Toward a better pharmacophore description of P-glycoprotein modulators, based on macrocyclic diterpenes from Euphorbia species

Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of features was performed in order to obtain a new improved four-point pharmacophore able to detect literature and in-house modulators and simultaneously specific enough to avoid the detection of most nonactive molecules in a universe of 152 (literature), 74 (in-house), and 46 (inactive) molecules. This pharmacophore detects 84.2% of the molecules described in the literature, along with 100% detection of in-house isolated compounds and 19.5% of false positives. The importance of the hydrophobic and electron acceptor moieties as essential features for recognition of different molecules by the P-gp drug-binding site is clarified. The best combination of acceptor, donor, hydrophobic, and aromatic characteristics that contribute for the increased selectivity shown by the described pharmacophore is evaluated, and the protonation state of the molecules is also addressed.     

New macrocyclic diterpenes from Euphorbia connata Boiss. with cytotoxic activities on human breast cancer cell lines

Acetone:chloroform (1:2) extract of the aerial parts of Euphorbia connata Boiss. (Euphorbiaceae) was investigated for its diterpenoids. This led to the isolation of one known and two new diterpenes, belonging to the pentahydroxy-13(17)-epoxy-8,10(18)-myrsinadiene and tetrahydroxy-5,6-epoxy-14-oxo-jatropha-11(E)-ene classes. The structures were elucidated based on ¹³C and ¹H NMR as well as 2D NMR, IR and MS spectra and the cytotoxicity for compounds 1–3 were evaluated by using MTT assay against two human breast cancer cell lines. Myrsinane-type compounds – 3,7,14,15-tetraacetyl-5-propanoyl-13(17)-epoxy-8,10(18)-myrsinadiene (1) and 3,7,10,14,15-pentaacetyl-5-butanoyl-13,17-epoxy-8-myrsinene (2) – exhibited moderate inhibitory effects, with IC₅₀ values of 24.53 ± 3.39 and 26.67 ± 1.41 μM against the MDA-MB cell line, and 37.73 ± 3.41 and 34.57 ± 2.12 μM against the MCF-7 cell line, respectively. Jatrophane-type diterpene – 5,6-epoxy-8,9,15-triacetyl-3-benzoyl-14-oxo-jatropha-11(E)-ene (3) – showed weak cytotoxicity, with IC₅₀ values of 55.67 ± 7.09 μM against MDA-MB, and moderate cytotoxicity with IC₅₀ values of 24.33 ± 3.21 μM against MCF-7 cell line.     

Staminolactones A and B and norstaminol A: three highly oxygenated staminane-type diterpenes from Orthosiphon stamineus

[formula: see text] Staminolactones A (1) and B (2) and norstaminol A (3), three highly oxygenated staminane-type diterpenes having mild cytotoxic activities against highly liver-metastatic colon 26-L5 carcinoma cells, were isolated from the aerial part of the Vietnamese medicinal plant Orthosiphon stamineus (Lamiaceae). Their structures were elucidated on the basis of the extensive spectral analyses.     

Isolation and characterization of biogenetically related highly oxygenated nortriterpenoids from Schisandra chinensis

Pre-schisanartanin (1) and schindilactones A-C (2-4) were isolated from Schisandra chinensis. Among them, compound 1 had an unprecedented carbon skeleton. More importantly, the structure features of this compound provided new insight into the biosynthesis of triterpenoids with schisanartane skeleton. Their structures were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction, and on the basis of the absolute structure of one related nortriterpenoid (5), which was determined for the first time by a modified Mosher method.     

Synthetic studies on the preparation of oxygenated spongiane diterpenes from carvone

The paper describes a new diastereoselective approach to oxygenated spongiane diterpenes functionally related to natural dorisenones. The strategy followed for the preparation of the spongiane framework, a B→AB→ABC→ABCD approach, is based on the preparation of epoxydecalone 11 (AB rings) from R-(−)-carvone, followed by an intramolecular Diels-Alder reaction for the construction of the C ring (compound 26). Further manipulation of the Diels-Alder adduct functionality allows the completion of the spongiane framework and the elaboration of several oxygenated spongiane-type compounds. The structures of two compounds 27 and 31, has been established by single-crystal X-ray crystallography.     

Syntheses of oxygenated spongiane diterpenes from carvone. Synthesis of dorisenone C

The synthesis of dorisenone C, a representative member of the spongiane-type diterpene family, is described. The synthesis follows a B→AB→ABC→ABCD approach and is based on the initial preparation of the previously known hydroxy-aldehyde 14 (AB rings) from R-(−)-carvone, followed by an intramolecular Diels-Alder reaction between an oxygenated diene moiety and an acetylenic dienophile for the construction of the C ring (compound 22), and adequate manipulation of the Diels-Alder adduct functionality for completion of the spongiane framework.     

Lagaspholones A and B: two new jatropholane-type diterpenes from Euphorbia lagascae

[structure: see text] Two new diterpenes, lagaspholones A (1) and B (2), have been isolated from the methanolic extract of Euphorbia lagascae, along with the known compounds (+)-dehydrovomifoliol, scopoletin, dehydrodiconiferyl diacetate, 3-indolcarbaldehyde, and 4-hydroxy-3,5-dimethoxybenzaldehyde. Their structures were elucidated by spectroscopic methods. Compounds 1 and 2 contain the rare jatropholane-type skeleton, characterized by a 5:6:7:3 fused ring system. A possible biosynthetic pathway for lagaspholones is proposed.     

Phelligridimer A, a highly oxygenated and unsaturated 26-membered macrocyclic metabolite with antioxidant activity from the fungus Phellinus igniarius

[structure: see text] A highly oxygenated and unsaturated 26-membered macrocyclic metabolite, phelligridimer A (1), has been isolated from the Chinese medicinal fungus Phellinus igniarius. Its structure was elucidated by spectroscopic methods. A possible biogenesis of 1 mediated by the fungal metabolite hispidin was postulated. Phelligridimer A showed antioxidant activity (IC50 of 10.2 microM) but was inactive to several human cancer cell lines (IC50 > 50 microM) and enzymes PTP1B (IC50 > 25 microM) and thrombin (IC50 > 10 microM).     

Three new ingol diterpenes from Euphorbia nivulia: evaluation of cytotoxic activity

The latex of Euphorbia nivulia afforded three new ingol diterpenes, 3-acetyl-8-methoxyl-7-angolyl-12-hydroxylingol (7), 3,12-diacetyl-7-hydroxy-8-methoxylingol (8), and 3,12-diacetyl-7-angolyl-8-hydroxylingol (9) along with five known ingol diterpenes 2-6 and a known triterpene cyclonivulinol (1). Their structures were established by means of spectroscopic analysis. Diterpenes 2-9 were evaluated for their cytotoxic activity.     

New oxygenated diterpenes from an Australian nudibranch of the genus Chromodoris

Chemical analysis of a chromodorid nudibranch has provided two new diterpene metabolites 1 and 2 together with the known metabolites 3-6. In an NMR study, the dialdehyde metabolite 1 underwent facile conversion to cyclic hemiacetals 8-9 on exposure to methanol, a reaction that mimics chemical conversions that may occur during the isolation of some diterpenes from molluscs and sponges. Compounds 1, 2, 5 and 8 showed moderate cytotoxicity against P388 cells (IC₅₀=1.2-4.1 μg/mL).     

Cyclomyrsinane and premyrsinane diterpenes from Euphorbia falcata modulate resistance of cancer cells to doxorubicin

Two new and one known cyclomyrsinane-type diterpenes (1–3) were isolated from the methanol extract of the whole, undried plant of Euphorbia falcata, native to Hungary. The structures and relative configuration of the compounds were established on the basis of extensive spectroscopic analysis, including HRESIMS and one- and two-dimensional NMR techniques. These compounds are hexa- and heptaesters of diterpene polyols, esterified with acetic, propanoic, isobutanoic, 2-methylbutanoic, and benzoic acids. This type of diterpenes was previously detected only in three Euphorbia species (Euphorbia teheranica, Euphorbia seguieriana, and Euphorbia prolifera). The compounds, together with premyrsinanes isolated previously from this plant were evaluated for their antiproliferative activity against HeLa, Ishikawa, and MCF7 mouse lymphoma cells, and for their capacity to modulate resistance to doxorubicin in L5178 mouse lymphoma cells that over-express the MDR1 efflux pump. Compounds did not show substantial antiproliferative activity against any of the tested cell lines. However all compounds act in a mild to a very strong synergism with doxorubicin against the MDR mouse lymphoma cell line.     

Structures of two highly oxygenated iridoid glucosides from Globularia alypum

Structures of two acylated iridoid glucosides $\text{1}$ and $\text{6}$ were determined on the basis of chemical transformation and spectroscopic evidence.     

Kansuinine J,a new macrocyclic diterpenoid from the roots of Euphorbia kansui

<正>A new macrocyclic diterpenoid,named kansuinine J(1),was isolated from the roots of Euphorbia kansui.Its structure was characterized on the basis of spectroscopic analysis.     

Some diterpenes from the sea pen stylatula SP.

The sea pen Stylatula sp. from the Gulf of California contained one major and several minor metabolites. The structure of stylatulide (2), the major metabolite, has been reported previously. In this paper, the structural elucidations of four minor metabolites, 17-epi-stylatulide (13), the lactone 14, the primary alcohol 15 and related methyl ester 17 are described. We have described several reactions of stylatulide (2) and its derivatives which illustrate the complexity of reactions on these compounds.     

Synthesis of purpurasol, a highly oxygenated coumarin from Pterocaulon purpurascens

Purpurasol 1, a 6,7,8-trioxygenated coumarin, isolated from Pterocaulon purpurascens (Asteraceae) and Haplophyllum obtusifolium (Rutaceae), was synthesized for the first time by a three-step synthesis starting from the natural coumarin fraxetin. This synthesis confirmed unambiguously the structure of purpurasol 1 and obtusifol.     

A convenient route to enantiomerically pure highly oxygenated decalins from sugar allyltin derivatives

Preparation of enantiomerically pure, highly oxygenated decalins via tandem Wittig-type Diels–Alder reactions from the corresponding sugar-derived dieno-phosphoranes and/or -phosphonates and sugar aldehydes is described. Application of the phosphonates is more convenient than phosphoranes since the former can be prepared in much higher yields and react with aldehydes under milder conditions. The intermediate trienes resulting from the Wittig-type process undergo spontaneous and highly stereoselective cyclization to the cis-decalins under the reaction conditions.     

Novel acyclic and macrocyclic highly unsaturated silahydrocarbons

Two novel silicon-containing acetylenic synthons, 1-[dimethyl(ethynyl)silyl]-2-[ethynyl(methyl)-(vinyl)silyl]ethyne and bis[(ethynyldimethylsilyl)ethynyl](methyl)vinylsilane, were obtained by the reaction of diethynyl(methyl)vinylsilane with ethylmagnesium bromide and ethynylfluorodimethylsilane. The reaction of magnesium derivatives of the products and diethynyl(methyl)vinylsilane with organylhalosilanes gave macrocyclic polyunsaturated silahydrocarbons containing numerous endo- and exocyclic miltiple bonds.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 10, 2004, pp. 1612–1616.Original Russian Text Copyright © 2004 by O. Yarosh, Zhilitskaya, N. Yarosh, Istomina, Albanov, Chuvashev, Voronkov.This revised version was published online in April 2005 with a corrected cover date.     

Synthesis of highly oxygenated carbocyclic derivatives: decalins and cyclohexanes from sugar allyltins

Sugar allyltin derivatives are readily converted into the carbobicyclic compounds with precisely defined stereochemistry. Model functionalization of the carbocyclic skeleton in such precursors with the decalin structure provides either highly oxygenated bi- or monocarbocyclic derivatives.