Design,Synthesis And Bioactivity Study Of Lndolo[3,2-b] Quinoline Boronic Acid Derivatives And Permethylated Neolamellarin A Analogues

Extensively exist in plants, animals and microorganisms, alkaloids are a kind of compounds which have significant bioactivities. In recent years, alkaloids originating from marine are drawing an increasing attention because of their novel chemical structures and unique bioactivities. Structural modification on natural alkaloids in order to obtain compounds which have better bioactivities, less toxicity and much convenience for mass production has always been the prevalent topic of pharmaceutical research. Therefore, a kind of indolo[3,2-b]quinoline originating from terricolous plant cryptolepines which has extensive bioactivities and a kind of alkaloids Neolamellarin A originating from marine animal sponges which has a novel pyrrolic skeleton have been chosen for structural modification as well as bioactivity research.The particular properties of boronic acid compounds allow them to possess an important position among the pharmaceutical research and development. One successful example is Bortezomib, which is the first boronic acid containing compound and the first proteasome inhibitor to gain approval for multiple myeloma treatment by the US FDA and European authorities. The dipeptide boronic acid compound exhibited extremely high selectivity for the proteasome, which is attributed to the boronic acid moiety complexing the threonine hydroxy group in the chymotrypsin-like active site of the 26S proteasome inside of cells. Based on boronic acid can react with cis-1,2- or cis-1,3-diols by forming five-or six-membered cyclic esters, boronic acid derivatives have been used as sensors for saccharide and biomarker detecting reagents for cell surface saccharides, such as sLex. Thus, regarding the boronic acid as the pharmacophore has plenty of theoretical foundation.In this dissertation, the alkaloid idolo[3,2-b]quinoline was modified with boronic acid, and the cytotoxicities, cellular localizations and antiviral activities of the synthesized compounds were evaluated; pyrrolic marine alkaloid Neolamellarin A permethylated derivatives were designed and synthesized, and their anti-tumor activities were evaluated.Modified the parent compound idolo[3,2-b]quinoline with boronic acid, four series of novel quindoline derivatives with or without boronic acid modifications were designed and synthesized,52 new target compounds were confirmed by 1HNMR, 13CNMR and HRMS.The in vitro inhibitory activity of the target compounds were evaluated against two human colon cancer cell lines (HT29 and HCT116) and two human lung cancer cell lines (H1299 and A549). The IC50 values of 15 target compounds in H1299,17 target compounds in A549,29 target compounds in HT29,34 target compounds in HCT116 were less than 5 μM. The IC50 values of 3 target compounds in H1299,8 target compounds in HT29,6 target compounds in HCT116 were less than 1 μM. Several idolo[3,2-b]quinoline boronic acid derivatives displayed favorable anti-tumor activities. For instance, the IC50 values of B-5b, B-5d and D-1d against human colon cancer cell lines HT29 are 0.7,0.8 and 0.9 μM; the IC50 values of C-3h against human colon cancer cell lines HCT116 is 1.6μM; the IC50 values of D-ld against human lung cancer cell lines A549 is 1.2 μM.The localization of the target compounds in A549 cells and HT29 cells was investigated. The boronic acid modification had impact on the cellular localizations and biological activities of its parental compounds. The idolo[3,2-b]quinoline derivatives without boronic acid modification were mostly found around or in the cell nucleus of A549 cells and HT29 cells. In contrast, the boronic acid modified idolo[3,2-b]quinoline derivatives were found mostly close to cell membranes. The boronic acid modifications reduced idolo[3,2-b]quinoline’s cytotoxicity mainly through decreased cell penetration and nuclear localization which we attributed to the increased cell surface carbohydrate interactions and/or increased difficulties in penetrating cell menbranes due to boronic acid modifications of the derivatives.The in vitro inhibitory activity of the target compounds B-1a, B-3a, B-4a, D-1c and D-1e were evaluated against influenzavirus at 10 μM. The inhibition rates were 59.7%, 48.1%,72.4% and 42.3%, respectively.33 Ningalin B analogues targeted to P-gp were designed and synthesized. All target compounds are novel and their structures are confirmed by 1H NMR,13C NMR and HRMS. All the synthesized target compounds have not been reported yet in literatures except for permethylated neolamellarin A. A concise and effective synthetic route has been discovered, in which the important intermediates 3,4-bisaryl-1H-pyrrole were synthesized by using deprotection of 1-benzyl-3,4-bisaryl-pyrroles, which were synthesized by using oxidative cyclization reaction of aromatic aldehydes and benzylamine.The in vitro inhibitory activity of the target compounds were evaluated against human colon cancer cell lines HT29 and human lung cancer cell lines A549. All the permethylated neolamellarin A analogues showed low cytotoxicities at 10 μM.