Synthesis and antimicrobial activities of some sulphur containing chromene derivatives.

A series of 3,3-dimethyl-3Hbenzothieno[3,2-f][1]-benzopyran analogues modified at the pyran 1,2-double bond were synthesized. The corresponding dihydro and (+/-)-cis-diol derivatives were converted into diacetate and cyclic carbonate upon acylation. The title compounds were characterized by spectroscopic analysis and screened for their antimicrobial activity in vitro.

Solvent/base effects in the selective domino synthesis of phenanthridinones that involves high-valent palladium species: experimental and theoretical studies.

The domino reaction of o-bromobenzamides 1a-m in the presence of K(2)CO(3) and the [PdCl(2)(PPh(3))(2)] catalyst granted a selective access to phenanthridinones 2 or to the new 1-carboxamide phenanthridinones 3 depending on the solvent, DMF or 1,4-dioxane, respectively. Investigations of the reaction parameters provided the first example of a direct correlation between the base dissociation and the solvent polarity on the selectivity observed. Moreover, mechanistic studies (NMR spectroscopy and ESI-MS monitoring) allowed us to characterize Pd(II) palladacycle 4 and biaryl species as common intermediates for these two domino processes. On that basis, C(sp(2))-C(sp(2)) bond formation is envisaged by generation of a Pd(IV) complex after oxidative addition of 1 into Pd(II) palladacycle 4, a rationale that is supported by DFT calculations. A general catalytic cycle is proposed to account for these observations.

Quercetin and kaempferol 3-O-[α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside]-7-O-α-L-rhamnopyranosides from Anthyllis hermanniae: structure determination and conformational studies.

The study reports the isolation and structural identification of two new flavonol triglycosides from the methanolic extract of Anthyllis hermanniae, exhibiting the same glycosylation pattern: quercetin 3-O-[α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside]-7-O-α-L-rhamnopyranoside (1) and kaempferol 3-O-[α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside]-7-O-α-L-rhamnopyranoside (2). A conformational study related to the central arabinoside moiety was carried out including the analysis of the contribution of NOE effects and acetylation to the elucidation of the 2-O-linked arabinoside configuration of the anomeric carbon. We also report the total synthesis of a model compound, quercetin 3-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside (3), which verifies the structures of the isolated compounds.

Synthesis and biological evaluation of N-substituted benzo[c]phenanthrolines and benzo[c]phenanthrolinones as antiproliferative agents.

Benzo[c]phenanthrolines and benzo[c]phenanthrolinones substituted by dialkylaminoalkyl side chains at position N5 and C6, respectively, were synthesised and their biological activity evaluated. They displayed interessant cytotoxicity associated with some DNA interactions. However, the low topoisomerase 1 affinity suggests that other cellular targets are responsible for the antiproliferative activity.

Synthesis and cytotoxic activity of benzo[a]acronycine and benzo[b]acronycine substituted on the A ring.

The impact of substitutions at position 10 in the A ring of the cytotoxic benzo[a]acronycine and benzo[b]acronycine series has been explored. 10-Bromobenzo[a] and 10-bromobenzo[b]acronycine were prepared in 12% and 15% yield respectively from commercially available chemicals. Their 1,2-dihydro-1,2-dihydroxy diesters were synthesized. The different derivatives were tested against two cell lines KB-3-1 and L1210. Their cytotoxic activities were found in the same range of magnitude as their non-substituted counterparts. These structure-activity relationships permitted to conclude that the introduction of a substituent at position 10 maintains the activity in both the benzo[a] and [b]acronycine series and open the way to further pharmacomodulations.

Chemical composition and antimicrobial activity of the essential oils of Anthospermum emirnense and Anthospermum perrieri (Rubiaceae).

The essential oils of Anthospermum emirnense Baker and Anthospermum perrieri Homolle ex Puff, obtained by hydrodistillation in 0.03 and 0.02% yield, respectively, were analyzed by GC/MS. In both cases, the major constituents consisted of sesquiterpene hydrocarbons and oxygenated sesquiterpenes. The two species showed an important qualitative similarity, with 40 compounds common to A. emirnense and A. perrieri, including ß-elemene, trans-ß-caryophyllene, caryophyllene oxide, and τ-cadinol, which were major components in both cases. When tested for antimicrobial activity, both essential oils showed similar profiles and exhibited interesting minimal-inhibitory-concentration (MIC) values towards Bacillus subtilis, Chryseobacterium indologenes, Flavimonas oryzihabitans, and Yersinia enterocolitica.

Synthesis, biological activity, and evaluation of the mode of action of novel antitubercular benzofurobenzopyrans substituted on A ring.

The 8-, 9-, 10-, and 11-halo, hydroxy, and methoxy derivatives of the antimycobacterial 3,3-dimethyl-3H-benzofuro[3,2-f][1]benzopyran were synthesized by condensation of the diazonium salts of 2-chloroanilines (13-17) with 1,4-benzoquinone (18), reduction of the intermediate phenylbenzoquinones 19-22 to dihydroxybiphenyls, cyclisation to halo-2-hydroxydibenzofurans 24-27, and construction of the pyran ring by thermal rearrangement of the corresponding dimethylpropargyl ethers 35-38. Palladium catalyzed nucleophilic aromatic substitution permitted conversion of the halo to the corresponding hydroxy derivatives which were methylated to methoxy-3,3-dimethyl-3H-benzofuro[3,2-f][1]benzopyran. All compounds substituted on the A ring were found more potent than the reference compound 1 against Mycobacterium bovis BCG and the virulent strain Mycobacterium tuberculosis H37Rv. The effect of the most active derivatives on mycolate synthesis was explored in order to confirm the preliminary hypothesis of an effect on mycobacterial cell wall biosynthesis. The linear 9-methoxy-2,2-dimethyl-2H-benzofuro[2,3-g][1]benzopyran (46) exhibiting a good antimycobacterial activity and devoid of cytotoxicity appeared to be the most promising compound.

Antimicrobial activity of the methanolic extract and compounds from the stem bark of Drypetes tessmanniana.

OBJECTIVE: To evaluate the antimicrobial activity of the methanol extract from the stem bark of Drypetes tessmanniana, fractions (DTB1-5) as well as compounds [friedelin (2), 3,7-dioxofriedelane (3), 3,15-dioxofriedelane (4), 3beta- O-(E)-3,5-dihydroxycinnamoyl-11-oxo-olean-12-ene (6), and 3beta,6alpha-dihydroxylup-20(29)-ene (7). METHODS: Agar disc diffusion was used to determine the sensitivity of the above samples, whilst the microdilution method was used for the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentrations (MMC). RESULTS: The diffusion test showed that the crude extract was able to prevent the growth of all tested organisms. All other samples showed selective activity. The inhibitory effect of the fraction DTB2 was noted on 63.7%, that of DTB1 and DBT3 on 54.6%, whilst DTB4 and DTB5 were active on 9.1% of the 11 tested organisms. The tested compounds prevented the growth of 81.8% of the tested microbial species for compounds 3 and 4, 36.7% for compound 6, and 18.2% for compound 7. The results of the MIC determinations indicated perceptible values for DTB and compound 4 on 81.8% of the tested organisms. For other samples, MICs were detected on 0-63.7%. The lowest MIC value (78.12 microg/mL) for the crude extract and fractions (DTB2) was observed on M. audouinii. The corresponding value for isolated compounds (156.25 microg/mL) was noted with compounds 3 on S. faecalis and 4 on M. audouinii audouinii. The results of the MMC determination suggested that the microbicidal effect of most of the tested samples on the studied microorganisms could be expected. CONCLUSION: The methanol extract from the stem bark of Drypetes. tessmanniana (Euphorbiaceae) as well as some of the isolated compounds might be potential sources of new antimicrobial drugs.

Structure-activity relationships of indole compounds derived from combretastatin A4: synthesis and biological screening of 5-phenylpyrrolo[3,4-a]carbazole-1,3-diones as potential antivascular agents.

A series of 5-(3',4',5'-trimethoxyphenyl)pyrrolo[3,4-a]carbazole-1,3(2H,10H)-diones was designed as cis-restricted analogues of 3-aroylindoles, arylthioindoles and 3-benzylidoneindolin-2-ones derived from combretastatin A4 (CA-4). Starting from various indoles, compounds were synthesized by means of a convenient two-step procedure involving a one-pot multicomponent reaction as key step. Intermediate tetrahydro[3,4-a]carbazoles and their corresponding carbazoles were submitted to biological screening tests involved in antivascular action, including the cytotoxicity against murine B16 melanoma cells, the rounding up of endothelial cells (EA.hy 926) and the inhibition of tubulin polymerization. Of the 31 compounds screened, those bearing a methoxy group at the 8-position endowed significant biological activities. A carbazole compound 30 was identified as a promising candidate for further development of novel vascular targeting agents.

Synthesis and biological evaluation of dialkylaminoalkylamino benzo[c][1,7] and [1,8]phenanthrolines as antiproliferative agents.

Benzo[c][1,7] and [1,8]phenanthroline substituted by dialkylaminoalkyl side chains at position C2 and C1, respectively, were synthesized and their biological activity evaluated. These compounds displayed more potent cytotoxicity toward L1210 cells than the parent unsubstituted compounds, associated with strong DNA interaction. The moderate TopoI inhibitory activity induced by the novel compounds suggests that other cellular targets should be responsible for the antiproliferative activity.

A novel series of cytotoxic iridoid glucosides derived from aucubin: design, synthesis and structure-activity relationships.

Five new unsaturated iridolactones 3-7 related to natural cytotoxic oxylipins, Tei 9826, and iridolactone 2, were prepared by parallel synthesis from natural aucubin. It was found that perpivaloyl iridoid glucosides 2, 3, and 4 were markedly cytotoxic against both L1210 and KB-3-1 cell lines.

The synthesis and angiotensin converting enzyme (ACE) inhibitory activity of chalcones and their pyrazole derivatives.

A series of chalcones (1-9) and pyrazoles (10-18) was prepared to investigate their potential activity as Angiotensin I-Converting Enzyme (ACE) inhibitors. Their structures were verified by elemental analysis, UV, IR, MS, (1)H NMR, (13)C NMR, and 2D NMR experiments. Among tested compounds, chalcone 7 exerted the highest activity with an IC(50) value of 0.219 mM, while the most potent pyrazole was 15 (IC(50) value of 0.213 mM).

Two new peltogynoids from Acacia nilotica Delile with kinase inhibitory activity.

Two new peltogynoids, acanilol (1) and acanilol B (2), were isolated from the stem bark of Acacia nilotica (L.) Delile, together with the known triterpene lupenone. The structures of the new compounds were established on the basis of their spectral data, mainly UV, NMR, and mass spectrometry. The new compounds were tested as kinase inhibitors against CDK1, GSK3, CK1, and DYRK1A, and acanilol B was identified as a DYRK1A inhibitor, with an IC(50) of 19 microM.

Synthesis and cytotoxic activity of psorospermin and acronycine analogues in the 3-propyloxy-acridin-9(10H)-one and -benzo[b]acridin-125H-one series.

In order to explore the structure-activity relationships in the acronycine and psorospermin series, simplified analogues of the highly cytotoxic (+/-)-(2R*,1'R*)-5-methoxy-11-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-11H-furo[2,3-c]acridin-6-one and (+/-)-(2R*,1'R*)-5-methoxy-13-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-13H-benzo[b]furo[3,2-h]-acridin-6-one lacking the fused furan ring, including 3-allyloxy-1-methoxy-10-methyl-acridin-9(10H)-one, 3-allyloxy-1-methoxy-5-methyl-benzo[b]acridin-12(5H)-one, the corresponding epoxides, and related dihydrodiol esters and diesters were prepared. Only the simplified oxirane compounds displayed significant antiproliferative activity compared to the parent compounds. The oxirane alkylating unit appears indispensible to observe significant antiproliferative activity in both series, but the presence of the angularly fused furan ring does not appear as a crucial structural requirement to observe significant cytotoxic activity.

Selective unusual Pd-mediated biaryl coupling reactions: solvent effects with carbonate bases.

A one-step Pd-catalyzed reaction performed on an o-bromobenzamide permitted the selective formation of either phenanthridinones 2 via an ipso substitution or new phenanthridinone-1-carboxamides 3 through a direct N-arylation. A direct correlation between the solvent polarity and the carbonate base on the selectivity has been observed. The proposed catalytic cycle involves the initial formation of a common intermediate and depends on the base assistance.

[Trehala, a meeting point between zoology, botany, chemistry, and biochemistry]. / Le Tréhala, une drogue a la croisée des chemins.

Trehala is a crude drug consisting of the pupal chambers formed by insects belonging to the genus Larinus that live on several Echinops species of the Middle-East. This sweet cocoon is locally used as human food and also for the treatment of cough and various pulmonary diseases. It first appeared in Western Europe in the collection of drugs from the Ottoman Empire displayed by François Della Sudda during the International Exhibition held in Paris in 1855. On the basis of this sample Nicolas Guibourt (1790-1867) gave, in 1858, the first full scientific description of the drug, its origin, and Larinus nidificans as the main insect species responsible for its formation. Marcellin Berthelot (1827-1907) isolated in the same year the sugar trehalose from the drug and gave a full account of its physical and chemical properties. In 1876, Müntz established that trehalose was identical with mycose isolated from Claviceps purpurea by Mitscherlich.

New friedelane triterpenoids with antimicrobial activity from the stems of Drypetes paxii.

Two new friedelane-type triterpenes named 12alpha-hydroxyfriedelane-3,15-dione and 3beta-hydroxyfriedelan-25-al, together with six known compounds were isolated from the stems of Drypetes paxii Hutch. (Euphorbiaceae). Their structures were established on the basis of conventional 1 dimensional (1D) NMR methods, 2D shift-correlated NMR experiments and mass spectra. The five friedelane-type triterpene derivatives and one olean-12-ene triterpene saponin were tested for antimicrobial activity against some gram-positive and gram-negative bacteria, and they appeared to be modestly active.

Influence of the stereoisomeric position of the reactive acetate groups of the benzo[b]acronycine derivative S23906-1 on its DNA alkylation, helix-opening, cytotoxic, and antitumor activities.

S23906-1 is a benzo[b]acronycine derivative acting as a DNA-alkylating agent through covalent bonding to the exocyclic amino group of guanines and subsequent local opening of the DNA helix. This compound was selected for phase I clinical trials based on its efficient antitumor activity in experimental models and its unique mode of action. S23906-1 is the racemate of cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. Here, we evaluated the cytotoxic and antitumor activities of the two pure cis-enantiomers and investigated the mechanism of action of both cis- and trans-racemates and their enantiomers in terms of DNA alkylation potency and locally drug-induced DNA helix opening process. Reaction with glutathione, as a detoxification process, was also studied. The trans-compounds, both as racemate or separated enantiomers, were found less potent than the corresponding cis-derivatives. Among the cis-enantiomers, the most efficient one regarding DNA alkylation bears the acetate on the reactive C1 position in the R configuration, both on purified DNA and genomic DNA extracted from cell cultures. By contrast, the most cytotoxic and tumor-active enantiomer bears the C1-acetate in the S configuration. Distinct cellular DNA-alkylation levels or covalent bonding to glutathione could not explain the differences. However, we showed that the S and R orientations of the acetate on C1 asymmetric carbon lead to different local opening of the DNA, as visualized using nuclease S1 mapping. These different interactions could lead to modulated DNA-repair, protein/DNA interaction, and apoptosis processes.

Cytotoxic activity of Brazilian Cerrado plants used in traditional medicine against cancer cell lines.

UNLABELLED: The search for new anti-cancer drugs is one of the most prominent research areas of natural products. Numerous active compounds isolated from Brazilian Cerrado plant species have been studied with promising results. AIM OF THE STUDY: To investigate the cytotoxic potential of 412 extracts from Brazilian Cerrado plants used in traditional medicine belonging to 21 families against tumor cell lines in culture. MATERIAL AND METHOD: Maceration of 50 plant species resulted in 412 hexane, dichloromethane, ethanol and hydroalcohol extracts. The cytotoxicity of the extracts was tested against human colon carcinoma (HCT-8), melanoma (MDA-MB-435), and brain (SF-295) tumor cell lines, using the thiazolyl blue test (MTT) assay. Bioassay-guided fractionation was performed for one active extract. RESULTS AND CONCLUSIONS: Twenty-eight of the 412 tested extracts demonstrated a substantial antiproliferative effect, at least 85% inhibition of cell proliferation at 50 microg/mL against one or more cell lines. Those extracts are obtained from different parts of Anacardiaceae, Annonaceae, Apocynaceae, Clusiaceae, Flacourtiaceae, Sapindaceae, Sapotaceae, Simaroubaceae and Zingiberaceae. Complete dose-response curves were generated and IC(50) values were calculated for these active extracts against four cell lines HCT-8, MDA-MB-435, SF-295 and HL-60 (leukemia), and their direct cytotoxic effects were determined. In summary, 14 extracts of 13 species showed toxicity in all tested tumor cell lines, with IC(50) values ranging from 0.1 to 19.1 microg/mL. The strongest cytotoxic activity was found for the hexane extract of Casearia sylvestris var. lingua stem bark, with an IC(50) of 0.1 microg/mL for HCT-8, 0.9 microg/mL for SF-295, 1.2 microg/mL for MDA-MB-435, and 1.3 microg/mL for HL-60, and Simarouba versicolor root bark, with an IC(50) of 0.5 microg/mL for HCT-8, 0.7 microg/mL for SF-295, 1.5 microg/mL for MDA-MB-435, 1.1 microg/mL for HL-60. Bioassay-guided fractionation of the last extract led to the isolation of glaucarubinone, which showed pronounced activity against the four cell lines studied. Further studies of the active extracts are necessary for chemical characterization of the active compounds and more extensive biological evaluations.

Cytotoxic activity and inhibitory effect on nitric oxide production of triterpene saponins from the roots of Physospermum verticillatum (Waldst & Kit) (Apiaceae).

Three triterpene saponins isolated from the roots of Physospermum verticillatum and identified as saikosaponin a (1), buddlejasaponin IV (2), and songarosaponin D (3) were investigated in vitro for their cytotoxic activity against a panel of seven different cancer cell lines including ACHN, C32, Caco-2, COR-L23, A375, A549, and Huh-7D12 cell lines. The hydrolysis of sugar unit was performed on saikosaponin a (1) to obtain saikosapogenin a (4). All isolated saponins exhibited strong cytotoxic activity against COR-L23 cell line with IC(50) values ranged from 0.4 to 0.6 microM. A similar activity was recorded for saikogenin a (4). None of the tested compounds affected the proliferation of skin fibroblasts 142BR suggesting a selective action against cancer cells. Moreover, buddlejasaponin IV (2) and songarosaponin D (3) exerted significant inhibition of NO production in LPS induced RAW 264.7 macrophages with IC(50) of 4.2 and 10.4 microM, respectively.