Madalena Pedro

Xanthones as inhibitors of growth of human cancer cell lines and Their effects on the proliferation of human lymphocytes In Vitro

Twenty-seven oxygenated xanthones have been assessed for their capacity to inhibit in vitro the growth of three human cancer cell lines, MCF-7 (breast cancer), TK-10 (renal cancer) and UACC-62 (melanoma). The effect of these xanthones on the proliferation of human T-lymphocytes was also evaluated. Differences on their potency towards the effect on the growth of the human cancer cell lines as well as on the proliferation of human T-lymphocytes can be ascribed to the nature and positions of the substituents on the xanthonic nucleus.

Catechols from abietic acid synthesis and evaluation as bioactive compounds.

Catechols from abietic acid were prepared by a short and good yielding chemical process and further evaluated for several biological activities namely, antifungal, antitumoral, antimutagenic, antiviral, antiproliferative and inhibition of nitric oxide. Their properties were compared with those of carnosic acid (6), a naturally occurring catechol with an abietane skeleton and known to possess potent antioxidant activity, as well as anticancer and antiviral properties. From all the synthetic catechols tested compound 2 showed the best activities, stronger than carnosic acid.

Isomeric Kielcorins and Dihydroxyxanthones: Synthesis, Structure Elucidation, and Inhibitory Activities of Growth of Human Cancer Cell Lines and on the Proliferation of Human Lymphocytes In Vitro

The synthesis, structure elucidation, and biological activities of five isomeric xanthonolignoids, (±)-trans-kielcorin C, (±)-cis-kielcorin C, (±)-trans-kielcorin D, (±)-trans-isokielcorin D, and (±)-trans-kielcorin E, are reported. The synthetic approach is based on the oxidative coupling of coniferyl alcohol with an appropriate xanthone. The influence of different oxidizing agents was studied, and the best results were obtained with potassium hexacyanoferrate(III). The structure elucidation was achieved by 2D-NMR techniques such as COSY, HETCOR, HSQC, and HMBC. Long-range C,H connectivities were used to establish the orientation of the substituents on the 1,4-dioxine rings, while NOE experiments were used to determine the configurations of these rings. These xanthonolignoids, as well as (±)-trans-kielcorin, (±)-trans-kielcorin B, (±)-trans-isokielcorin B, and the xanthonic building blocks 3,4-, 1,2-, and 2,3-dihydroxy-9H-xanthen-9-ones, and 2,3-dihydroxy-4-methoxy-9H-xanthen-9-one, were evaluated for their in vitro effect on the growth of three human cancer cell lines, MCF-7 (breast), TK-10 (renal), and UACC-62 (melanoma), and on the proliferation of human lymphocytes.

Multidimensional optimization of promising antitumor xanthone derivatives.

A promising antitumor xanthone derivative was optimized following a multidimensional approach that involved the synthesis of 17 analogues, the study of their lipophilicity and solubility, and the evaluation of their growth inhibitory activity on four human tumor cell lines. A new synthetic route for the hit xanthone derivative was also developed and applied for the synthesis of its analogues. Among the used cell lines, the HL-60 showed to be in general more sensitive to the compounds tested, with the most potent compound having a GI50 of 5.1 μM, lower than the hit compound. Lipophilicity was evaluated by the partition coefficient (K(p)) of a solute between buffer and two membrane models, namely liposomes and micelles. The compounds showed a logK(p) between 3 and 5 and the two membrane models showed a good correlation (r(2)=0.916) between each other. Studies concerning relationship between solubility and structure were developed for the hit compound and 5 of its analogues.

Effect of Natural 2,5-Diaryl-3,4-dimethyltetrahydrofuran Lignans on Complement Activation, Lymphocyte Proliferation, and Growth of Tumor Cell Lines

(+)-Machillin F, isolated from the bark of Persea membranacea, Kosterm and four other 2,5-diaryl-3,4-dimethyltetrahydrofuran-type lignans from Talauma hodgsonii Hook, F. & Thoms., (−)-galbacin, (−)-talaumidin, (−)-talaumidin methyl ether, and acetyl talaumidin, were evaluated for their influence on the classical and alternative pathways of activation of human complement system, mitogen-induced proliferation of human lymphocytes, and growth of human tumor cell lines. All these lignans exhibited moderate inhibitory activities. (+)-Machillin F showed the highest anticomplementary activity, and (−)-talaumidin methyl ether exhibited the strongest suppressive effect on lymphocyte proliferation. (−)-Talaumidin, acetyl talaumidin, and (+)-machillin F inhibited the growth of MCF-7, TK-10, and UACC-62 cell lines, whereas (−)-galbacin was inactive against UACC-62 and (−)-talaumidin methyl was inactive against both TK-10 and UACC-62. A characterization of the structural features of these lignans that is important to their biological activities is discussed.

Chemical Study and Biological Activity Evaluation of Two Azorean Macroalgae: Ulva rigida and Gelidium microdon

The green macroalga Ulva rigida C. Agardh (Chlorophyta) and the red macroalga Gelidium microdon Kutzing (Rhodophyta), collected from the Azorean archipelago, were investigated for their secondary metabolites and their in vitro growth inhibitory effect on three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma), as well as for their antifungal and antibacterial activities. The methanol extract of U. rigida furnished isofucosterol (1), 7(E)-3β-hydroxy-5α,6α-epoxymegastigmane (2) and (+)-dehydrovomifoliol (3) while the methanol extract of G. microdon yielded cholesterol (4) and lumichrome (5). The crude extracts of both macroalgae were found to be moderately active against the three cell lines whereas compound 1 showed a weak effect and compound 2 was inactive. The crude extracts of the two macroalgae were found to be moderately active against some fungi and bacteria while compounds 1 and 2 were inactive against all microorganisms tested.

Dibromotyrosine derivatives, a maleimide, aplysamine-2 and other constituents of the marine sponge Pseudoceratina purpurea

A collection of the marine sponge Pseudoceratina purpurea from the Gulf of Thailand furnished aplysamine-2, two new bromotyrosine derivatives purpuroceratic acids A and B, two known bromotyrosine derivatives, 3-maleimide-5-oxime and common sponge constituents. Aplysamine-2, purpuroceratic acid A and 3-maleimide oxime were evaluated for their in vitro anticancer activity against three cancer cell lines, but only aplysamine-2 exhibited moderate dose dependent growth inhibitory effects.

Further Halotyrosine Derivatives from the Marine Sponge Suberea aff. praetensa

Reexamination of the marine sponge Suberea aff. praetensa, (Row) from the Gulf of Thailand furnished in addition to bromotyrosine derivatives found previously 5-bromo- and 5- chlorocavernicolin, cavernicolins 1 and 2, two other brominated tyrosine metabolites, a known bisoxazolidone and a new unusual rearranged tyrosine metabolite subereatensin. Several of the metabolites exhibited significant inhibitory effects against five human cancer cell lines.

Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis

Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.

Modulation of Autophagy by a Thioxanthone Decreases the Viability of Melanoma Cells

(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N10-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted. A pharmacophore approach was used for mapping TXA1 onto pharmacophores for autophagy induction. Autophagy analyses included transmission electron microscopy for visualization of autophagic structures, fluorescence microscopy for observation of monodansylcadaverine (MDC) staining, pattern of LC3 expression in the cells and acridine orange staining, and Western blot for autophagic proteins expression; (3) Results: TXA1 induced autophagy of melanoma cells at the GI50 concentration (3.6 μM) and apoptosis at twice that concentration. Following treatment with TXA1, autophagic structures were observed, together with the accumulation of autophagosomes and the formation of autophagolysosomes. An increase in LC3-II levels was also observed, which was reverted by 3-methyladenine (3-MA) (an early stage autophagy-inhibitor) but further increased by E-64d/pepstatin (late-stage autophagy inhibitors). Finally, 3-MA also reverted the effect of TXA1 in cellular viability; (4) Conclusion: TXA1 decreases the viability of melanoma cells by modulation of autophagy and may, therefore, serve as a lead compound for the development of autophagy modulators with antitumor activity.