New ent-kaurane diterpenoid dimer from Pulicaria inuloides

A new naturally occurring ent-kaurane diterpenoid dimer, 15β, 15′β-oxybis (ent-kaur-16-en-19-oic acid) (1) along with six known compounds, 15β-hydroxy-ent-kaur-16-en-19-oic acid (2), 15β-hydroxy-ent-kaur-16-en-19-oate-β-d-glucopyranoside (3), 6-hydroxykaempferol-3, 7-dimethyl ether (4), quercetagetin 3, 7, 3′-trimethyl ether (5), β-sitosterol (6) and β-sitosterol glucoside (daucosterol) (7) were isolated from the aerial parts of Pulicaria inuloides DC. Compounds 2–5 were isolated for the first time from genus Pulicaria. The structures of compounds 1–7 were established on the basis of extensive 1D and 2D NMR spectroscopic techniques in combination with ESI-MS. The antimicrobial activity of the isolated compounds was evaluated against Staphylococcus aureus, Escherichia coli and Candida albicans. Sulphorhodamine B cytotoxic assay against HepG2 (liver cancer) cell line and ABTS antioxidant assay were carried out.     

Microbial transformation of two 15α-hydroxy-ent-kaur-16-ene diterpenes by Mucor plumbeus

The microbiological transformation of candidiol (15α,18-dihydroxy-ent-kaur-16-ene) by Mucor plumbeus led to 3β,15α,18-trihydroxy-ent-kaur-16-ene, 6α,15α,18-trihydroxy-ent-kaur-16-ene, 3α,15α,18-trihydroxy-ent-kaur-16-ene, 11β,15α,18-trihydroxy-ent-kaur-16-ene and 15α,17,18-trihydroxy-11β,16β-epoxy-ent-kaurane, whilst the incubation of 15α,19-dihydroxy-ent-kaur-16-ene gave 9β,15α,19-trihydroxy-ent-kaur-16-ene, 3α,15α,19-trihydroxy-ent-kaur-16-ene, 11β,15α,19-trihydroxy-ent-kaur-16-ene, 6α,15α,19-trihydroxy-ent-kaur-16-ene, 15α,17,19-trihydroxy-11β,16β-epoxy-ent-kaurane, 19-(β-d-glucopyranosyl)-15α-hydroxy-ent-kaur-16-ene and 19-(β-d-glucopyranosyl)-15-oxo-ent-kaur-16-ene. An interesting rearrangement in dilute acid medium of 9β,15α,19-trihydroxy-ent-kaur-16-ene into 16-oxo-19-hydroxy-ent-abiet-8(9),15-diene, is also described in this work.     

A silica gel orthogonal high-performance liquid chromatography method for the analyses of steviol glycosides: novel tetra-glucopyranosyl steviol

A silica gel orthogonal method using acetonitrile: water was developed for the analyses of fractions rich in very polar steviol glycosides and resolve regions of co-elution of these compounds in reversed-phase. Additionally, we also used this normal phase analytical method to scale up the purification process of steviol glycosides. Using these approaches, one novel minor tetra-glucopyranosyl diterpene glycosides together with three known compounds were purified from a commercial Stevia rebaudiana leaf extract. Compound 1 was unambiguously elucidated as 13-[(2-O-β-D-glucopyranosyl-β-D-glucopyranosyl)oxy]ent-kaur-16-en-19-oic acid-(6-O-β-D-glucopyranosyl-β-D-glucopyranosyl) ester (rebaudioside Y) based on high-performance liquid chromatography retention times, tandem mass spectrometry dissociation pattern and 1D and 2D NMR experiments. Known compounds were isolated in gram quantities and identified as rebaudioside D, E and M.     

A Chemical Study of Burley Tobacco Flavour (Nicotiana tabacum L.) VII. Identification and synthesis of twelve irregular terpenoids,related to solanone,including 7,8-dioxabicyclo[3.2.1]octane and 4,9-dioxabicyclo[3.3.1]nonane derivatives

Twelve novel constituents isolated from Burley tobacco condensate by semi-preparative GLC. have been identified as (E)-3,4-epoxy-5-isopropyl-nonane-2,8-dione ( A ), exo-(1-methyl-4-isopropyl-7,8-dioxabicyclo[3.2.1]oct-6-yl)methyl ketone ( B ), exo-1-(1-methyl-4-isopropyl-7,8-dioxabicyclo[3.2.1]oct-6-yl)-ethanol ( C ), (E)-5-isopropyl-8-hydroxy-8-methyl-non-6-en-2-one ( D ), (E)-5-isopropyl-6,7-epoxy-8-hydroxy-8-methyl-nonan-2-one ( E ), endo-2-(1-methyl-4-isopropyl-7,8-dioxabicyclo[3.2.1]oct-6-yl)-propan-2-ol ( F ), 3,3,5-trimethyl-8-isopropyl-4,9-dioxabicyclo[3.3.1]nonan-2-ol ( G ), (E)-5-isopropyl-non-3-ene-2,8-diol ( H ), 5-isopropyl-nonane-2,8-diol ( I ), (E)-5-isopropyl-8-hydroxy-non-6-en-2-one ( J ), 5-isopropyl-8-hydroxy-nonan-2-one ( K ), and (E)-3-isopropyl-6-methyl-hepta-4,6-dien-1-ol ( L ). Compounds A–K were synthesized from norsolanadione ( 2 ), and compound L from 2-isopropyl-5-oxo-hexanal ( 15 ). The relative configuration of the bicyclic internal acetals B, C, F, G and their δ-keto-epoxide precursors A and E is discussed. All these Burley tobacco flavour components belong to a growing family of metabolites structurally related to solanone ( 1 ). They are believed to arise from the breakdown of cembrene-type precursors.     

New synthesis of diterpenoid (16<Emphasis Type="Italic">S</Emphasis>)-dihydrosteviol

A new procedure has been developed for the synthesis of diterpenoid (16S)-dihydrosteviol [(16S)-13-hydroxy-ent-kauran-19-oic acid] by acid hydrolysis (0.7% hydrochloric acid) of SWETA food sweetener and subsequent reduction of the resulting mixture of caurenoids with hydrazine hydrate over Raney nickel. The molecular geometry of (16S)-dihydrosteviol, as well as of Δ¹⁵-steviol (13-hydroxy-ent-kaur-15-en-19-oic acid), was determined for the first time by X-ray analysis.     

Microbiological transformations of 19-oxygenated ent-kauranes

The microbiological transformations of three 19-oxygenated ent-kauranes with Rhizopus nigricans, Aspergillus ochraceous and Calonectria decora have been investigated. The most common transformation observed is hydroxylation at the C-1 and C-7 positions. For ent-kaur-16-en-19-oic acid allylic hydroxylation and hydration of the double bond also occur.     

Neighbouring group participation in the reaction of 7-oxo-ent-kaur-16-ene derivatives with diacetoxyiodobenzene. Synthesis of gibberellin analogues

The reaction of different 7-oxo-ent-kaur-16-ene derivatives with diacetoxyiodobenzene has been evaluated for the preparation of gibberellin analogues. Thus, the reaction of 7-oxo-ent-kaur-16-en-18-oic acid methyl ester (3) with this reagent afforded 4-epi-GA₁₂ dimethyl ester (6). This reaction constitutes a good procedure for the preparation of this type of compounds. In some cases, alternative reactions that led to the introduction in the substrate of a conjugated 5,6-double bond or to the formation of a ketal at the 6-position were also produced. The formation of these compounds, or of gibberellin analogues, depends on the neighbouring group participation of the different C-18 and C-19 substituents at C-4.     

The Constituents from the Stems of Annona cherimola

Thirty-five compounds including twenty-one alkaloids, lysicamine ( 1 ), liriodenine ( 2 ), atherospermidine ( 3 ), oxoxylopine ( 4 ), oxoanolobine ( 5 ), oxoglaucine ( 6 ), (-)-anonaine ( 7 ), (-)-asimilobine ( 8 ), (-)-xylopine ( 9 ), (-)-anolobine ( 10 ), (-)-norisocorydine ( 11 ), (+)-laurotetanine ( 12 ), (+)-isocorydine ( 13 ), (-)-N-methylasimilobine ( 14 ), (+)-N-methyllaurotetanine ( 15 ), (-)-norushinsunine ( 16 ), (-)-ushinsunine ( 17 ), (-)-N-formylanonaine ( 18 ), (+)-stepharine ( 19 ), (+)-orentaline ( 20 ), and (-)-kikemanine ( 21 ); four kauranes, ent-kaur-16-en-19-oic acid ( 22 ), 16β-hydroxy-17-acetoxy-ent-kauran-19-al ( 23 ), 17-acetoxy-16β-ent-kauran-19-oic acid ( 24 ), and 16β-hydroxy-17-acetoxy-ent-kauran-19-oic acid ( 25 ); two amides, N-trans-femloyltyramine ( 26 ), and N-trans-caffeoyltyramine ( 27 ); one purine, adenosine ( 28 ); one lactam amide, squamolone ( 29 ); and six steroids, β-sitosterol ( 30 ), stigmasterol ( 31 ), β-sitostenone ( 32 ), stigmasta-4,22-dien-3-one ( 33 ), 6β-hydroxy-β-sitosterone ( 34 ), and 6β-hydroxystigmasterone ( 35 ) are isolated from the stems of Annona cherimola. These compounds were characterized and identified by physical and spectral evidence. Among them, (-)-norisocorydine (11) was elucidated as a new enantiomer with a levorotary configuration, which is isolated for the first time.     

Kaurane-Type Diterpenoids from Liverworts

Seven kaurane-type diterpenoids were isolated from the Taiwanese liverworts Jungermannia truncata. Among them, three are new structures. They are: ent-16-kauren-3, 15-dione (6), ent-16(S)-kauran-3,15-dione (7), and ent-14α-hydroxy-16-kauren-15-one (11). From Plagiochila pulcherrima, three known kaurane alcohols were also isolated along with sesquiterpenoids plagiochilines A, B, C and ent-4β, 10α-dihydroxyaromadendrane.     

Two New C(20)‐Oxygenated ent‐Kaurene Diterpenoids from Isodon henryi

Two new C(20)‐oxygenated ent‐kaurene diterpenoids, taibaihenryiins A ( 1 ) and B ( 2 ), along with five known compounds, shikokianin ( 3 ), longikaurin D, 2α‐hydroxyursolic acid, longikaurin F, and lasiodin, were isolated from the EtOH extract of the leaves and tender branches of Isodon henryi (Hemsl .) Kudo . The structures of the new compounds were determined as 11α‐acetoxy‐7,20‐epoxy‐1α,6β,7β‐trihydroxy‐ent‐kaur‐16‐en‐15‐one ( 1 ) and 7,20‐epoxy‐3β,6β,7β,11α‐tetrahydroxy‐ent‐kaur‐16‐en‐15‐one ( 2 ) on the basis of detailed spectroscopic analyses.     

Two New, 1‐Oxygenated ent‐Kaurane‐Type Diterpenes from Croton kongensis

One new ent‐8,9‐secokaurane diterpene, kongensin D ( 1 ), and one new ent‐kaurane diterpene, kongensin E ( 2 ), along with one known compound, (7α)‐7,18‐dihydroxy‐ent‐kaur‐16‐en‐15‐one 18‐acetate ( 3 ), were isolated from the aerial parts of Croton kongensis. The structures of the new compounds were elucidated by means of HR‐MS and in‐depth NMR experiments, and by comparison with literature data. Compounds 1 and 2 showed an unusual oxygenation pattern with an OH or AcO group at C(1).     

Biotransformation of 7-oxo-ent-kaur-16-ene derivatives by Gibberella fujikuroi

The microbiological transformation of 7-oxo-ent-kaur-16-ene by the fungus Gibberella fujikuroi gave fujenoic acid as the main compound, whilst the incubation of 18-hydroxy-7-oxo-ent-kaur-16-ene and 3α,18-dihydroxy-7-oxo-ent-kaur-16-ene afforded the corresponding 6β-hydroxy-derivatives. These facts indicate that the formation of fujenoic acid in this biotransformation should occur via a 7-oxo-6β-hydroxy derivative. In the three biotransformations, an 11β-hydroxylation was also produced, in low yield, indicating that a 7-oxo-group also directs hydroxylation at C-11.     

ent‐Kaurane Diterpenoids from Isodon phyllostachys

Phytochemical investigation of the medicinal plant Isodon phyllostachys led to the isolation of four new ent‐kaurane diterpenoids, phyllostacins F–I ( 1 – 4 , resp.), together with 11 known compounds, rosthorin A ( 5 ), rabdoternin C ( 6 ), enmenol ( 7 ), oridonin ( 8 ), lasiocarpanin ( 9 ), xerophilusin B ( 10 ), ponicidin ( 11 ), macrocalin B ( 12 ), phyllostachysin A ( 13 ), sculponeatin C ( 14 ), and macrocalyxoformin E ( 15 ). The structures of the new compounds were established by spectroscopic methods, including extensive 1D‐ and 2D‐NMR analyses. Compounds 1, 2, 7, 10 , and 13 were evaluated for their inhibitory activity against K562 and HepG2 cell lines.     

Chemical Constituents from Annona Glabra

A new kaurane diterpenoid, annoglabasin G (16α‐hydro‐19‐acetoxy‐ent‐kauran‐17‐al) ( 1 ), along with 27 compounds including 18 kaurane diterpenoids, 16β‐hydro‐ent‐kauran‐17‐oic acid ( 2 ), 16α‐hydro‐ent‐kauran‐17‐oic acid ( 3 ), 19‐nor‐ent‐kauran‐4α‐ol‐17‐oic acid ( 4 ), 16α‐hydro‐19‐ol‐ent‐kauran‐17‐oic acid ( 5 ), ent‐kaur‐16‐en‐19‐oic acid ( 6 ), 16α‐hydroxy‐ent‐kauran‐19‐oic acid ( 7 ), 16α,17‐dihydroxy‐ent‐kauran‐19‐oic acid ( 8 ), 16β,17‐dihydroxy‐ent‐kauran‐19‐oic acid ( 9 ), 16α‐hydro‐ent‐kauran‐17,19‐dioic acid ( 10 ), 16β‐hydroxy‐17‐acetoxy‐ent‐kauran‐19‐oic acid ( 11 ), 16β‐hydro‐17‐hydroxy‐ent‐kauran‐19‐al ( 12 ), 16α‐hydro‐17‐hydroxy‐ent‐kauran‐19‐al ( 13 ), 16β,17‐dihydroxy‐ent‐kauran‐19‐al ( 14 ), 16α‐hydro‐19‐al‐ent‐kauran‐17‐oic acid ( 15 ), 16α‐hydro‐17‐acetoxy‐ent‐kauran‐19‐al ( 16 ), 16α‐hydro‐19‐acetoxy‐ent‐kauran‐17‐oic acid ( 17 ), ent‐kaur‐15‐en‐19‐oic acid ( 18 ) and ent‐kaur‐15‐en‐17‐ol‐19‐oic acid ( 19 ); four acetogenins, annomontacin ( 20 ), annonacin ( 21 ), isoannonacinone ( 22 ) and squamocin ( 23 ); four steroids, β‐sitosterol ( 24 ), stigmasterol ( 25 ), β‐sitosteryl‐D‐glucoside ( 26 ) and stigmasteryl‐D‐glucoside ( 27 ) and one oxoaporphine, liriodenine ( 28 ), were isolated from the fresh fruits of Annona glabra. These compounds were characterized and identified by physical and spectral evidence.     

Identification of Kaurane-Type Diterpenes as Inhibitors of Leishmania Pteridine Reductase I

The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, an in-house database of 360 kauranes (tetracyclic diterpenes) was generated, and a combined ligand- and structure-based virtual screening (VS) approach was performed to select potential inhibitors of Leishmania major (Lm) pteridine reductase I (PTR1). The best-ranked kauranes were employed to verify the validity of the VS approach through LmPTR1 enzyme inhibition assay. The half-maximal inhibitory concentration (IC₅₀) values of selected bioactive compounds were examined using the random forest (RF) model (i.e., 2β-hydroxy-menth-6-en-5β-yl ent-kaurenoate (135) and 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid (302)) were below 10 μM. A compound similar to 302, 3α-p-coumaroyloxy-ent-kaur-16-en-19-oic acid (302a), was also synthesized and showed the highest activity against LmPTR1. Finally, molecular docking calculations and molecular dynamics simulations were performed for the VS-selected, most-active kauranes within the active sites of PTR1 hybrid models, generated from three Leishmania species that are known to cause cutaneous leishmaniasis in the new world (i.e., L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes to other species-dependent variants of this enzyme.     

Two New Diterpenoids and other Constituents from Isodon Nervosus

Two new ent‐kaurane diterpenoids, 15β‐hydroxy‐6,7‐seco‐6,11β:6,20‐diepoxy‐1α,7‐olide‐ent‐kaur‐16‐ene ( 1 ), 11α,15α‐dihydroxy‐6β‐methoxy‐6,7‐seco‐6,20‐epoxy‐1α,7‐olide‐ent‐kaur‐16‐ene ( 2 ), together with four known diterpenoids, nodosin ( 3 ), isodocarpin ( 4 ), odonicin ( 5 ) and maoyecrystal F ( 6 ) were isolated from the aerial parts of Isodon nervosus. The structures of the new compounds were elucidated on the basis of their spectral evidence, especially on 2D NMR.     

Three New, 1‐Oxygenated ent‐8,9‐Secokaurane Diterpenes from Croton kongensis

Three new ent‐8,9‐secokaurane diterpenes, kongensins A–C ( 1 – 3 ), were isolated from the aerial parts of Croton kongensis, together with two known compounds, rabdoumbrosanin ( 4 ) and (7α,14β)‐7,14‐dihydroxy‐ent‐kaur‐16‐en‐15‐one ( 5 ). The structures of the new compounds were elucidated by HR‐MS as well as in‐depth 1D‐ and 2D‐NMR analyses. Compounds 1 – 3 showed an unusual oxygenation pattern, with an AcO or OH group at C(1), in combination with a Δ⁸⁽¹⁴⁾ unsaturation ( 1 ) or an 8,14‐epoxide function ( 2, 3 ).     

<em>An ent</em>-Kaurane-Type Diterpene in <em>Croton antisyphiliticus</em> Mart

Croton antisyphiliticus is a medicinal plant widely used in the treatment of microbial infections, especially those affecting the genital tract. Crude extract, fractions and pure compound isolated from roots of this species were investigated to validate their antimicrobial activity against Escherichia coli and Staphylococcus aureus. The compound ent-kaur-16-en-18-oic acid was isolated as a major component (0.7% of crude extract), and its MIC value determined against S. aureus (ATCC 6538) was 250 μg/mL. This is the first phytochemical work on the species monitored with antimicrobial assay.     

New bromotyrosine alkaloids from the marine sponge Psammaplysilla purpurea

Seven new bromotyrosine alkaloids Purpurealidin A, B, C, D, F, G, H and the known compounds Purealidin Q, Purpurealidin E, 16-Debromoaplysamine-4 and Purpuramine I have been isolated from the marine sponge Psammaplysilla purpurea. Their structure was elucidated on the basis of detailed 1D, 2D NMR and MS spectroscopic data. Purpurealidin B, 16-Debromoaplysamine-4 and Purpuramine I exhibited in vitro antimicrobial activities against E. coli, S. aureus, and V. cholerae. In addition, Purpurealidin B and 16-Debromoaplysamine-4 were also active against Shigella flexineri and Salmonella typhi while Purealidin Q was bactericidal only against Salmonella typhi.