Chemical Constituents Of Three Liverworts, Bibenzyl Derivatives Preparation And Their Biological Activities

The bryophytes[Musci(mosses),Marchantiophyta(liverworts) and Anthocerotae (hornworts)],are morphologically placed between the algae and the pteridophytes(fern). Although they are located at the low position on evolutionary scale,various types of lipophilic terpenoids and aromatic compounds,which show significant biological activities,are isolated from the bryophytes in the past decades.Now the bryophytes have been well know as a source of biologically active,naturally occurring compounds. Bisbibenzyls,a class of characteristic components derived from liverworts,are attracting more and more attention because of their wide range of biological significance.Due to limited availability and poor structural diversity among natural acyclic bisbibenzyls,it is necessary to biosynthesize them for detailed pharmacological studies.In addition,macrocyclic bisbibenzyls have been recognized as a novel class of stereochemically intriguing molecules due to the highly strained cyclic structures.It is important to perform detailed studies on the bisbibenzyl stereochemistry for understanding their biosynthesis and mechanism of pharmacological action.Seven compounds were isolated from the ethyl ether extract of Dumortiera hirsute, which shed lights on chemotaxonomy and chemical ecology of this liverwort species. Among the compounds,dumhirone A(1) was a new phenylethyl cyclohexadienone derivative and 3,4 -O-isopropylideneshikimic acid(2) was a new natural product.Ten compounds were obtained from the ethyl ether extract of Plagiochiasma intermedium,including seven bisbibenzyls(8-14) and two benzaldehyde derivatives(15, 16).Compound riccardin C(13) possessed the in vitro antifungal property against the fluconazole-sensitive and resistant strains of Candida albicans,with the same MIC of 32μg/mL.Furthermore,13 was demonstrated to act as a fungal resistance modifying agent when combined with fluconazole on three resistant strains of C.albicans.The MICs of fluconazole was dramatically reduced by at most 256-fold.Compound 13 was also toxic to mature biofilms of 13 clinical C.albicans strains(killing rate 95.09%-98.93%).Finally,the P.intermedium essential oil showed inhibitory effects in vitro against the plant pathogenic fungus Fusarium oxysporum f.sp.lycopersici.Almost complete inhibition of mycelial growth was observed at 1024μg/ml concentration as compared to the control(full growth).This may reveal the ecological role of the liverwort essential oil.Five compounds,including two ent-kaurane dipenoids ent-kauran-7α,11β, 14β-triol-15-one)(17) and 11α-hydroxy-ent-kaur-16-en-15-one(18),and one eudesmanolide 11(13)-dihydrotelekin(19),were isolated from the ethanol extract of Chiloscyphus polyanthus.Among them,compound 17 was a new ent-kaurane dipenoid. Compound 19(100μg/ml) was a specific inhibitor on hyphal elongation of C.albicans.Biotransformation of dihydroresveratrol by crude Momordica charantia peroxidase produced six new acyclic bisbibenzyls(21-26).Their structures were established on the basis of NMR and MS analyses,which were C-C,C-O-C,and C-CH₂-C dimers of dihydroresveratrol.Compounds 23 and 25 are acyelic bisbibenzyls of new types not isolated from the plant kingdom previously.Compounds 21-26 were tested for antiproliferative activity against human prostate cancer PC3 cell line in vitro and compounds 22 and 26 were found to be more potent than the parent compound with IC₅₀ values of 14.2 and 16.6μM.The absolute stereochemistry of macrocyclic bisbibenzyls marchantin E and riccardin D were investigated in detail through HPLC-CD,VCD and computational methods.Two stereoisomers were resolved from marchantin E and their absolute configurations were determined by comparison of their experimental CD spectrum with those calculated for S-marchantin E and R-marchantin E.Two configurationally semistable atropisomers were resolved from riccardin D.the biaryl axis is semistable chiral element based on analysis of stereogenic elements,conformational analysis and molecular dynamics simulations.The rotational barriers were determined as 114.97 kJ/mol by computational method.The absolute configurations of these semistable atropisomers were assigned as M-riccardin D and P-riccardin D using a combination of electronic circular dichroism(ECD) and vibrational circular dichroism(VCD).