Steroids, Tri- and Meroterpenoids with a Quinone Structure—A Review

Terpenoids with quinoid structures are found as natural products. This includes steroidal quinones, quinones with a secosteroid structure and meroterpenoid quinones. Importantly, catechol estrogens as endogenous metabolites of estradiol and estrone are precursors of reactive quinones and semiquinones, which are thought to contribute to estrogen-induced carcinogenesis. On the other hand, a number of quinones that include substituted naphthoquinones and anthraquinones are highly cytotoxic and have been used in cancer treatment. This makes the structures interesting synthetic targets. The following is a review of important natural and synthetic terpenoid and steroid quinone hybrids.

Meroterpenoids from Ganoderma Species:A Review of Last Five Years

Meroterpenoids are hybrid natural products that partially originate from the terpenoid pathway.Ganoderma meroterpenoids(GMs)are a type of meroterpenoids containing a 1,2,4-trisubstituted phenyl and a polyunsaturated terpenoid part.Over last 5 years,great efforts have been made to conduct phytochemistry research on the genus Ganoderma,which have led to the isolation and identification of a number of GMs.These newly reported GMs showed diverse structures and a wide range of biological activities.This review gives an overview of new GMs from genus Ganoderma and their biological activities and biosynthetic pathway,focusing on the period from 2013 until 2018.

Structurally Diverse Polymethylated Phloroglucinol Meroterpenoids from Baeckea frutescens

Phytochemical investigation of the MeOH extract of twigs and leaves of Baeckea frutescens led to the isolation of seven new polymethylated phloroglucinol meroterpenoids(PPMs),named baeckfrutones M-S(1-7).Their structures and absolute configurations were determined by spectroscopic analyses,chiral-phase HPLC analysis,and electronic circular dichroism(ECD)calculations.PPM 1 is a novel meroterpenoid possessing a 6/6/5/3 tetracyclic skeleton in PPMs,whereas 3 and 4 are the first hydroxytasmanone type phloroglucinol-monoterpene hybrids.(+)-2 and 7 displayed potent antiinflammatory activity with IC50 values of 20.86±0.60 and 36.21±1.18 lL,respectively.

Guajadials C-F, four unusual meroterpenoids from Psidium guajava

Guajadials C-F(1-4),four sesquiterpenoid-based meroterpenoids with unprecedented skeletons were isolated from the leaves of Psidium guajava.Their structures and relative configurations were established by extensive spectroscopic analysis.A possible biosynthetic pathway for 1-4 was also proposed.

Hyperlanins A and B, Two Highly Rearranged Meroterpenoids from Hypericum lancasteri

Hyperlanins A(1)and B(2),two highly rearranged polycyclic polyprenylated acylphloroglucinol(PPAP)-related meroterpenoids based on different new carbon skeletons,were isolated from Hypericum lancasteri.Compound 1 incorporates an unprecedented 5/6/7/5 ring system featuring a 3,13-dioxatetracyclo[9.2.1.12.5.01.8]pentadecane core.Compound 2 possesses a unique compact 6/6/5/6/6/5/6 ring system with a caged tetracyclo[6.2.1.13.8.05,11]dodecane motif.Their structures were established by spectroscopic data,X-ray diffraction,and computational approaches.Both compounds showed anti-inflammatory activity in vitro.Compounds 1 and 2 could decrease the lipopolysaccharide(LPS)-/nigericin-induced IL-1βrelease in THP-1 cells.Both compounds also showed inhibition in hypoxia-inducible factor-1α(HIF-1αa)pathway luciferase reporter assay.

Rapid discovery of two unprecedented meroterpenoids from Daphne altaica Pall.using molecular networking integrated with MolNetEnhancer and Network Annotation Propagation

Under the guidance of the approach which integrates molecular networking,MolNetEnhancer and Net-work Annotation Propagation(NAP),daphnaltaicanoids A and B(1 and 2)with unprecedented 9-oxa-tetracyclo[6.6.1.0^(2,6).0^(8,13)]pentadecane and tetracyclo[5.3.0.1^(2,5).2^(4,11)]tridecane central frameworks were iso-lated from Daphne altaica Pall.,representing two types of unparalleled meroterpenoid cores.Their struc-tures were elucidated by extensive spectroscopic analysis,nuclear magnetic resonance(NMR)calcula-tions,DP4+analysis and electronic circular dichroism(ECD)calculations.The plausible biosynthetic path-ways for 1 and 2 were postulated.Biologically,2 exerted potent neuroprotective activities which were su-perior to trolox at 12.5 and 25μmol/L.Moreover,1 and 2 exhibited more noticeable acetylcholinesterase inhibitory activities than donepezil.Molecular docking simulations were performed to explore the inter-molecular interaction of compounds 1 and 2 with acetylcholinesterase.The bioactivity evaluation results highlight the prospects of 1 and 2 as a novel category of neurological agents.

Divergent total synthesis of marine meroterpenoids(+)-dysidavarones A–C

Here,we report a concise and divergent enantioselective total synthesis of marine sesquiterpene quinone meroterpenoids(+)-dysidavarones A–C(1–3)using predysidavarone 6 as a key common intermediate.The highly strained and bridged eight-membered carbocycle of predysidavarone 6 was constructed by a one-pot intermolecular alkylation and intramolecular arylation of Wieland–Miescher ketone derivative 11 and benzyl bromide 12.The total synthesis of(+)-dysidavarones A–C(1–3)was achieved from predysidavarone 6 in a divergent manner by a late-stage introduction of the ethoxy group,which reveals the possible source of the ethoxy group within(+)-dysidavarones A–C(1–3)and provides a late-stage modifiable route for the synthesis of dysidavarone analogs for further anti-cancer activity evaluation.

A review of meroterpenoids and of their bioactivity from guava(Psidium guajava L.)

Psidium guajava Linn.(family Myrtaceae),is commonly known as guava.Guava is consumed in large quantities throughout the world due to its ease of cultivation and high nutritional value.As an important perennial fruit tree distributed around the world,guava has been widely used to manage various diseases in traditional medicine.Guava has been shown significant bioactivity such as antioxidant,anti-inflammatory,immunomodulatory,antimicrobial,antidiabetic,and anticancer properties.A large number of studies indicated that guava contains various type of phytochemicals including monoterpenes,sesquiterpenes,triterpenes,phenolics,and meroterpenoids.Among them,meroterpenoids are characteristic components of guava,which are hybrid of acylphloroglucinol with terpenoids(monoterpenes,sesquiterpenes).Modern pharmacological investigations showed intricate Psidium meroterpenoids possess a wide range of bioactivities.Although a large and growing body of literatures have investigated the Psidium meroterpenoids isolated from guava,a comprehensive review of Psidium meroterpenoids and their bioactivities has not been conducted.Therefore,this review provides a comprehensive compile of 75 meroterpenoids isolated from guava and their bioactivities between 2007 and May 2022.Furthermore,the possible biosynthesis way and future directions of Psidium meroterpenoids have also been discussed.

Guajamers A-I, Rearranged Polycyclic Phloroglucinol Meroterpenoids from Psidium guajava Leaves and Their Antibacterial Activity

Eight new polycyclic phloroglucinol meroterpenoids guajamers A-H(1-8),a methylated benzoylphloroglucinol meroterpenoid guajamer I(9)representing a new skeleton,and two known analogues(10 and 11)were isolated from the leaves of Psidium guajava.The structures of new molecules were elucidated by detailed analysis of spectroscopic data,and those of 1,2,8,and 9 were unambiguously confirmed by single-crystal X-ray diffraction study.Structurally,compounds 1-8 were sesquiterpene and monoterpene-based meroterpenoids with rearranged skeletons,while compound 9 was the first case of 3-alkyl-5-formyl-benzoylphloroglucinol-coupled sesquiterpene containing an unusual C-l-spiro-fused 6/6/9/4 polycyclic skeleton.In addition,all the isolated compounds were evaluated for their antibacterial activity against three bacterial strains,and most of them(compounds 2-7,10,and 11)showed antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis with MIC values of 8-32 μmol/L.These findings suggested that meroterpenoids isolated from Psidium guajava can be considered as potential antibacterial leading compounds for pharmaceutical industry.

Hyperterpenoids A and B:Two pairs of unprecedented 6/6/4/6/6 polycyclic cyclobutane meroterpenoids with potent neuroprotective and anti-inflammatory activities from Hypericum beanii

Hyperterpenoid A(1)and B(2),two pairs of enantiomers,with an unprecedented 6/6/4/6/6 polycyclic skeleton,along with one known compoud hypermonone A(3)were isolated from Hypericum beanii.The racemate(±)-1 and(±)-2 were successfully separated into the two optically pure enantiomers(ee>99%)using a preparative HPLC system.Their absolute configurations were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction method.The related plausible biogenetic pathways were pre sented.Compound 1-3 showed significant neuroprotective activity and potential antiinflammatory activity.The result that(+)-2 and(-)-2 presented different anti-inflammatory properties,may lead us to new discovery of structure activity relationship between racemates,enantiomers,and diastereomers,as well as further research regarding the binding of drugs to target proteins.

Hyperinoids A and B,two polycyclic meroterpenoids from Hypericum patulum

Hyperinoids A(1)and B(2),two prenylated acylphloroglucinol related meroterpenoids,were isolated from Hypericum patulum.Compound 1 incorporates an unprecedented 11,12-dioxatetracyclo[5.4.3.01,7.04,14]tetradecane system,while 2 possesses a unique 10,11-dioxatetracyclo[5.3.3.01,7.04,13]tridecane syste m.Their structures were established by spectro scopic analysis and X-ray crystallographic data.Compounds 1 and 2 were identified as potent NF-κB inhibitors and suppressed the LPS-induced inflammatory responses in RAW 246.7 macrophages and primary mouse BMDM cells.

Psiguamers A-C, three cytotoxic meroterpenoids bearing a methylated benzoylphloroglucinol framework from Psidium guajava and total synthesis of 1 and 2

Three sesquiterpene-based meroterpenoids psiguamers A-C(1-3)with new skeletons were isolated from Psidium guajava leaves.Compounds(±)-1 and(±)-2 were two pairs of humulene-de「ived meroterpenoids bearing a rare methylated benzoylphloroglucinol unit,while 3 was an unprecedented adduct of bicyclogermacrene and methylated benzoylphloroglucinol.Their structures were determined based on comprehensive analyses of spectroscopic data,calculated electronic circular dichroism(ECD)spectra,total synthesis,and X-ray crystallographic data.The biomimetic synthesis of(±)-1 and(±)-2 was achieved.Compound(+)-1 exhibited cytotoxic activities against five human tumor cell lines(HCT-116,HepG2,BGC-823,A549,and U251),with IC_(50) values of 2.94,9.01,6.45,5.42,and 5.33 μmol/L,respectively.

Arnequinol A and arnequinone A, two unique meroterpenoids from Arnebia euchroma

Arnequinol A(1),featuring an unprecedented 6/6/3 tricyclic carbon skeleton fused with a heptatomic oxo-bridge,together with arnequinone A(2)bearing a highly conjugated methyl-shifting benzogeijerene skeleton,were isolated from Arnebia euchroma.Their structures were elucidated by extensive spectro-scopic methods and quantum chemical calculations of the 13 C nuclear magnetic resonance(NMR)data and electronic circular dichroism(ECD)spectra.The plausible biosynthetic pathways for 1 and 2 were presented.In in vitro test,compound 2 showed potent neuroprotective activity against serum-deprivation induced PC12 cell damage at a concentration of 10μmol/L.

Periconones B-E,new meroterpenoids from endophytic fungus Periconia sp.

Periconones B-E（1-4）,four new polyketide-terpenoid hybrid molecules were isolated from the endophytic fungus Periconia sp.F-31.Their structures and absolute configurations were established by extensive spectroscopic data analysis and electronic circular dichroism（ECD）.Compound 4 exhibited in vitro cytotoxic activity against the human MCF-7 tumor cell line with an IC_（50） value of 4.2 μmol/L,and compound 1 displayed anti-HIV activity with an IC_（50） value of 18.0 μmol/L.

Amphichoterpenoids A-C,unprecedented picoline-derived meroterpenoids from the ascidian-derived fungus Amphichorda felina SYSU-MS7908

Amphichoterpenoids A-C(1-3),unprecedented picoline-derived meroterpenoids possessing a pyrano[3,2-c]pyridinyl-g-pyranone scaffold,were characterized from the ascidian-derived fungus Amphichorda felina SYSU-MS7908.Their structures were elucidated by spectroscopic methods,X-ray diffraction and electronic circular dichroism(ECD)calculations.A plausible biosynthetic pathway was proposed.The isolated compounds displayed moderate inhibitory activity against acetylcholinesterase with 50%inhibiting concentration(IC_(50))values of 18.8-53.2 mmol/L.

New meroterpenoids and C-methylated flavonoid isolated from Baeckea frutescens

Phytochemical investigation of the aerial parts of Baeckea frutescens resulted in the isolation of three new mono-or sesquiterpene-based meroterpenoids, frutescones S-U(1-3), and one pair of new(±)-5,7-dihydroxy-8-isobutyryl-6-methyldihydroflavonol(4). Their structures and absolute configurations were established by HR-ESI-MS, 1D and 2D NMR, and quantum chemical ECD calculation. Compound 1 exhibited inhibitory effect on NO production in LPS-activated RAW 264.7 macrophages with an IC50 value being 0.81 μmol·L–1.

Enantiomeric pairs of meroterpenoids from Rhododendron fastigiatum

Five pairs of optically pure meroterpenoid enantiomers(1 a/1 b-5 a/5 b)and two known compounds(6 and 7)were isolated from Rhododendron fastigiatum.Compounds 1 a/1 b-5 a/5 b were resolved from naturally scalemic mixtures by chiral HPLC.Their structures were elucidated by spectroscopic methods,X-ray crystallographic experiments,and ECD analyses.Compounds 1 a/1 b,2 a/2 b,3 b,4 a/4 b,and 5 a/5 b were new meroterpenoids with different polycyclic systems.Two enantiomeric pairs(2 a/2 b and 3 a/3 b),6,and 7 exhibited inhibitory effects on protein tyrosine phosphatase 1 B(PTP1 B)in vitro.

Quinones from Cordia species from 1972 to 2023:isolation,structural diversity and pharmacological activities

Plants of the genus Cordia(Boraginaceae family)are widely distributed in the tropical regions of America,Africa,and Asia.They are extensively used in folk medicine due to their rich medicinal properties.This review presents a comprehensive analysis of the isolation,structure,biogenesis,and biological properties of quinones from Cordia species reported from 1972 to 2023.Meroterpenoids were identified as the major quinones in most Cordia species and are reported as a chemotaxonomic markers of the Cordia.In addition to this property,quinones are reported to display a wider and broader spectrum of activities,are efficient scaffold in biological activity,compared to other classes of compounds reported in Cordia,hence our focus on the study of quinones reported from Cordia species.About 70 types of quinones have been isolated,while others have been identified by phytochemical screening or gas chromatography.Although the biosynthesis of quinones from Cordia species is not yet fully understood,previous reports suggest that they may be derived from geranyl pyrophosphate and an aromatic precursor unit,followed by oxidative cyclization of the allylic methyl group.Studies have demonstrated that quinones from this genus exhibit antifungal,larvicidal,antileishmanial,anti-inflammatory,antibiofilm,antimycobacterial,antioxidant,antimalarial,neuroinhibitory,and hemolytic activities.In addition,they have been shown to exhibit remarkable cytotoxic effects against several cancer cell lines which is likely related to their ability to inhibit electron transport as well as oxidative phosphorylation,and generate reactive oxygen species(ROS).Their biological activities indicate potential utility in the development of new drugs,especially as active components in drug-carrier systems,against a broad spectrum of pathogens and ailments.

Cytotoxic Acylphloroglucinol Derivatives from Callistemon salignus

Callisalignenes G–I(1–3),three new meroterpenoids of b-triketone and monoterpene,along with two known analogues(4 and 5),were isolated from Callistemon salignus.Their structures and absolute configurations were unambiguously established by a combination of NMR and MS analysis and electronic circular dichroism(ECD)evidence.Callisalignenes H(2)and I(3)have a rare sec-butyl moiety at C-7.Meroterpenoids 1–3 exhibited cytotoxicity against HCT116 cells with IC50 values of 8.51±1.8,9.12±0.3,and 16.33±3.3 lM,respectively.

Single-cell RNA sequencing facilitates the elucidation of the complete biosynthesis of the antidepressant hyperforin in St. John's wort

Hyperforin is the compound responsible for the effectiveness of St.John's wort(Hypericum perforatum)as an antidepressant,but its complete biosynthetic pathway remains unknown.Gene discovery based on co-expression analysis of bulk RNA-sequencing data or genome mining failed to discover the missing steps in hyperforin biosynthesis.In this study,we sequenced the 1.54-Gb tetraploid H.perforatum genome assem-bled into 32 chromosomes with the scaffold N50 value of 42.44 Mb.By single-cell RNA sequencing,we iden-tified a type of cell,“Hyper cells”,wherein hyperforin biosynthesis de novo takes place in both the leaves and flowers.Through pathway reconstitution in yeast and tobacco,we identified and characterized four transmembrane prenyltransferases(HpPT1-4)that are localized at the plastid envelope and complete the hyperforin biosynthetic pathway.The hyperforin polycyclic scaffold is created by a reaction cascade involving an irregular isoprenoid coupling and a tandem cyclization.Our findings reveal how and where hy-perforin is biosynthesized,enabling synthetic-biology reconstitution of the complete pathway.Thus,this study not only deepens our comprehension of specialized metabolism at the cellularlevel but also provides strategic guidance for elucidation of the biosynthetic pathways of other specializied metabolites in plants.