Polyoxygenated Cyclohexenes Research Articles

Antimalarial polyoxygenated cyclohexene derivatives from the roots of Uvaria cherrevensis

Three new polyoxygenated cyclohexene derivatives named cherrevenisyls A and B (1 and 2), and ellipeiopsol E (3), along with fifteen known compounds, were isolated from the roots of Uvaria cherrevensis. Their structures were determined by spectroscopic methods including 2D NMR techniques and mass spectrometry. The absolute configurations of 1 and 2 were assigned. Compounds 1, 2 and 5 showed antimalarial activity against Plasmodium falciparum with IC50 ranging from 3.34–7.34μg/mL. Compounds 5–18 exhibited cytotoxicity against three cancer cell lines (KB, MCF-7 and NCI-H187) with IC50 values in ranging from 1.26–49.03μg/mL.

A new polyoxygenated cyclohexene derivative from Artabotrys hainanensis

A new polyoxygenated cyclohexene derivative, artahainanol A (1), together with three known analogues (2–4), was isolated from the stems and leaves of Artabotrys hainanensis. Among them, 1 is an unusual polyoxygenated cyclohexene containing 14 carbon atoms on the carbon skeleton. All known compounds (2–4) were isolated from the genus Artabotrys for the first time. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–4 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 2.68 to 18.32 μM.

2-Phenylnaphthalenes and a polyoxygenated cyclohexene from the stem and root extracts of Uvaria cherrevensis (Annonaceae)

Three new 2-phenylnaphthalene derivatives, cherrevenaphthalenes A–C (1–3), and a new polyoxygenated cyclohexene derivative, (−)-uvaribonol F (4) together with six known compounds, 5–10, were isolated from the stem and root extracts of Uvaria cherrevensis (Annonaceae). The structures of all isolated compounds were elucidated by spectroscopic analysis. The structures of 3 and 4 were further confirmed by single crystal X-ray diffraction methods. Compound 2 exhibited modest antiplasmodial activity against the P. falciparum stains TM4/8.2 and K1CB1 with IC50 values of 18.8±3.63 and 23.4±4.08μM, respectively, and weak cytotoxicity to a Vero cell line. Furthermore, compound 4 displayed cytotoxic activity against a KB cell line with an IC50 value of 22.1±0.42μM but was non-cytotoxic to the Vero cell line. Compound 5 revealed stronger cytotoxicity towards the KB cell line, with an IC50 value of 5.05±0.86μM and was nearly equally cytotoxic to the Vero cell line.

Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves.

Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A-F (6-11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15-21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C.kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2-40 μM, and against HEK293 mammalian cells (IC50 2.7-3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03-8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.

Filling Some Blanks in a Divergent Approach to Gabosines: Enantioselective Synthesis of (–)‐Epiepoxydon, (+)‐Phyllostine, (–)‐Gabosine D, and (–)‐Gabosine E

The levorotatory enantiomers of gabosines D and E were synthesized through a divergent approach that could equally well be applied to the synthesis of the dextrorotatory enantiomers, which have been isolated from natural sources. The approach relies on an initial desymmetrization of p‐methoxyphenol, followed by an enzymatic resolution that separately provides the two enantiomers of synthon 3. This versatile synthon can be further transformed into the diverse polyoxygenated cyclohexane target molecules. Key steps in the synthesis of (–)‐gabosines D and E from (4R,6S)‐3 are the stereoselective hydroxymethylation at the α‐carbonyl position leading to (+)‐4, and the subsequent reagent‐controlled epoxidation of the carbon–carbon double bond. A branching in the sequence also allowed the synthesis of the anhydrogabosines (–)‐epiepoxydon and (+)‐phyllostine.

Chemical constituents from Piper hainanense and their cytotoxicities

Two new compounds, (Z,R)-1-phenylethylcinnamate (1) and (1R,2R,3R,6S)-pipoxide (2) were isolated from the aerial part of Piper hainanense, along with 12 known compounds, including nine benzene derivatives (4–11), one isobutylamide (12), and two polyoxygenated cyclohexene derivatives (13–14). Their structures were elucidated on the basis of the HRESIMS, 1D and 2D NMR spectroscopic analyses, and ECD in cases of 2 and 3. The absolute configuration of ellipeiopsol B (3) was determined for the first time. All these compounds 1–14 were reported from the titled plant for the first time. Most of the isolates were tested for their cytotoxicities against five human cancer cell lines. Four of which, 2, 3, 9, 14 showed moderate bioactivities. Among them, the new compound 2 showed potential cytotoxicity against SMMC-7721, MCF-7, and SW-480 with IC50 values of 9.7, 15.0, and 13.2 μM, respectively.

3-Methyl-4,5-dihydro-oxepine, polyoxygenated seco-cyclohexenes and cyclohexenes from Uvaria flexuosa and their anti-inflammatory activity

The phytochemical investigation of the methanolic extract of Uvaria flexuosa (Annonaceae) leaves led to the isolation of seven compounds including, 3-methyl-4,5-dihydro-oxepine (flexuvaroxepine A), four polyoxygenated seco-cyclohexene (flexuvarin A–D) and two polyoxygenated cyclohexene (flexuvarol A–B) derivatives, together with four known flavones. The structures of the isolated compounds were elucidated using different spectroscopic techniques. A plausible biogenetic route of the new compounds was discussed. The anti-inflammatory activity of the isolated compounds was evaluated by superoxide anion generation and elastase release assays. Among the tested compounds, flexuvarol B and chrysin showed the most potent anti-inflammatory effect by inhibiting superoxide anion generation and elastase release from human neutrophils in response to fMLP with IC50 2.25–5.55μM. Moreover, 5-hydroxy-6,7-dimethoxy-flavone showed selective inhibitory activity on superoxide anion generation (IC50=1.19±0.34μM).

Polyoxygenated cyclohexene derivatives isolated from Dasymaschalon sootepense and their biological activities

Six new naturally occurring polyoxygenated cyclohexene derivatives together with eight related known derivatives, two known alkaloids, and two known flavonoid derivatives were isolated from bioassay-guided fractionation of the ethyl acetate extract of the leaves and twigs of Dasymaschalon sootepense. The structure elucidation and determination of absolute configurations were established by various spectroscopic methods, X-ray diffraction techniques as well as comparison with the literature data. Several isolated compounds were evaluated for their cytotoxic, anti-HIV-1 RT and anti-inflammatory activities.

A new polyoxygenated cyclohexene and a new megastigmane glycoside from Uvaria grandiflora.

A new polyoxygenated cyclohexene, (-)-3-O-debenzoylzeylenone (1), and a new megastigmane glycoside, grandionoside A (2), were isolated from the aerial parts of Uvaria grandiflora collected in Vietnam, together with ten known compounds including polyoxygenated cyclohexenes (3-6), a triterpenoid (7), an alkaloid (8), a long chain alcohol (9), hexenyl glycopyranoside (10), and saponins (11-12). Their chemical structures were elucidated by a combination of extensive NMR spectroscopy with X-ray crystallographic analysis for 1, and chemical conversion for 2. Compound 1 exhibited significant cytotoxicity against the LU-1 and SK-Mel-2 cell lines with IC50 values of 4.68 and 3.63 μM, respectively. Remarkably, the cytotoxicity of 12 against the LU-1, KB, Hep-G2, MKN-7, and SW-480 cell lines was comparable to that of ellipticine, the positive control, with IC50 values ranging from 1.24 to 1.60 μM.

First Total Synthesis of Piperenol B and Configuration Revision of the Enantiomers Piperenol B and Uvarirufol A

AbstractWe report herein the first total synthesis of piperenol B, a polyoxygenated cyclohexene derivative with reported pharmacological activity isolated from Piper cubeb. The chiral building block for this synthetic approach is derived from microbial cis‐ipso,ortho‐dihydroxylation of sodium benzoate, which was optimized to the multi‐ten‐gram scale by reaction medium engineering. Final‐stage deprotection of an acetonide was investigated in detail, leading to an efficient eight‐step protocol for the synthesis of piperenol B with a total yield of 10 %. Most importantly, the previously assigned absolute configuration of piperenol B was revised and unequivocally established by 2D NMR analysis and the Mosher's ester method.

A new polyoxygenated cyclohexane and other constituents from Kaempferia rotunda and their cytotoxic activity

The isolation of secondary metabolites from a methanolic extract of Kaempferia rotunda yielded 12 compounds (1–12), including a new polyoxygenated cyclohexane compound, (–)-3-acetyl-4-benzoyl-1-benzoyloxymethyl-1,6-diepoxycyclohexan-2,3,4,5-tetrol (1). The structures of the isolated compounds were determined based on their spectroscopic data and comparison with references. All of the isolated compounds were tested for their cytotoxic activity against pancreatic (PSN-1) and breast (MDA-MB231) cancer cell lines. Compound 12 showed moderate cytotoxic activity against PSN-1 and MDA-MB231 without showing any cytotoxicity against the normal cell line, TIG-3.

ChemInform Abstract: Highly Stereocontrolled and Regiocontrolled Syntheses of Polyoxygenated [2.2.2]Oxabicyclic Synthons.

AbstractStarting from commercially available electron poor 2‐pyrones the synthesis of polyoxygenated cyclohexanes is reported via an inverse‐electron demand Diels—Alder cycloaddition with tert‐butyldimethylsilyl vinyl ether as key step.

New polyoxygenated cyclohexene and polyoxygenated seco-cyclohexene from Uvaria boniana

A new polyoxygenated cyclohexene bonianol A (1) and another new polyoxygenated seco-cyclohexene bonianol B (2) were isolated from the leaves of Uvaria boniana, and their structures were established on the basis of spectroscopic methods including IR, HR-ESI-MS, 1D, and 2D NMR.

Anti-inflammatory and anticancer activities of (−)-zeylenol from stems of Uvaria grandiflora

Uvaria grandiflora has stimulated rigorous phytochemical investigation aimed at determining chemical structures and biological activities. In recent years, many polyoxygenated cyclohexenes have been isolated from this genus. This study reports that zeylenol isolated from the stems of U. grandiflora possess potential anti-inflammatory, anticancer, and caspase-3 activities. The structure of this compound was elucidated from spectroscopic analysis, particularly 2D NMR techniques. The anti-inflammatory effect and toxicity of zeylenol were evaluated in animal models and compared to that of reference drugs. In addition, the cytotoxicity of the isolated compound against human breast cancer MDA-MB231 and hepatocellular carcinoma HepG2 cell lines were studied. The test ( )-zeylenol at the dose of 1 mg/ear significantly inhibited oedema formation by 90%, 69%, 52%, and 52% after 15, 30, 60, and 120 min, respectively. Zeylenol was found to be toxic to both MDA-MB231 and HepG2 cells in a dose response manner with IC50 values of 54 10 and > 80 µM, respectively. The compound induced MDA-MB231 cell apoptosis via caspase-3 activation. Zeylenol probably possesses anti-inflammatory activity by inhibiting the synthesis or release of various inflammatory mediators and might be used to induce human breast cancer MDA-MB231 cell apoptosis.

Polyoxygenated cyclohexene derivatives from Monanthotaxis congoensis

A phytochemical investigation of Monanthotaxis congoensis afforded eight polyoxygenated cyclohexenes as well as the known crotepoxide. Structures were determined using NMR, MS, and optical rotation analyses. One compound displayed moderate antiproliferative activity against NCI-H460 and M14 cancer cells.

Uvacalols I, J and K: new polyoxygenated cyclohexenes with all trans relative configurations from the roots of Uvaria calamistrata Hance

Three new polyoxygenated cyclohexene derivatives with all trans relative configurations, named uvacalols I, J and K (1–3), were isolated from the roots of Uvaria calamistrata Hance. Their structures were determined to be (1R, 2S, 3S, 4R)-1-ethoxyl-5-benzoyloxymethylcyclohex-5-en-2,4-diol-3-benzoate (1), 1-ethoxyl-5-benzoyloxymethylcyclohex-5-en-3,4-diol-2-benzoate (2), and 5-benzoyloxymethylcyclohex-5-en-1,2,4-triol-3-benzoate (3), respectively, by extensive NMR experiments and chemical derivatisation.

Three polyoxygenated cyclohexenes from Uvaria calamistrata

Three new polyoxygenated cyclohexenes, named uvacanols F, G, H (1–3), were isolated from the roots of Uvaria calamistrata (Annonaceae). Their structures were determined to be 2-acetoxyl-5-chlorine-benzoyloxymethylcyclohex-1 (6)-ene-4-ol-3-benzoate (1), benzoyloxy-methylcyclohex-1 (6)-ene-2,3,4-triols-5-benzoate (2), 3-acetoxyl-benzoyloxymethylcyclohex-1 (6)-ene-4,5-diols-2-benzoate (3) by spectroscopic methods and chemical derivatization.

Stereocontrolled Approach to Phenyl Cyclitols from (SR)-[(p-Tolylsulfinyl)methyl]-p-quinol

Reactions of enantiopure (SR)-[(p-tolylsulfinyl)methyl]-p-quinol with ArAlMe(2) reagents allowed a highly diastereoselective 1,4-addition of the aryl group with an efficient desymmetrization of the prochiral cyclohexadienone moiety. The asymmetric synthesis of phenyl-substituted polyoxygenated cyclohexane derivatives was achieved by combining this reaction with a stereoselective reduction and elimination of the beta-hydroxysulfoxide, after oxidation to sulfone, to recover a carbonyl group, and a stereoselective epoxidation.

Two new polyoxygenated cyclohexenes from Uvaria kweichowensis

Two new polyoxygenated cyclohexenes, kweichowenols C and D, were isolated from the leaves of Uvaria kweichowensis, and their structures were established on the basis of their spectral data. The two new compounds showed some antitumor activity by the MTT assay.

Polyoxygenated cyclohexane derivatives and other constituents from Kaempferia rotunda L.

Methanol extracts of Kaempferia rotunda L. rhizomes yielded seven compounds including six polyoxygenated cyclohexane derivatives identified as (−)-6-acetylzeylenol ( 1), four acylated derivatives of 1-benzoyloxymethyl-1,6-epoxycyclohexan-2,3,4,5-tetrol ( 3– 6), a Diels–Alder adduct of 3-benzoyl-1-benzoyloxymethylcyclohexa-4,6-dien-2,3-diol ( 7), and a triacylated derivative of salicin ( 9). The cyclohexane diepoxide, crotepoxide ( 8), was also obtained. Spectroscopic methods were used for structure determination. The methanol extract of the rhizomes of K. rotunda and (−)-2-acetyl-4-benzoyl-1-benzoyloxymethyl-1,6-epoxycyclohexan-2,3,4,5-tetrol (2-acetylrotepoxide B; 6), had antifeedant activity against larvae of Spodoptera littoralis. (−)-Zeylenol ( 2) also showed antifeedant activity, whereas (−)-6-acetylzeylenol ( 1) was inactive.