Antiprotozoal activity of 8-acyl and 8-alkyl incomptine A analogs

The activities of 11 C-8-O-acyl and alkyl analogs of the antiprotozoal sesquiterpene lactone, incomptine A (1) against Entamoeba histolytica and Giardia lamblia, were determined. Here, the effects of different lengths and amounts of branching of the acyl and alkyl groups on the antiprotozoal activity of the synthesized incomptine A-analogs are reported.     

Antileishmanial activity and ultrastructural changes of sesquiterpene lactones isolated from Calea pinnatifida (Asteraceae)

Bioactivity-guided fractionation of antileishmanial active CH₂Cl₂ phase of MeOH extract from leaves of Calea pinnatifida led to isolation of two sesquiterpene lactones calein C (1) and calealactone C (2), which structures were stablished on the basis of spectroscopic analysis. Compounds 1 and 2 displayed potent activity against Leishmania amazonensis promastigotes with EC₅₀ of 1.7 and 4.6 µg mL⁻¹, respectively. Compound 2 presented low cytotoxicity for J774 macrophages and displayed activity against amastigote forms of L. amazonensis similar to miltefosine with CC₅₀ values of 31.73 and 27.18 µg mL⁻¹, respectively. Additionally, compounds 1 and 2 caused ultrastructural changes in promastigotes leading to a loss of their classical structural morphology, as evidenced by electron microscopy. Also compound 2 decreased the mitochondria membrane potential. To the best of our knowledge, this is the first occurrence of 1 and 2 in C. pinnatifida. The results obtained highlighted the importance of studying sesquiterpene lactones isolated from Calea pinnatifida in terms of antileishmanial activity, in order to understand the mechanism of action of the isolated compounds in promastigotes forms of L. amazonensis.     

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis,antiproliferative activity,and tubulin effects

We have synthesized a series of polymethoxylated rigid analogs of combretastatin A-4 which contain a benzoxepin ring in place of the usual ethylene bridge present in the natural combretastatin products. The compounds display antiproliferative activity when evaluated against the MCF-7 and MDA human breast carcinoma cell lines. 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-benzoxepine (11g) was found to be the most potent product when evaluated against the MCF-7 breast cancer cell line. A brief computational study of the structure–activity relationship for the synthesized compounds is presented. These 4,5-diarylbenzoxepins are identified as potentially useful scaffolds for the further development of antitumor agents which target tubulin.     

Sesquiterpene lactones from the leaves of Magnolia sirindhorniae

Five sesquiterpene lactones, costunolide (1), santamarine (2), reynosin (3), parthenolide (4), and lipiferolide (5), were isolated from the leaves of Magnolia sirindhorniae. Their structures were identified by analysis of spectroscopic data and comparison with those reported in the literature. Compound 5 was isolated from the Magnolia for the first time, and this is the first report of the isolation of the sesquiterpene lactones from M. sirindhorniae.     

Allelopathic potential of two sesquiterpene lactones from Magnolia grandiflora L.

The allelopathic effects of the two sesquiterpene lactones, costunolide and parthenolide, isolated from the leaves of Magnolia grandiflora L. were evaluated on the wheat (Triticum aestivum L.), lettuce (Lactuca sativa L.), radish (Raphanus sativus L.) and onion (Allium cepa L.). Seed germination of the test species was significantly reduced at 500 μg/ml by both compounds. Both sesquiterpenes showed pronounced inhibition of root length of the test species and the inhibitory effect was concentration-dependent. In addition, shoot growth of the four species was significantly inhibited at all the concentrations tested (10–500 μg/ml). Parthenolide reduced germination and inhibited seedling growth more than costunolide. Inhibition of root growth was generally greater than that of shoot growth. The results encourage the use of these sesquiterpenes as models for development of new herbicides.     

Antimicrobial activity of human α-defensin 5 and its linear analogs: N-terminal fatty acylation results in enhanced antimicrobial activity of the linear analogs

Human α-defensin 5 (HD5) exhibits broad spectrum antimicrobial activity and plays an important role in mucosal immunity of the small intestine. Although there have been several studies, the structural requirements for activity and mechanism of bacterial killing is yet to be established unequivocally. In this study, we have investigated the antimicrobial activity of HD5 and linear analogs. Cysteine deletions attenuated the antibacterial activity considerably. Candidacidal activity was affected to a lesser extent. Fatty acid conjugated linear analogs showed antimicrobial activity comparable activity to HD5. Effective surface charge neutralization of bacteria was observed for HD5 as compared to the non-fatty acylated linear analogs. Our results show that HD5 and non-fatty acylated linear analogs enter the bacterial cytoplasm without causing damage to the bacterial inner membrane. Although fatty acylated peptides exhibited antimicrobial activity comparable to HD5, their mechanism of action involved permeabilization of the Escherichia coli inner membrane. HD5 and analogs had the ability to bind plasmid DNA. HD5 had greater binding affinity to plasmid DNA as compared to the analogs. The three dimensional structure of HD5 favors greater interaction with the bacterial cell surface and also with DNA. Antibacterial activity of HD5 involves entry into bacterial cytoplasm and binding to DNA which would result in shut down of the bacterial metabolism leading to cell death. We show how a moderately active linear peptide derived from the α-defensin HD5 can be engineered to enhance antimicrobial activity almost comparable to the native peptide.     

Heterocyclic aminoparthenolide derivatives modulate G2-M cell cycle progression during Xenopus oocyte maturation

Aminoparthenolide derivatives have been prepared by reaction of parthenolide with various heterocyclic amines to afford corresponding Michael addition products. These novel compounds were evaluated for their modulatory effects on Xenopus oocyte maturation. Two compounds, 6e and 6f, were identified that promote G₂-M cell cycle progression.     

Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs

Parthenolide is a naturally occurring terpene with promising anticancer properties, particularly in the context of acute myeloid leukemia (AML). Optimization of this natural product has been challenged by limited opportunities for the late-stage functionalization of this molecule without affecting the pharmacologically important α-methylene-γ-lactone moiety. Here, we report the further development and application of a chemoenzymatic strategy to afford a series of new analogs of parthenolide functionalized at the aliphatic positions C9 and C14. Several of these compounds were determined to be able to kill leukemia cells and patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC₅₀ values in the low micromolar range. These studies demonstrate that different O–H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized analogs 22a and 25b were identified as the most interesting compounds in terms of antileukemic potency and selectivity toward AML versus healthy blood cells.     

Linear bactenecin analogs with cell selectivity and anti‐endotoxic activity

Bactenecin (Bac) is a 12‐residue disulfide‐linked antimicrobial peptide isolated from the granules of bovine neutrophils. In this study, to develop novel linear Bac analogs with cell selectivity and anti‐endotoxic activity, we designed and synthesized a series of linear Bac analogs with amino acid substitution in Cys^3,11 and/or Val^6,7 of Bac. Among Bac analogs, some analogs (Bac‐W, Bac‐KW, Bac‐L, Bac‐KL, Bac‐LW, and Bac‐KLW) with higher hydrophobicity showed the amalgamated property of cell selectivity and anti‐endotoxic activity. Furthermore, Bac‐W, Bac‐KW, Bac‐LW, and Bac‐KLW showed serum stability comparable with that of disulfide‐bonded Bac. Therefore, these Bac analogs (Bac‐W, Bac‐KW, Bac‐LW, and Bac‐KLW) can serve as promising antibiotics for the development of therapeutic agents for treatment against endotoxic shock and bacterial infection. In addition, our results suggest that a little increase in hydrophobicity may be responsible for the decreased cell selectivity of the multiple Arg‐containing peptides (Bac‐W, Bac‐L, and Bac‐LW) over the multiple Lys‐containing peptides (Bac‐KW, Bac‐KL, and Bac‐KLW). Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Pharmacological insight into the anti-inflammatory activity of sesquiterpene lactones from Neurolaena lobata (L.) R.Br. ex Cass

PurposeNeurolaena lobata is a Caribbean medicinal plant used for the treatment of several conditions including inflammation. Recent data regarding potent anti-inflammatory activity of the plant and isolated sesquiterpene lactones raised our interest in further pharmacological studies. The present work aimed at providing a mechanistic insight into the anti-inflammatory activity of N. lobata and eight isolated sesquiterpene lactones, as well as a structure–activity relationship and in vivo anti-inflammatory data.MethodsThe effect of the extract and its compounds on the generation of pro-inflammatory proteins was assessed in vitro in endothelial and monocytic cells by enzyme-linked immunosorbent assay. Their potential to modulate the expression of inflammatory genes was further studied at the mRNA level. In vivo anti-inflammatory activity of the chemically characterized extract was evaluated using carrageenan-induced paw edema model in rats.ResultsThe compounds and extract inhibited LPS- and TNF-α-induced upregulation of the pro-inflammatory molecules E-selectin and interleukin-8 in HUVECtert and THP-1 cells. LPS-induced elevation of mRNA encoding for E-selectin and interleukin-8 was also suppressed. Furthermore, the extract inhibited the development of acute inflammation in rats.ConclusionsSesquiterpene lactones from N. lobata interfered with the induction of inflammatory cell adhesion molecules and chemokines in cells stimulated with bacterial products and cytokines. Structure–activity analysis revealed the importance of the double bond at C-4–C-5 and C-2–C-3 and the acetyl group at C-9 for the anti-inflammatory activity. The effect was confirmed in vivo, which raises further interest in the therapeutic potential of the compounds for the treatment of inflammatory diseases.     

甜菜树属——我国云南产山柚子科一原始新属及其植物地理学意义

报道了产于我国云南红河流域山柚子科的一个原始新属——甜菜树属,该属具大型圆锥花序,两性,是Lepionurus, Melientha和Champereia 3个单型属的祖型,无疑起源于康滇古陆即今之云南高原,其发现对研究山柚子科的起源与分化具重要意义。     

Synthesis and antifungal activity of aromatic bis-gamma-lactones analogous to avenaciolide

Avenaciolide is a bis-gamma-lactone isolated from Aspergillus avenaceus and possesses antifungal activity. Here, we describe the total syntheses and characterization by elemental analyses, and IR and NMR spectroscopy of three new bis-gamma-lactones analogous to avenaciolide, where the octyl group of the natural product was replaced by aromatic groups. The effects of the avenaciolide, the novel compounds, and their synthetic precursors on the mycelia development and conidia germination of Colletotrichum gloeosporioides were evaluated in vitro. The new compounds were as active as avenaciolide in the tested conditions, while the synthetic precursors were inactive. The preparation and characterization of 15 new synthetic intermediates are also described.     

Anticancer activity profiling of parthenolide analogs generated via P450-mediated chemoenzymatic synthesis

The plant-derived sesquiterpene lactone parthenolide (PTL) was recently found to possess promising anticancer activity but elaboration of this natural product scaffold for optimization of its pharmacological properties has proven challenging via available chemical methods. In this work, P450-catalyzed C–H hydroxylation of positions C9 and C14 in PTL was coupled to carbamoylation chemistry to yield a panel of novel carbamate-based PTL analogs (‘parthenologs’). These compounds, along with a series of other C9- and C14-functionalized parthenologs obtained via O–H acylation, alkylation, and metal-catalyzed carbene insertion, were profiled for their cytotoxicity against a diverse panel of human cancer cell lines. These studies led to the discovery of several parthenologs with significantly improved anticancer activity (2–14-fold) compared to the parent molecule. Most interestingly, two PTL analogs with high cytotoxicity (LC₅₀ ～ 1–3 μM) against T cell leukemia (Jurkat), mantle cell lymphoma (JeKo-1), and adenocarcinoma (HeLa) cells as well as a carbamate derivative with potent activity (LC₅₀ = 0.6 μM) against neuroblastoma cells (SK-N-MC) were obtained. In addition, these analyses resulted in the identification of parthenologs featuring both a broad spectrum and tumor cell-specific anticancer activity profile, thus providing valuable probes for the future investigation of biomolecular targets that can affect cell viability across multiple as well as specific types of human cancers. Altogether, these results highlight the potential of P450-mediated chemoenzymatic C–H functionalization toward tuning and improving the anticancer activity of the natural product parthenolide.     

Chemical constituents from the roots of Elephantopus scaber L.

A chemical investigation of the roots of Elephantopus scaber L. led to the isolation of thirteen compounds, including four sesquiterpenoids (5, 6, 7, 8), two phenols (1, 2), three triterpenoids (9, 10, 11), two caffeoylquinic acids (3, 4), one alkaloid (12), and one sterol (13). Among these molecules, compound 2 (2-butenoic acid, 3-methyl-[4-(1,5-dimethyl-4-hexenyl)-3-hydroxyphenyl] methyl ester) was identified for the first time from this species, while compounds 1 (curcuphenol) and 12 (patriscabratine) were isolated for the first time from the genus Elephantopus.     

Cadinenes and other metabolites from Verbesina sphaerocephala A. Gray

The phytochemical study of the aerial parts of Verbesina sphaerocephala A. Gray afforded six sesquiterpene lactones of cadinene type, five of them described for the first time, along with known phenyl propanoids, terpenoids, and phenolic compounds. Structures on new compounds were elucidated by spectroscopic techniques including CD and X-ray analyses, and known compounds were identified by comparing their spectral data with those previously reported. Cadinene-like sesquiterpene lactones could be characteristic metabolites of V. sphaerocephala.