Design, Synthesis And Bioactivity Study Of Neolamellarin A Analogues

Extensively exist in plants, animals and microorganisms, alkaloids are a kind ofcompounds which have significant bioactivities. In recent years, alkaloids originatingfrom marine are drawing an increasing attention because of their novel chemicalstructures and unique bioactivities. Structural modification on natural alkaloids inorder to obtain compounds which have better bioactivities, less toxicity and muchconvenience for mass production has always been the prevalent topic ofpharmaceutical research. The lamellarins and related pyrrole-derived alkaloids haveshown a diverse range of bioactivities such as cytotoxicity and antitumor activity，such as lamentation O showed good cytotoxic activity for HCT116human coloncancer cell lines with IC50of1μM, Neolamellarin A from the sponge is a selectiveinhibitor of HIF-1.During the Laboratory preliminary work we have found full-methyl derivatives ofNeolamellarin A have a good MDR reversal activity wiht lower cytotoxic activity,while multi-hydroxy derivatives show a strong cytotoxic activity. Neolamellarin Aand its multi-hydroxy derivatives can not pass the blood brain barrier in vivo as aresult of their low lipophilicity,which hinder their the absorption and distribution. Inoder to improve the lipo-hydro partition coefficient of the compounds and maintaintheir moderate cytotoxic activity, we exposed part phenolic hydroxyl while protectedthe remaining with methoxy groups.35target new compounds were designed andsynthesized which have not been reported and were confirmed by nuclear magneticresonance (1H NMR and13C NMR) and mass spectrometry (HRMS) authentication.Benzyl group and methyl group substituted Neolamellarin A derivatives weresynthesized by using oxidative cyclization reaction of aromatic aldehydes andbenzylamine, and then the benzyl group was removed under a hydrogen/Pd/Csystem to give a series of The hydroxyl and the methoxy substituted Neolamellarin A analogues for further structural reform in the future.The in vitro inhibitory activity of the target compounds were evaluated againsthuman lung cancer cell lines H1299. All the benzyl and methyl group substitutedNeolamellarin A derivatives act on the tumor cells at10μM concentration and cellviability was above70%suggesting a low cytotoxic activity.The phenolic hydroxyltarget compounds were evaluated cytotoxic activity screening. For instance, the IC50values of5o,5r against human lung cancer cell lines H1299are less than10μM;the IC50values of5p,5q against H1299cell lines is less than15μM,which showedgood cytotoxic activity. On the part of the target compounds were evaluated Hsp90inhibitory activity screening. Compound5p showed higher than the positive controldrug17-AAG inhibitory activity.