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1.
Eur J Med Chem ; 157: 229-247, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-30096654

ABSTRACT

In this study, anti-IPF lead compounds 42 and 44, derived from natural sesquiterpene lactones Isoalantolactone and alantolactone, were discovered by screening from a high-throughput TGF-ß1 reporter luciferase assay. Notably, they could reduce the myofibroblast activation and extracellular matrix deposition both in vitro and in vivo. Additionally, compounds 42 and 44 could significantly attenuate bleomycin-induced pulmonary fibrosis in mice. Further validation of pharmacokinetics study and toxicity evaluation indicated that compound 44 might be a promising anti-IPF drug candidate.


Subject(s)
Drug Discovery , Idiopathic Pulmonary Fibrosis/drug therapy , Lactones/pharmacology , Sesquiterpenes, Eudesmane/pharmacology , Sesquiterpenes/pharmacology , Transforming Growth Factor beta1/antagonists & inhibitors , Animals , Bleomycin , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Fibroblasts/drug effects , High-Throughput Screening Assays , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/metabolism , Lactones/chemical synthesis , Lactones/chemistry , Mice , Molecular Structure , NIH 3T3 Cells , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes, Eudesmane/chemistry , Structure-Activity Relationship , Transforming Growth Factor beta1/metabolism
2.
Molecules ; 22(11)2017 Oct 27.
Article in English | MEDLINE | ID: mdl-29077042

ABSTRACT

1ß-hydroxy alantolactone, a sesquiterpene lactone mainly isolated from Inula genus plants, exhibits potent anti-inflammatory and anticancer activities. In this work, 1ß-hydroxy alantolactone was isolated and five derivatives were prepared through different reactions at the C1-OH and C13-methylene motifs. The structure-activity relationships (SAR) of anti-inflammatory effects against NO production in RAW264.7 cells showed that the α-methylene-γ-butyrolactone motif was essential for NO production suppression and that retaining the C1-OH group can remarkably improve this effect. The NF-κB signaling pathway plays a pivotal role in the regulation of NO expression. Moreover, the levels of p65 and p50 phosphorylation were investigated and active compound 1 inhibited phosphorylation of p65 and p50 in TNF-α-induced NF-κB signaling. Further molecular docking suggested that 1 may target the p65 of NF-κB.


Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Inula/chemistry , Lactones/chemistry , Lactones/pharmacology , Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Eudesmane/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Cell Line , Cell Survival/drug effects , Gene Expression , Genes, Reporter , Inhibitory Concentration 50 , Lactones/chemical synthesis , Mice , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , NF-kappa B/metabolism , Nitric Oxide/metabolism , RAW 264.7 Cells , Sesquiterpenes, Eudesmane/chemical synthesis
3.
Org Lett ; 17(6): 1505-8, 2015 Mar 20.
Article in English | MEDLINE | ID: mdl-25760410

ABSTRACT

A tert-leucine-derived chiral diamine catalyzes the asymmetric Michael addition of nitromethane to five-, six-, and seven-membered ß-substituted cyclic enones with excellent enantioselectivity, offering scalable, asymmetric access to all-carbon quaternary stereocenters. The reaction scope can be expanded to include linear acyclic enones, and excellent levels of enantioselectivity are also observed. Furthermore, this organocatalytic, asymmetric nitro-Michael reaction is amenable to multigram scale-up and applications in the construction of an eudesmane sesquiterpenoid skeleton.


Subject(s)
Ketones/chemistry , Ketones/chemical synthesis , Sesquiterpenes, Eudesmane/chemical synthesis , Catalysis , Diamines/chemistry , Leucine/analogs & derivatives , Molecular Structure , Nitro Compounds/chemical synthesis , Nitro Compounds/chemistry , Sesquiterpenes, Eudesmane/chemistry , Stereoisomerism , Valine/analogs & derivatives
4.
Nat Prod Res ; 29(8): 756-63, 2015.
Article in English | MEDLINE | ID: mdl-25495595

ABSTRACT

Telekin is a eudesmane sesquiterpene-lactone naturally occurring in many medicinal plants with antitumour and anti-inflammatory activity. In this study, a series of 13-amino derivatives of telekin have been synthesised through Michael addition reaction, and their relative configurations were exemplified by the single crystal X-ray diffraction of the dimethylamine adduct. The in vitro cytotoxicity against three tumour cell lines of these amine derivatives was evaluated. The piperidine and 4-hydroxypiperidine adducts displayed stronger cytotoxic activity than telekin.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Eudesmane/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Plants, Medicinal/chemistry
5.
Chem Pharm Bull (Tokyo) ; 62(7): 725-8, 2014.
Article in English | MEDLINE | ID: mdl-24990508

ABSTRACT

Transannular cyclizations of germacrone-4,5-epoxide under acidic and thermal conditions have been reported in our previous study. However, this process gave the different and interesting results under basic conditions. (4S,5S)-Germacrone-4,5-epoxide (1) was treated under basic conditions to yield four products (2-5). Compound 2 was an isomer of 1--(4S,5S,9Z)-4,5-epoxygermacra-7(11),9-dien-8-one--and the remaining three compounds (3-5) were eudesmane-type derivatives. Compounds 4 and 5 are new compounds. The structures of the new compounds were determined using high resolution (HR)-MS, one dimensional (1D)-NMR, 2D-NMR and circular dichroism (CD) spectroscopic data. Products 3-5 had the same carbon skeleton as that of eudesmane-type compounds; however, these compounds showed different arrangement of isoprene units to the natural eudesmane-type sesquiterpenes.


Subject(s)
Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Germacrane/chemistry , Circular Dichroism , Cyclization , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Conformation , Sesquiterpenes, Eudesmane/chemical synthesis , Stereoisomerism
6.
Org Lett ; 15(7): 1584-7, 2013 Apr 05.
Article in English | MEDLINE | ID: mdl-23484913

ABSTRACT

The first asymmetric total syntheses of sesquiterpene lactones (+)-eudesmadiene-12,6-olide (1) and (+)-frullanolide (2) have been accomplished from 4-bromo-2-methoxyphenol (5) in 12 and 13 synthetic steps, respectively, and the absolute configurations of these two natural products were determined.


Subject(s)
Lactones/chemical synthesis , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes/chemical synthesis , Frullania/chemistry , Guaiacol/analogs & derivatives , Guaiacol/chemistry , Lactones/chemistry , Molecular Structure , Sesquiterpenes/chemistry , Sesquiterpenes, Eudesmane/chemistry , Stereoisomerism
7.
Chem Commun (Camb) ; 48(91): 11241-3, 2012 Nov 25.
Article in English | MEDLINE | ID: mdl-23064601

ABSTRACT

The first total synthesis of (+)-5-epi-eudesm-4(15)-ene-1ß,6ß-diol has been achieved in 12 steps starting from the known (-)-cis-piperitol and by using a chelation controlled glycolate enolate Ireland-Claisen rearrangement and an intramolecular nitrile oxide dipolar cycloaddition as key steps.


Subject(s)
Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes/chemical synthesis , Crystallography, X-Ray , Cycloaddition Reaction , Litsea/chemistry , Molecular Conformation , Sesquiterpenes/chemistry , Stereoisomerism
8.
J Org Chem ; 77(9): 4217-25, 2012 May 04.
Article in English | MEDLINE | ID: mdl-22506722

ABSTRACT

We present in this report the development of a convergent and highly stereocontrolled cycloaddition strategy toward the synthesis of C-1, C-6, and C-14 tris-oxygenated eudesmane sesquiterpenoids. This approach was demonstrated in the first total synthesis of (±)-6ß,14-epoxyeudesm-4(15)-en-1ß-ol (1), a structurally unique ethereal eudesmane sesquiterpenoid, via an effective Diels-Alder construction of a compact functionalized tricycle intermediate from readily available N-benzylfurfurylamine (2) and homoprenyl maleic anhydride (3) as the C(5) and C(10) building blocks, respectively.


Subject(s)
Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Eudesmane/chemical synthesis , Cyclization , Molecular Structure , Stereoisomerism
9.
Toxicon ; 57(1): 100-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21044643

ABSTRACT

Several sesquiterpene lactone were synthesized and their inhibitive activities on phospholipase A(2) (PLA(2)) from Bothrops jararacussu venom were evaluated. Compounds Lac01 and Lac02 were efficient against PLA(2) edema-inducing, enzymatic and myotoxic activities and it reduces around 85% of myotoxicity and around 70% of edema-inducing activity. Lac05-Lac08 presented lower efficiency in inhibiting the biological activities studied and reduce the myotoxic and edema-inducing activities around only 15%. The enzymatic activity was significantly reduced. The values of inhibition constants (K(I)) for Lac01 and Lac02 were approximately 740 µM, and for compounds Lac05-Lac08 the inhibition constants were approximately 7.622-9.240 µM. The enzymatic kinetic studies show that the sesquiterpene lactones inhibit PLA(2) in a non-competitive manner. Some aspects of the structure-activity relationships (topologic, molecular and electronic parameters) were obtained using ab initio quantum calculations and analyzed by chemometric methods (HCA and PCA). The quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA(2) (Lac01-Lac04) present lower values of highest occupied molecular orbital (HOMO) energy and molecular volume (VOL) and bigger values of hydrophobicity (LogP). These results indicate some topologic aspects of the binding site of sesquiterpene lactone derivatives and PLA(2).


Subject(s)
Bothrops , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Phospholipase A2 Inhibitors , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes, Eudesmane/pharmacology , Animals , Binding Sites , Crotalid Venoms/chemistry , Drug Antagonism , Edema/chemically induced , Edema/pathology , Hindlimb , Injections, Intramuscular , Lactones/chemical synthesis , Lactones/pharmacology , Male , Mice , Muscle, Skeletal/drug effects , Muscle, Skeletal/enzymology , Muscle, Skeletal/pathology , Necrosis/chemically induced , Necrosis/pathology , Phospholipases A2/isolation & purification , Structure-Activity Relationship
12.
Nature ; 459(7248): 824-8, 2009 Jun 11.
Article in English | MEDLINE | ID: mdl-19440196

ABSTRACT

From menthol to cholesterol to Taxol, terpenes are a ubiquitous group of molecules (over 55,000 members isolated so far) that have long provided humans with flavours, fragrances, hormones, medicines and even commercial products such as rubber. Although they possess a seemingly endless variety of architectural complexities, the biosynthesis of terpenes often occurs in a unified fashion as a 'two-phase' process. In the first phase (the cyclase phase), simple linear hydrocarbon phosphate building blocks are stitched together by means of 'prenyl coupling', followed by enzymatically controlled molecular cyclizations and rearrangements. In the second phase (the oxidase phase), oxidation of alkenes and carbon-hydrogen bonds results in a large array of structural diversity. Although organic chemists have made great progress in developing the logic needed for the cyclase phase of terpene synthesis, particularly in the area of polyene cyclizations, much remains to be learned if the oxidase phase is to be mimicked in the laboratory. Here we show how the logic of terpene biosynthesis has inspired the highly efficient and stereocontrolled syntheses of five oxidized members of the eudesmane family of terpenes in a modicum of steps by a series of simple carbocycle-forming reactions followed by multiple site-selective inter- and intramolecular carbon-hydrogen oxidations. This work establishes an intellectual framework in which to conceive the laboratory synthesis of other complex terpenes using a 'two-phase' approach.


Subject(s)
Carbon/chemistry , Hydrogen/chemistry , Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Eudesmane/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Biomimetics , Molecular Structure , Oxidation-Reduction , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry
13.
Org Lett ; 11(2): 289-92, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19093809

ABSTRACT

A catalytic enantioselective approach to the eudesmane sesquiterpenoids is reported. The strategic use of a palladium-catalyzed enantioselective alkylation of vinylogous ester substrates forged the C(10) all-carbon quaternary center. This key transformation enabled a diastereoselective olefin hydrogenation to create the syn stereochemistry at C(7). The devised synthetic strategy allowed for the preparation of the antibacterial agent (+)-carissone and a formal synthesis of the P/Q-type calcium channel blocker (-)-alpha-eudesmol.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Sesquiterpenes, Eudesmane/chemical synthesis , Anti-Bacterial Agents/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Catalysis , Palladium/chemistry , Sesquiterpenes, Eudesmane/chemistry , Stereoisomerism , Substrate Specificity
14.
Phytochemistry ; 69(8): 1689-94, 2008 May.
Article in English | MEDLINE | ID: mdl-18420237

ABSTRACT

Eudesmane-type sesquiterpenoids 3alpha-(2,3-epoxy-2-methylbutyryloxy)-4alpha-formoxy-11-hydroxy-6,7-dehydroeudesman-8-one (1) and 3alpha-(2,3-epoxy-2-methylbutyryloxy)-4alpha,7alpha,11-trihydroxyeudesman-8-one (2), together with 10 known structurally related eudesmanes were isolated from the CHCl3 extract of aerial parts of Pluchea sagittalis (Lamarck) Cabrera. Their structures were deduced by extensive application of 1 and 2D NMR spectroscopic techniques and high and low resolution CIMS. X-ray crystallographic analysis of the known compound 3alpha-(2,3-epoxy-2-methylbutyryloxy)-4alpha-formoxycuauthemone (9) is reported here for the first time, and confirms the structural features for the series of the reported eudesmanes. All eudesmanes were tested for their antifeedant activity by incorporating them to an artificial diet of larvae of the polyphagous insect Spodoptera frugiperda at a concentration of 100ppm. Our results, from feeding choice tests, indicated that most of the compounds deter larval feeding at the cited concentration.


Subject(s)
Asteraceae/chemistry , Feeding Behavior/drug effects , Plant Preparations/pharmacology , Sesquiterpenes, Eudesmane/pharmacology , Sesquiterpenes/pharmacology , Spodoptera/drug effects , Animals , Crystallography, X-Ray , Larva/drug effects , Molecular Structure , Plant Components, Aerial/chemistry , Plant Preparations/chemistry , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes, Eudesmane/chemistry
15.
J Org Chem ; 72(2): 643-6, 2007 Jan 19.
Article in English | MEDLINE | ID: mdl-17221988

ABSTRACT

Two chromatographically inseparable, diastereomeric eudesmane cyclic sulfites have been semisynthesized from alpha-santonin. This diastereomeric mixture was resolved by enzymatic acetylation with CCL. Each cyclic sulfite derivative was individually characterized on the basis of its spectroscopic and crystallographic properties.


Subject(s)
Lipase/chemistry , Sesquiterpenes, Eudesmane , Sulfites , Candida/enzymology , Crystallography, X-Ray , Cyclization , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Reference Standards , Sensitivity and Specificity , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes, Eudesmane/chemistry , Stereoisomerism , Sulfites/chemical synthesis , Sulfites/chemistry
16.
Chirality ; 17(3): 163-6, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15704208

ABSTRACT

A facile synthetic route to two seco-eudesmanes, 4,5-dioxo-10-epi-4,5-seco-gamma-eudesmane (1) and 4,5-dioxo-10-epi-4,5-seco-gamma-eudesmol (2) from (+)-dihydrocarvone has been described. Avoiding expensive reagents, this highly economic method is especially suited for the synthesis of 4,5-seco-eudesman-type and iphionan-type sesquiterpenes with a double bond at positions 11 and 12.


Subject(s)
Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes/chemical synthesis , Cyclohexane Monoterpenes , Monoterpenes/chemistry , Stereoisomerism
17.
J Org Chem ; 70(1): 338-41, 2005 Jan 07.
Article in English | MEDLINE | ID: mdl-15624944

ABSTRACT

Two new 7-epi-eudesmane derivatives, together with two new germacrane compounds, have been isolated from the microbial-transformation of a (1alpha,10beta),(4beta,5alpha)-diepoxygermacrane using the hydroxylating fungi Rhizopus nigricans. The rearranged skeleton and the stereochemistry of the chiral centers have been determined by means of their spectral data, and the absolute configuration has been confirmed by single-crystal X-ray analyses. A possible mechanism based on an enzyme-catalyzed isomerization to a 1alpha-hydroxy-(4beta,5alpha)-epoxygermacr-9(E)-ene intermediate and a subsequent cyclization process is proposed in order to explain the formation of the 7-epi-eudesmane compounds.


Subject(s)
Rhizopus/enzymology , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes, Germacrane/chemistry , Biotransformation , Catalysis , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Rhizopus/metabolism , Sesquiterpenes, Eudesmane/chemistry , Stereoisomerism
18.
Chirality ; 16(8): 483-5, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15290681

ABSTRACT

This paper describes a novel approach for the introduction of a C-1 hydroxyl on the decalin ring system, starting from (-)-carvone. Utilizing the substrate-controlled Mukaiyama aldol reaction and alkaline cyclization as key steps, the C-1 oxygenated decalin eudesmane skeleton 2' and its four isomers were synthesized efficiently. Furthermore, X-ray structural analysis showed that the claimed structure for the natural product is incorrect.


Subject(s)
Naphthalenes/chemistry , Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes/chemistry , Sesquiterpenes/chemical synthesis , Biological Factors/chemical synthesis , Biological Factors/chemistry , Cyclization , Cyclohexane Monoterpenes , Isomerism , Models, Molecular , Molecular Structure , Monoterpenes , Terpenes/chemistry
19.
Org Biomol Chem ; 1(13): 2314-20, 2003 Jul 07.
Article in English | MEDLINE | ID: mdl-12945703

ABSTRACT

Two new cyclic sulfite eudesmane derivatives have been investigated. Their (R) and (S) sulfur configuration and the structural arrangement of their "A" rings have been assigned by means of their 13C and 1H NMR chemical shifts and have been confirmed by single-crystal X-ray analyses. Microbial-transformation of these epimer cyclic sulfites and their dihydroxyeudesmane precursor have been studied using the hydroxylating fungus Rhizopus nigricans. Increased biocatalysis rates and considerable differences in the biotransformation of both cyclic sulfite eudesmanes have been found. Promising 8alpha,11-dihydroxy derivatives have been isolated from the (S)-diastereomer bioconversion.


Subject(s)
Rhizopus/chemistry , Sesquiterpenes, Eudesmane/chemistry , Sulfites/chemistry , Biotransformation , Crystallography, X-Ray , Hydroxylation , Magnetic Resonance Spectroscopy/methods , Models, Chemical , Molecular Structure , Reproducibility of Results , Rhizopus/metabolism , Sesquiterpenes, Eudesmane/chemical synthesis , Sesquiterpenes, Eudesmane/metabolism , Stereoisomerism , Temperature , Time Factors
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