation over the increasing concentration,and there is good linear relationship between the dosage and the effect.