Synthetic Derivatives of Natural ent-Kaurane Atractyligenin Disclose Anticancer Properties in Colon Cancer Cells, Triggering Apoptotic Cell Demise.

The antitumor activity of different ent-kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19-di-oxo analogues obtained from atractyligenin by modifying the C-2, C-15, and C-19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10-300 µM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di-oxidized compounds were more effective than their alcoholic precursors. The di-oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco-2) at 24 h when used at low doses (2.5-15 µM), while they turned out to be poorly effective in differentiated Caco-2 cells, a model of polarized enterocytes. The data reported here provide evidence that di-oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase-3 and fragmentation of its target PARP-1.

The chemical composition of the aerial parts' essential oil of Geocaryum capillifolium (Guss.) Coss growing in Sicily (Italy).

The three genera Geocaryum Coss., Conopodium W.D.J. Koch, and Bunium L. are closely related, and their correct identification is complex. The first two genera are distributed in Europe and North Africa, while several Bunium species also occur in Asia. In the present study, we analysed the chemical composition of the essential oil of the aerial parts of Geocaryum capillifolium (Guss.) Coss. a rare species collected in Sicily, which also grows in the Iberian Peninsula, Algeria, and Greece, was analysed using GC-MS. The main constituents of the essential oil were sesquiterpene hydrocarbons involving cis-ß-farnesene (31.2%), trans-ß-caryophyllene (20.0%), and germacrene D (8.5%). The chemical profile of the essential oil presented here was compared with the oils of previously investigated Geocaryum, Conopodium, and Bunium taxa, as reported in the literature. To the best of our knowledge, no report has been previously published about the essential oil of the Sicilian accession of this species.

Centaurea polyacantha and C. maroccana: the chemical composition of the aerial parts essential oils of these Centaurea species (Asteraceae) collected in Morocco.

In the present study, the chemical composition of the essential oil from the aerial parts of two Centaurea species not previously investigated, C. polyacantha Willd. (sect. Seridia, Asteraceae) and C. maroccana Ball. (sect. Calcitrapa, Asteraceae), collected in Morocco, was evaluated by GC-MS. The main components of the essential oil of the first one were limonene (18.2%), ß-bisabolene (11.5%), (Z)-ß-farnesene (8.6%), and spathulenol (8.3%), whereas the C. maroccana essential oil, practically devoid of terpenoids, was shown to be rich in some unusual Centaurea metabolites: 1-hexadecanol (24.9%), docosane (23.7%), and 1-octadecanol (19.5%). Furthermore, a complete literature review on the composition of the essential oils of all the other taxa of Centaurea, belonging to sections Seridia and Calcitrapa, studied so far, was performed.

Chemical composition of the essential oil of Cyanus adscendens (Bartl.) Soják and C. orbelicus (Velen.) Soják growing wild in Bulgaria, and PCA analysis of genus Cyanus Mill.

Cyanus Mill. genus, belonging to the Asteraceae family, includes more than 50 taxa, mainly growing in Central and Southern Europe, North Africa, Asia Minor, and the Caucasus. Previous investigations on Cyanus taxa have shown that they are rich source of flavonoids and phenolic compounds but, differently from species of genus Centaurea, almost devoid of sesquiterpene lactones. In the present study, the chemical composition of the essential oils from aerial parts of Cyanus adscendens (CA) and C. orbelicus (CO), collected in Bulgaria, and not previously investigated, was evaluated by GC-MS. The main components of CA were α-bergamotene (31.3%), (Z,Z,Z)-9,12,15-octadecatrien-1-ol (14.5%) and calarenepoxide (11.0%). Caryophyllene oxide (12.0%), together with α-cadinol (10.9%) and spathulenol (8.8%), were recognized as the main constituent of C. orbelicus EO. Furthermore, a complete review on the composition of all essential oils of the Cyanus taxa studied so far has been inserted and cluster analysis (PCA) was carried out.

Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway.

Oleanolic acid (OA) and Lupeol (LU) belong to the class of natural triterpenes and are endowed with a wide range of biological activities, including cytotoxicity toward several cancer cell lines. In this context, we investigated a set of compounds obtained from the two natural precursors for the cytotoxicity against leukemia HL60 cells and the multidrug-resistant (MDR) variant HL60R. Six new semi-synthetic triterpenes have been synthetized, fully characterized, and were investigated together with other triterpenes compounds for their pharmacological mechanism of action. The interaction of the more cytotoxic compounds with the nuclear factor kappa B (NF-κB) pathway has been also evaluated with the aid of docking. The lupane-like compounds were more active than the precursor, while the oleane-like compounds showed more complex behavior. Both OA and LU derivatives possess a similar interaction pattern with the p65 subunit of NF-κB, justifying the similar trend in their ability to inhibit the binding of p65 to DNA. Further, some of the derivatives tested were able to increase IκB-α levels preventing the translocation of NF-κB to the nucleus. In conclusion, this study offers a deeper insight on the pharmacological action of triterpenes toward leukemia cells, and it improves the background useful for the development of new anti-cancer drugs.

The Chemistry and the Anti-Inflammatory Activity of Polymethoxyflavonoids from Citrus Genus.

Polymethoxyflavonoids (PMFs) are a large group of compounds belonging to the more general class of flavonoids that possess a flavan carbon framework decorated with a variable number of methoxy groups. Hydroxylated polymethoxyflavonoids (HPMFs), instead, are characterized by the presence of both hydroxyl and methoxy groups in their structural unities. Some of these compounds are the aglycone part in a glycoside structure in which the glycosidic linkage can involve the -OH at various positions. These compounds are particular to Citrus genus plants, especially in fruits, and they are present mainly in the peel. A considerable number of PMFs and HPMFs have shown promising biological activities and they are considered to be important nutraceuticals, responsible for some of the known beneficial effects on health associated with a regular consumption of Citrus fruits. Among their several actions on human health, it is notable that the relevant contribution in controlling the intracellular redox imbalance is associated with the inflammation processes. In this work, we aim to describe the status concerning the chemical identification and the anti-inflammatory activity of both PMFs and HPMFs. In particular, all of the chemical entities unambiguously identified by isolation and complete NMR analysis, and for which a biochemical evaluation on the pure compound was performed, are included in this paper.

Functional investigation and applications of the acetylesterase activity of the Citrus sinensis (L.) Osbeck peel.

The hydrolysis of acetyl moieties on a set of commercially relevant substrates was performed by employing the whole tissue of Citrus sinensis (L.) Osbeck peel as an efficient biocatalyst in mild reaction conditions with high degree of regioselectivity. The reaction is done in aqueous media and the product is easily recovered. Optimal reaction conditions were deduced and two practical applications were investigated: the elaboration of acetylglicerols and the preparation of vitamin K1 precursor. Peel waste (flavedo and albedo) from orange juice manufacturing was successfully employed as a biocatalyst.

A Review of the Phytochemistry, Traditional Uses and Biological Activities of the Essential Oils of Genus Teucrium.

The genus Teucrium is a large and polymorphic genus of the Lamiaceae family distributed in mild climate zones, particularly in the Mediterranean basin and Central Asia. Studies of nonvolatile constituents of Teucrium species showed that they are a rich source of neo-clerodane diterpenoids, considered as chemotaxonomic markers of the genus. In addition to the nonvolatile metabolites, there has been a large interest in the essential oils of this genus. In this review, a complete survey of the chemical composition and biological properties of the essential oils isolated from Teucrium taxa is provided. In traditional medicine, since ancient times, species of this genus have been widely implemented for their biological properties, including antimicrobial, anti-inflammatory, antispasmodic, insecticidal, anti-malaria, etc. Therefore, a complete review of all of the traditional uses of Teucrium taxa are also reported.

Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement.

Oleanolic and ursolic acids are two ubiquitous isomeric triterpene phytochemicals known for their anticancer activity. A set of derivatives of the two compounds with a modified oxidation state and lipophylicity at C-3 and C-28 positions, were prepared and tested as anticancer agents versus the lines HepG2, Hep3B and HA22T/VGH of hepatocarcinoma, a strongly aggressive tumor that is not responsive toward the standard therapies. New derivatives containing a three carbons side chain on the C-3 position were synthetized in both stereoisomeric forms by the Barbier-Grignard procedure and three of them were found to be active toward all of the three targets. The implication of the transcriptional nuclear factor NF-κB in the mechanism of action was assessed for the more active compounds in the set, as hepatocellular carcinoma (HCC) cyto-types are known to overexpress NF-κB.

A Review of the Phytochemistry, Traditional Uses, and Biological Activities of the Genus Ballota and Otostegia.

The 2 genera Ballota and Otostegia, belonging to the Lamiaceae family, are closely related taxonomically and found mainly in the Mediterranean area, Middle East, and North Africa. Since ancient times, they have been largely employed in traditional medicine for their biological properties such as antimicrobial, anti-inflammatory, antispasmodic, insecticidal, anti-malaria, etc. Phytochemical investigations of Ballota and Otostegia species have revealed that diterpenoids are the main constituents of the genera. A large number of flavonoids and other metabolites were also identified. This review, covering literature from 1911 up to 2018, includes traditional uses, chemical profiles (both of volatile and nonvolatile metabolites), and biological properties of all the taxa of these 2 genera studied to date.

Volatile constituents of aerial parts of two Mediterranean species of Inula: Inula crithmoides L. and I. verbascifolia (Willd.) Hausskn. (Asteraceae).

Inula crithmoides L. grows along the Mediterranean coasts and is used as an edible vegetable as the young leaves or shoots are eaten raw, cooked or pickled. Inula verbascifolia (Willd.) Hausskn. is a quite localised species growing mainly along the Adriatic Sea coasts. In this study the volatile components of the aerial part of both species are described. Gas chromatography and gas chromatography mass spectrometry analysis showed the presence of 41 components in I.crithmoides and 75 compounds in I.verbascifolia, respectively, and a very different profile in the composition of the two species. The chemotaxonomy of I. crithmoides, by comparison with other data reported in the literature, is discussed.

Synthetic studies on neoclerodane diterpenes from Salvia splendens: oxidative modifications of ring A.

Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known naturally occurring non-nitrogenous and specific κ-opioid agonist. Some oxidative modifications of the A ring in the congeners of 1 isolated from Salvia splendens salviarin, splenolide B, splendidin and in the non-natural 8-epi-salviarin gave new derivatives, some of which were tested as agonists at opioid receptors. However, none of these compounds were active. The presence of the C-18, C-19 lactone could be at the origin of the observed lack of binding affinity.

Synthetic studies of neoclerodane diterpenoids from Salvia splendens and evaluation of Opioid Receptor affinity.

Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific kappa-opioid agonist. Several structural congeners of 1 isolated from Salvia splendens (2 - 8) together with a series of semisynthetic derivatives (9 - 24), some of which possess a pyrazoline structural moiety (9, 19 - 22), have been tested for affinity at human mu, delta, and kappa opioid receptors. None of these compounds showed high affinity binding to these receptors. However, 10 showed modest affinity for kappa receptors suggesting other naturally neoclerodanes from different Salvia species may possess opioid affinity.

Sesquiterpene compounds from Inula viscosa.

Two new compounds, 2,5-dihydroxyisocostic acid and 2,3-dihydroxycostic acid together with three known sesquiterpene compounds, Isocostic acid, Carabrone and Tomentosin, have been isolated from the acetone extract of Inula viscosa (L.) Aiton. The structures of all new compounds were determined by spectroscopic methods, in particular 1D and 2D (1)H- and (13)C-NMR. The (13)C-NMR spectra of Isocostic acid and of Tomentosin are reported here for the first time.

Clerodane diterpenoids from Salvia splendens.

Four new clerodane diterpenoids, salvisplendins A-D (1-4), have been isolated from an acetone extract of the flowers of Salvia splendens, together with an artifact (5), arising from salvisplendin D (4) by addition of diazomethane, and the already known clerodane olearin (6). The structures of the new compounds (1-5) were established mainly by 1D and 2D NMR spectroscopic studies and, in the case of salvisplendin A (1), by chemical correlation with splenolide B (7). Complete 1H and 13C NMR assignments for olearin (6), not published hitherto, are also reported.

Benzyl ions from 1,1-(2,2'-dimethoxyphenyl)-substituted 2-methylpropanes under electron ionization.

The electron ionization (EI)-induced fragmentations of a series of 1,1-(2,2'-dimethoxyphenyl)-substituted 2-methylpropanes (1-20) in both 70 eV and mass-analyzed ion kinetic energy (MIKE) spectra have been investigated. The EI-MS spectra of these compounds are characterized by the presence of abundant benzyl ions. These ions result from competitive hydrogen migration from the 2- and 2'-methoxy groups on the carbenium center of the diphenylmethyl cations formed by benzylic cleavage of the molecular ions. The relative abundances of the benzyl ions arising from such competitive processes are discussed and rationalized. The steric effect of the 3- or 3'-substituents is the main discriminating factor between the two competitive processes. The structural information, arising either from the 70 eV or the MIKE spectra, is discussed.

Complete 1H and 13C NMR assignments of clerodane diterpenoids of Salvia splendens.

Unambiguous and complete assignments of 1H and 13C NMR chemical shifts for five clerodane diterpenes, four of them isolated from Salvia splendens (salviarin, splendidin and splenolides A and B) and one obtained by acetylation of splenolide A, are presented. The assignments are based on 2D shift-correlated [1H,1H-COSY, 1H,13C-gHSQC-1J(C,H) and 1H,13C-gHMBC-nJ(C,H) (n=2 and 3)] and nuclear Overhauser effect (NOE) experiments. The conformation of the rings of these compounds is supported by the 3J(H,H) values and NOE results.

Investigation of the aqueous transmetalation of pi-allylpalladium with indium salt: the use of the Pd(OAc)2-TPPTS catalyst.

pi-Allylpalladium complexes could be generated in water by the palladium(0) water soluble catalyst prepared in situ from palladium acetate and TPPTS. These complexes were transmetalated with indium to react with benzaldehyde. The aqueous solution of Pd(0)(TPPTS)(n) could be reused without deterioration of the catalyst in the first and second recycling. The system proved to be efficient with primary and secondary allylic substrates. The stereochemical outcome of the allylation through umpolung of allylpalladium, was also studied using models with a restraint conformation.