Synthesis And Biological Evaluation Of Natural Alkynyl Phenols And Analogues

Natural products and their derivatives have always been the main source of new drug discovery,and especially,the natural products with active pharmacophores are the starting point for the development of new drugs.The plants of genus Selaginella are perennial herbs with a variety of pharmacological activities,such as anti-infective,anti-inflammatory,anti-mutagenic,anti-caries,immune and anti-retroviral activities.Selaginellins are a new class of natural pigments with unique acetylene skeletons which have been found only in genus Selaginella in recent years.These natural compounds have previously been reported to exhibit important biological activities including antioxidant,neuroprotective,antibacterial,antiviral,PTP1B and PDE-4 inhibitory activities,and have recently been found to have antitumor activity.In view of the novel structure,promising biological activities and rare natural occurance of Selaginellins,this thesis aims to study the total synthesis of Selaginellins and their analogues,in order to provide a basis for the biological activity and structure-activity relationship of these natural products.Based on the putative biosynthesis pathway of Selaginellins,the full synthetic route of Selaginellin N was first designed.Firstly,the phenol and alkynol groups are successively introduced via Suzuki?Sonogashira coupling reaction by the different reactivity of the ortho bromine and iodine of benzoate,and then the tertiary alcohol intermediate is obtained by nucleophilic addition of the organometallic reagent,and finally the skeleton of the Selaginellins is obtained by dehydration of tertiary alcohol.Using this synthetic route,we have successfully synthesized compounds 1a,1b,and 1c,1d,which bear the skeleton of Selariscinin D and Selaginellin S.Due to the large molecular steric hindrance of Selaginellin N,its total synthesis encountered great difficulties.In addition,we have found that natural Selaginellins generally share a common biphenyldiarylacetylene structure,presumably having potential as a pharmaceutically active group.Therefore,we designed a synthetic route of Selaginellin N analogue with lower steric hindrance,and synthesized 10 biphenyldiarylacetylene compounds2a²j.The anti-proliferative activity of these compounds against cancer cells?MCF-7,HepG2and Hela?was measured by MTT assay,and compounds 1c,2d,2g,2h,2i and 2j were found to exhibit strong anti-proliferative activity.Hypoxia-inducible factor-1?HIF-1?is a key factor in the control of hypoxia-inducible pathways by regulating the expression of a large number of genes involved in tumor progression and therapeutic resistance,which has been recognized as an attractive target for cancer therapy.The in vitro inhibitory activity of the synthetic compounds against HIF-1 pathway was determined by the dual luciferase reporter assay.Except compound 2j,most of the tested compounds showed moderate to good activity,with compounds 1a,2f and 2h showing higher HIF-1 inhibitory activity(IC₅₀ of 5.4,1.9 and 2.5?M,respectively)and relatively low cytotoxicity,indicating great potential as HIF-1inhibitors.These results afford a new strategy for the discovery of new HIF-1 inhibitors and anti-proliferative agents from natural or synthetic diaryl acetylene derivatives.