Discovery of prenylated indole alkaloid and natural xanthone from cold-seep sediment derived fungus Talaromyces funiculosus SD-523

A new prenylated indole alkaloid 11,17-epi-mangrovamide A(1),a new natural occurring product,1,7-dihydroxy-6-methyl-8-hydroxymethyl-xanthone(2),two known alkaloids,mangrovamide A(3)and mangrovamide G(4),and four known polyketide derivatives(5–8)were isolated and identified from the cold-seep sediment derived fungal strain Talaromyces funiculosus SD-523.Their structures were elucidated by combination of nuclear magnetic resonance(NMR),high resolution electrospray ionization mass spectroscopy(HRESIMS),quantum chemical electronic circular dichroism(ECD),and DP4+probability analysis as well as by comparison of the data with literature reports.All isolated compounds were tested for antibacterial activities.

Synthesis of Bioactive Natural Polymethoxyflavones and Their Vinyl Ether Derivatives

Bioactive natural polymethoxyflavones 1―6 and their vinyl ether derivatives 7―15 were synthesized by bromination,aromatic nucleophilic substitution,methylation,benzyl protection,Friedel-Crafts acetylation,aldol condensation,cyclization,DDQ dehydrogenation,regioselective demethylation,debenzylation and O-prenylation or O-farnesylation with resorcinol and appropriate substituted benzaldehydes as starting materials.Among them,compounds 7―15 are new compounds.Natural products 2―4 were firstly total synthesized.The syntheses of compounds 1,5 and 6 were efficiently improved by the new synthetic routes.The structures of all synthetic compounds were confirmed by NMR,IR spectra and MS.

Cloning and Characterization of Protein Prenyltransferase Alpha Subunit in Rice

Protein prenylation plays a crucial role in plant development and stress response.We report the function of pren yltra nsferase a-sub unit in rice.Protein-protei n in teractions showed that the fam esyl-transferase(OsPFT)/geranylgeranyltransferase-l(OsPGGT l-a)protein interacted together with OsPFT-P and OsPGGT l-p.The a-and p-subunits of OsPFT formed a heterodimer for the transfer of a farnesyl group from famesyl pyrophosphate to the CaaX-box-containing peptide N-dansyl-GCVLS.Furthermore,the tissue expressi on patter ns of the OsPFT and OsPGGT I sub units were similar,and these sub units were localized in the cytoplasm and nucleus.Moreover,OsPFT/OsPGGT/-a-deletion homozygous rice mutants had a lethal phenotype,and the heterozygous mutants exhibited reduced pollen viability.These results indicated that prenylation plays an important role in rice development.

Prenylated flavonoids from Tephrosia apollinea

In continuation of our chemical investigation on some medicinal plants of the genus Tephrosia, re-investigation of the methylenechloride/methanol （1：1） extract of the air-dried aerial part of Tephrosia apollinea afforded a new prenylated flavonoid 1, in addition to an aromatic ester, a sesquiterpene, a lignan and several known prenylated flavonoids. The structures were established by （^1H NMR, ^13C NMR, DEPT, ^1H-^1H COSY, HMQC, HMBC, NOESY and HRMS）. Relative configurations of 9 and 10 were confirmed by X-ray analysis.

ISOLATION, STRUCTURE ELUCIDATION AND SYNTHESIS OF A NEW PRENYLATED FLAVONOL, MAACKIAFLAVONOL, FROM MAACKIA TENUIFOLIA

A new prenylated flavonol, maackiaflavonol, was isolated from the ethanol extract of the roots of Maackia tenuifolia. Its structure was elucidated as 7-hydrox-8-prenylflavonol by means of spectroscopic analysis (UV, IR, MS, NMR and 1H-1H COSY) and confirmed by total synthesis.

Two New Dihydroflavanoids from Patrinia villosa Juss

Two new dihydroflavonoids were obtained from the traditional Chinese medicinal herb Patrinia villosa Juss. Their structures were elucidated as （2S）-5, 7, 2＇, 6＇-tetrahydroxy-6, 8-di （γ, γ-dimethylallyl） flavanone （1） and （2S）-5, 7, 2＇, 6＇-tetrahydroxy-6-1avandulylated flavanone （2） by spectroscopic methods including UV, IR, HR-TOF-MS, 1D NMR and 2D NMR techniques.

Prenylated Coumarins from Heracleum stenopterum,Peucedanum praeruptorum,Clausena lansium,and Murraya paniculata

Four hitherto unknown prenylated coumarins,namely 600-O-b-D-apiofuranosylapterin(1),40-O-isobutyroylpeguangxienin(2),6-(3-methyl-2-oxobutyroyl)-7-methoxycoumarin(3),and 6-hydroxycoumurrayin(4),were isolated from the ethanol extract of Heracleum stenopterum,Peucedanum praeruptorum,Clausena lansium,and Murraya paniculata,respectively.Their chemical structures were established on the basis of extensive spectroscopic analysis.Compound 2 exhibited in vitro cytotoxic activity against five human cancer cell lines(HL-60,A-549,SMMC-7721,MCF-7,and SW-480)with IC50 values ranging from 15.9 to 23.2μM.

Minor Prenylated Flavonoids from the Twigs of Macaranga adenantha and Their Cytotoxic Activity

Three new minor prenylated flavonoids,named macadenanthins A–C(1–3),together with three known ones(4–6),were isolated from the twigs of Macaranga adenantha.Their structures were elucidated on the basis of extensive spectroscopic analysis including NMR,UV and MS.The prenyl moieties in compounds 1–3 were further modified by cyclization and hydroxylation.The new compounds were tested for their cytotoxicity against four cancer cell lines(MCF-7,Hep G2,Hela and P388)and showed IC50 values in the range of 13.76–22.27 lM.

New Prenylated flavonol from Hypericum japonicum

One new prenylated flavonol, 7,8-(2'',2'' -dimethylpyrano)-5,3',4'-trihydroxy-3-methoxyflavone was isolated from Hypericum japonicum. The chemical structure was determined by spectroscopic methods.

A new bioactive prenylated dihydroflavanoid from Dolichos tenuicaulis (Baker) Craib

A new prenylated dihydroflavonoid was obtained from the root of Dolichos tenuicaulis （Baker） Craib. The structure was elucidated as （2S）-5,2＇,6＇-trihydroxy-3＇″, 8-di （γ,γ-dimethyl-allyl）-2＇″, 2＇″-dimethylpyrano-[5＇″,6＇″： 6,7]-2＇″″,4＇″″-cyclohexadiene-1 ＇″″-one-[2＇″″,3＇″″： 3＇,4＇]-flavanone, named dolichnin A, by spectroscopic methods including UV, IR, HR-EI-MS, 1D NMR and 2D NMR techniques, and subsequently, the anticancer activity of this compound to inhibit human cancer cells＇ growth including A549, BEL-7402, Hep-3B, SMMC7721, HT-29, MCF-7, SGC-7902, K562, A498 and PC3 cell lines by MTT method was evaluated in vitro.

Geranylated or prenylated flavonoids from Cajanus volubilis

Five new flavonoid derivatives,cajavolubones A-E(1-5),along with six known analogues(6-11)were isolated from Cajanus volubilis,and their structures were elucidated by spectroscopic analysis and quantum chemical calculations.Cajavolubones A and B(1 and 2)were identified as two geranylated chalcones.Cajavolubone C(3)was a prenylated flavone,while cajavolubones D and E(4 and 5)were two prenylated isoflavanones.Compounds 3,8,9 and 11 displayed cytotoxicity against HCT-116 cancer cell line.

Immunosuppressant mycophenolic acid biosynthesis employs a new globin-like enzyme for prenyl side chain cleavage

Mycophenolic acid(MPA,1)and its derivatives are first-line immunosuppressants used in organ transplantation and for treating autoimmune diseases.Despite chemical synthetic achievements,the biosynthetic formation of a seven-carbon carboxylic acid pharmacophore side chain of 1,especially the processes involving the cleavage of the prenyl side chain between DHMP(4)and DMMPA(5),remains unknown.In this work,we identified a membrane-bound prenyltransferase,PgMpaA,that transfers FPP to 4 to yield FDHMP(6).Compound 6 undergoes the first cleavage step via a new globin-like enzyme PgMpaB to form a cryptic intermediate 12.Heterologous expression of PgMpa genes in Aspergillus nidulans demonstrates that the second cleavage step(from 12 to 5)of 1 is a PgMpa clusterindependent process in vivo.Our results,especially the discovery of the broad tolerance of substrates recognized by PgMpaB,set up a strategy for the formation of"pseudo-isopentenyl"natural products using fungal globin-like enzymes.

Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction

Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality;thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.

Microbial soluble aromatic prenyltransferases for engineered biosynthesis

Prenyltransferase(PTase)enzymes play crucial roles in natural product biosynthesis by transferring isoprene unit(s)to target substrates,thereby generating prenylated compounds.The prenylation step leads to a diverse group of natural products with improved membrane affinity and enhanced bioactivity,as compared to the nonprenylated forms.The last two decades have witnessed increasing studies on the identification,characterization,enzyme engineering,and synthetic biology of microbial PTase family enzymes.We herein summarize several examples of microbial soluble aromatic PTases for chemoenzymatic syntheses of unnatural novel prenylated compounds.

Flavonoids isolated from Sinopodophylli Fructus and their bioactivities against human breast cancer cells

Four prenylated flavonoids compounds 1-4,named sinopodophyllines A-D,and a flavonoid glycoside(compound 13),sinopodophylliside A,together with 19 known compounds(compounds 5-12 and 14-24) were isolated from the fruits of Sinopodophyllum hexandrum.The structures of new compounds were elucidated by extensive spectroscopic analysis,including HRESIMS,1D and 2D NMR.Compounds 1-6,9-11,and 14-17 were tested for their cytotoxicity against human breast-cancer T47 D,MCF-7 and MDA-MB-231 cells in vitro,and compounds 2,5,6,10 and 11 showed significant cytotoxicity(IC50 values < 10 μmol·L^(-1))against T47 D cells.

New prenylated flavonoid glycosides derived from Epimedium wushanense byβ-glucosidase hydrolysis and their testosterone production-promoting effects

Six new prenylated flavonoid glycosides,including four new furan-flavonoid glycosides wushepimedoside A–D(1–4)and two new prenyl flavonoid derivatives wushepimedoside E–F(5–6),and one know analog epimedkoreside B(7)were isolated from biotransformation products of the aerial parts of Epimedium wushanense.Their structures were elucidated according to comprehensive analysis of HR-MS and NMR spectroscopic data,and the absolute configurations were assigned using experimental and calculated electronic circular dichroism(ECD)data.The regulatory activity of compounds 1–7 on the production of testosterone in primary rat Leydig cells were investigated,and 4 and 5 exhibited testosterone production-promoting activities.Molecular docking analysis suggested that bioactive compounds 4 and 5 showed the stable binding with 3β-HSD and 4 also had good affinity with Cyp17A1,which suggested that these compounds may regulate testosterone production through stimulating the expression of the above two key proteins.

Synthesis and pharmacological properties of naturally occurring prenylated and pyranochalcones as potent anti-inflammatory agents

An efficient approach has been developed for the synthesis of naturally occurring prenylated chalcones viz. kanzonol C （1）, stipulin （2）, crotaorixin （3）, medicagenin （4）, licoagrochalcone A （5） and abyssinone D （6） along with the pyranochalcones paratocarpin C （7）, anthyllisone （8） and 3-O-methylabyssinone A （9）. The key step of the synthesis is a Claisen-Schmidt condensation. Subsequently, their anti-inflammatory effects were investigated in lipopolysaccharides （LPSs）-induced RAW-264.7 macrophages. Of the synthesized chalcones, compounds 5 （IC50= 10.41 μmol[L）, 6 （IC50= 9.65 μmol/L） and 8 （IC50= 15.34 μmol/L） show remarkable activity with no cytotoxicity. Compound 9 （IC50 = 4.5 μmol/L） exhibits maximum （83.6%） nitric oxide （NO） inhibition, but shows slight cytotoxicity. The results reveal that the chalcones bearing the prenyl group at 3- and/or 5-position on ring A （acetophenone moiety）, i.e., 1-4 and 7 show weak, or no inhibition activity, whereas chalcones having the prenyl group only on ring B （aldehyde part）, i.e., 5, 6 and 8 show significant activity on the production of inflammatory mediated NO with no cytotoxicity.