François Tillequin

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.

A new synthetic access to furo[3,2-f]chromene analogues of an antimycobacterial

From the structure of 3,3-dimethyl-3H-benzofuro[3,2-f][1]-benzopyran, a selective in vitro inhibitor of mycobacterial growth, we have undertaken a structure-activity relationship investigation. We wish to report here our results on the use of [2+3] cycloadditions between 2-formylbenzoquinone and various enol derivatives to give various 4-formyl-5-hydroxy benzofurans. In the next step, an ytterbium triflate-catalysed reaction with 2-methylpropene allowed the preparation of various original furo[3,2-f]chromenes derivatives. Their biological evaluation on the growth of Mycobacterium smegmatis as well as Mycobacterium tuberculosis pointed out that some analogues were four times more active than the initial hit.

Isolation and antibacterial activity of phenylpropanoid derivatives from Ballota nigra

In addition to the previously isolated phenylpropanoid glycosides verbascoside 1, forsythoside B 2, arenarioside 3 and ballotetroside 4, another four compounds were isolated from generative aerial parts of Ballota nigra: three phenylpropanoid glycosides, alyssonoside 5, lavandulifolioside 6 and angoroside A 7 and a non-glycosidic derivative (+)-(E)-caffeoyl-L-malic acid 8. The antibacterial activity of the five major compounds (1-4 and 8) was tested against gram-positive and gram-negative bacteria. Three of them (1-3) exhibited a moderate antimicrobial activity against Proteus mirabilis and Staphylococcus aureus including one methicillin-resistant strain.

Design of selectively activated anticancer prodrugs: elimination and cyclization strategies.

Cancer chemotherapy is associated with severe side effects which may be reduced by selective liberation, at the tumour site, of a cytotoxic agent from a non-toxic prodrug. Several strategies are used to achieve the required selective activation: with enzymes which are present in higher concentration in, or close, to the tumour (beta-glucuronidase, plasmin), with enzymes covalently linked to a macromolecular carrier able to recognize antigen positive cancer cells (ADEPT: Antibody Directed Enzyme Prodrug Therapy) or with reductive processes which are favoured in an hypoxic environment. Most of the prodrugs include a linker (or spacer) between the trigger and the drug (or effector). The design of such linkers is crucial in order to achieve a fast drug liberation under physiological conditions. The linker groups may be classified in two categories based on elimination or cyclization processes. The advantages and the limitations of each strategy are discussed.

Diversity-oriented synthesis of furo[3,2-f]chromanes with antimycobacterial activity

We previously reported the synthesis and the antimycobacterial activity of 4-(7,7-dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridine. From this result, we sought to design simple synthetic accesses to related structures allowing the preparation of a diverse set of analogues. Two approaches were investigated. From 3-(2-bromo-7,7-dimethyl-8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)propyl acetate, we prepared 2-arylated derivatives via Suzuki-Miyaura reactions between this bromine-bearing compound and various arylboronates. Moreover, and even more simple, we prepared the ((6-hydroxy-2,2,7,8-tetramethylchroman-5-yl)methyl)triphenylphosphonium salt via a selective bromination of 2,2,5,7,8-pentamethylchroman-6-ol. From this salt, a two stage Wittig reaction with an array of activated acids allowed the quick preparation of many analogues. The biological evaluation of the effect of these compounds on the growth of Mycobacterium bovis as well as Mycobacterium tuberculosis pointed out a fourfold improvement of the antimycobacterial properties for one of the compounds made. However, the many analogues which inhibited the growth of M. tuberculosis in the 0.6-5 microg/mL range turned out to be also cytotoxic on VERO cells growth at the same concentration range.

Biological Potential and Structure-Activity Relationships of Most Recently Developed Vascular Disrupting Agents: An Overview of New Derivatives of Natural Combretastatin A-4

Tumor blood vessels are an important emerging target for anti-cancer therapy. The antimitotic agent combretastatin A-4 (CA-4), a cis-stilbene natural product isolated from the South African tree Combretum caffrum Kuntze, is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. CA-4 inhibits tubulin polymerization by interacting at the colchicine binding site on tubulin. This alters the morphology of endothelial cells and causes vascular shutdown and regression of tumor vasculature. Some tubulin-binding vascular-disrupting agents (VDAs) are currently in clinical trials for cancer therapy. As a consequence of the potential favorable applications of these compounds, several analogs projected to induce rapid and selective vascular shutdown in tumors have been synthesized during the last few years. Many of these molecules have already been tested for their effects on tubulin polymerization as well as for their antiproliferative activity and other biological properties, and possible mechanisms of action have been investigated. The aim of the present review is to offer an overview of most recently developed combretastatin derivatives, focusing on biological effects exerted by these compounds. The published data about new analogs are presented and compared, and a detailed investigation of structure-activity relationships is described.

Phenylpropanoids from Ballota nigra L. inhibit in vitro LDL peroxidation.

From the European plant Ballota nigra L. various polyphenols including phenylpropanoid derivatives were isolated. There is increasing evidence that oxidized low‐density lipoproteins (Ox‐LDL) might be involved in the pathogenesis of atherosclerosis and it has been reported that polyphenols inhibit LDL peroxidation and atherogenesis. The goal of this study was to test whether the major polyphenolic compounds extracted from Ballota nigra, four phenylpropanoid glycosides, verbascoside, forsythoside B, arenarioside, and ballotetroside and one non‐glycosidic phenylpropanoid, caffeoyl‐L‐malic acid, inhibit Cu2+‐induced LDL peroxidation. The effectiveness of these compounds was compared to the activity of quercetin, a well‐known polyphenol inhibitor of Cu2+‐induced LDL oxidation. Antioxidant efficacious doses (ED 50) of arenarioside and ballotetroside were 1.8 µM and 7.5 µM respectively, while in the same conditions, the ED 50 of forsythoside B and verbascoside were similar (1 µM) and those of quercetin and of caffeoyl‐L‐malic acid were 2.3 µM and 9.5 µM respectively.

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).

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.

Prenylated isoflavonoids from Erythrina sensegalensis

Abstract Two novel prenylated isoflavonoids, 3,5,4′-trihydroxy-8-(γ,γ-dimethylallyl)-2″, 2″-dimethylpyrano [5″,6″:6,7]coumaronochromone and 5,2′,4′-trihydroxy-8-(γ,γ-dimethylallyl)furano [4″,5″:6,7] isoflavone, have been isolated from the stem bark of the Cameroonian medicinal plant, Erythrina senegalensis , in addition to five known pentacyclic triterpenes, β-amyrin, maniladiol, erythrodiol, oleanolic acid and cornulacic acid. Their structures were determined by spectroscopic methods.