Further Withaphysalin Derivatives from Acnistus arborescens

Two new epimeric chlorinated withaphysalins, rel-(4 beta,5 beta,6 alpha,18S,22R)- and rel-(4 beta,5 beta,6 alpha,18R,22R)-6-chloro-18,20-epoxy-18-ethoxy-4,5-dihydroxy-1- oxowitha-2,24-diene-26,22-lactone (1 and 2 resp.), together with the new rel-(4 beta,5 beta,6a,18R,22R)-6-chloro-18,20-epoxy-4,5-dihydroxy-18-methoxy-1-oxowitha-2,24-diene-26,22-lactone (3) and rel-(3 beta,4 beta,5 beta,6 beta,18R,22R)-5,6:18,20-diepoxy-3,18-diethoxy-4-hydroxy-1-oxowith-24-ene-26,22-lactone (4) were isolated from the leaves of Acnistus arborescens and named withaphysalins TW, respectively. The final structures and the complete 1H- and 13C-NMR assignments of the three chlorowithaphysalins 13 were performed by means of HR-ESI-MS and 1D- and 2D-NMR experiments, including COSY, HSQC, and HMBC, beside comparison with spectral data of analogous compounds from the literature. The structure of 4 was also confirmed by means of a single-crystal X-ray diffraction analysis.

Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB)

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC50 values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.

Correlations between Conjugation Length, Macromolecular Dynamics, and Photophysics of Phenylene-Vinylene/Aliphatic Multiblock Copolymers

This work reports a detailed spectroscopy study of a series of multiblock conjugated nonconjugated copolymers built by p-phenylene vinylene type units (PV) and octamethylene spacers, namely, poly(1,8-octanedioxy-2,6-dimethoxy-1,4-phenylene-1,2-ethenylene) (LaPPS18). The relative proportions of the PV and aliphatic segments were estimated on the basis of solid-state NMR and Raman spectroscopy. The overall structure was characterized by wide angle X-ray diffraction; H-1 wide-line dipolar chemical shift correlation (DIPSHIFT), and centerband-only detection of exchange (CODEX) NMR data, that together with glass transition temperatures allowed us to identify the groups involved in the molecular dynamics. These different structural properties were used to explain the photoluminescence properties in terms of peak position and spectral profile

Neutral Gold Complexes with Tridentate SNS Thiosemicarbazide Ligands

Na[AuCl4].2H(2)O reacts with tridentate thiosemicarbazide ligands, H(2)L1, derived from N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chloride and thiosemicarbazides under formation of air-stable, green [AuCl(L1)] complexes. The organic ligands coordinate in a planar SNS coordination mode. Small amounts of gold(I) complexes of the composition [AuCl(L3)] are formed as side-products, where L3 is an S-bonded 5-diethylamino-3-phenyl-1-thiocarbamoyl-1,2,4-triazole. The formation of the triazole L3 can be explained by the oxidation of H(2)L1 to an intermediate thiatriazine L2 by Au3+, followed by a desulfurization reaction with ring contraction. The chloro ligands in the [AuCl(L1)] complexes can readily be replaced by other monoanionic ligands such as SCN- or CN- giving [Au(SCN)(L1)] or [Au(CN)(L1)] complexes. The complexes described in this paper represent the first examples of fully characterized neutral Gold(III) thiosemicarbazone complexes. All the [AuCl(L1)] compounds present a remarkable cell growth inhibition against human MCF-7 breast cancer cells. However, systematic variation of the alkyl groups in the N(4)-position of the thiosemicarbazone building blocks as well as the replacement of the chloride by thiocyanate ligands do not considerably influence the biological activity. On the other hand, the reduction of Au-III to Au-I leads to a considerable decrease of the cytotoxicity.

Dihydrocinnamic acid derivatives from Hortia species and their chemotaxonomic value in the Rutaceae

Phytochemical studies of Hortia brasiliana and Hortia oreadica (Rutaceae) have led to the identification of three novel dihydrocinnamic acids: 5-methoxy-2,2-dimethyl-2H-1-benzopyran-8-propanoic acid, 5,6-dimethoxy-2,2-dimethyl-2H-1-benzopyran-8-propanoic acid and erythro-2-hydroxy-4-methoxy-3-(1,2,3-trihydroxy-3-methylbutyl) benzenepropanoic acid from H. brasiliana and the second compound and six known dihydrocinnamic acids from H. oreadica. Engler included Hortia as the single Neotropical genus in the Toddalioideae subtribe Toddaliinae. However, the range of dihydrocinnamic acid derivatives found in H. brasiliana and H. oreadica show that they contain similar compounds to other species of Hortia and clearly point to their phytochemical affinities with other Rutoideae species. (C) 2012 Elsevier Ltd. All rights reserved.

Femtosecond Laser in Polymeric Materials: Microfabrication of Doped Structures and Micromachining

The use of laser light to modify the material's surface or bulk as well as to induce changes in the volume through a chemical reaction has received great attention in the last few years, due to the possibility of tailoring the material's properties aiming at technological applications. Here, we report on recent progress of microstructuring and microfabrication in polymeric materials by using femtosecond lasers. In the first part, we describe how polymeric materials' micromachining, either on the surface or bulk, can be employed to change their optical and chemical properties promising for fabricating waveguides, resonators, and self-cleaning surfaces. In the second part, we discuss how two-photon absorption polymerization can be used to fabricate active microstructures by doping the basic resin with molecules presenting biological and optical properties of interest. Such microstructures can be used to fabricate devices with applications in optics, such as microLED, waveguides, and also in medicine, such as scaffolds for tissue growth.

Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)coumarin derivatives: Effect on inducible nitric oxide synthase

A series of 3-(triazolyl)-coumarins were synthesized and tested as anti-inflammatory agents. It was possible to infer that these compounds do not alter the interaction of LPS with TLR-4 or TLR-2, as the intracellular pathways involved in the TNF-alpha secretion and COX-2 activity were not affected. Nevertheless, the compounds inhibited iNOS-derived NO production, without affecting the eNOS activity. The outcome of the docking studies showed that it pi center dot center dot center dot pi interactions with the heme group are important for the iNOS inhibition, thus making compound 3c a promising lead. Moreover, the efficacy of this compound was visualized by the reduced number of neutrophils in the LPS-inflamed subcutaneous tissue. Together, biological and docking data show that triazolyl-substituted coumarins, that can act on iNOS, are a good scaffold to be explored. (C) 2012 Elsevier Masson SAS. All rights reserved.

Docking, synthesis and pharmacological activity of novel urea-derivatives designed as p38 MAPK inhibitors

p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transducing enzyme involved in many cellular regulations, including signaling pathways, pain and inflammation. Several p38 MAPK inhibitors have been developed as drug candidates to treatment of autoimmune disorders, such as rheumatoid arthritis. In this paper we reported the docking, synthesis and pharmacological activity of novel urea-derivatives (4a-e) designed as p38 MAPK inhibitors. These derivatives presented good theoretical affinity to the target p38 MAPK, standing out compound 4e (LASSBio-998), which showed a better score value compared to the prototype GK-00687. This compound was able to reduce in vitro TNF-alpha production and was orally active in a hypernociceptive murine model sensible to p38 MAPK inhibitors. Otherwise, compound 4e presented a dose-dependent analgesic effect in a model of antigen (mBSA)-induced arthritis and anti-inflammatory profile in carrageenan induced paw edema, indicating its potential as a new antiarthritis prototype. (c) 2012 Elsevier Masson SAS. All rights reserved.

Synthesis and characterization of a diruthenium(II,III)-ketoprofen compound and study of the in vitro effects on CRC cells in comparison to the naproxen and ibuprofen derivatives

A new diruthenium(II,III) complex, of formula [Ru2Cl(ket)(4)], Ruket, containing the non-steroidal anti-inflammatory drug ketoprofen was synthesized and mainly characterized by electrospray ionization mass spectrometry (ESI-MS), UV-Vis-IR electronic spectroscopy and FTIR and Raman vibrational spectroscopies. The four drug-carboxylato bridging ligands stabilize a Ru-2(II,III) mixed valent core in a paddlewheel type structure as confirmed by ESI mass spectra, electronic and vibrational spectroscopies and magnetic measurements. Ruket and the analogous compounds containing ibuprofen, Ruibp, and naproxen, Runpx, were tested for the biological effects in the human colon carcinoma cells HT-29 and Caco-2 expressing high and low levels of COX-2 respectively. All compounds only weakly affected the proliferation of the colorectal cancer cells HT-29 and Caco-2, and similarly only partially inhibited the production/activity of MMP-2 and MMP-9 by HT-29 cells, suggesting that COX-2 inhibition by these drugs can only partially be involved in the pharmacological effects of these derivatives. (c) 2012 Elsevier Ltd. All rights reserved.

Density Functional Theory (DFT) Study of Edaravone Derivatives as Antioxidants

Quantum chemical calculations at the B3LYP/6-31G* level of theory were employed for the structure-activity relationship and prediction of the antioxidant activity of edaravone and structurally related derivatives using energy (E), ionization potential (IP), bond dissociation energy (BDE), and stabilization energies(Delta E-iso). Spin density calculations were also performed for the proposed antioxidant activity mechanism. The electron abstraction is related to electron-donating groups (EDG) at position 3, decreasing the IP when compared to substitution at position 4. The hydrogen abstraction is related to electron-withdrawing groups (EDG) at position 4, decreasing the BDECH when compared to other substitutions, resulting in a better antioxidant activity. The unpaired electron formed by the hydrogen abstraction from the C-H group of the pyrazole ring is localized at 2, 4, and 6 positions. The highest scavenging activity prediction is related to the lowest contribution at the carbon atom. The likely mechanism is related to hydrogen transfer. It was found that antioxidant activity depends on the presence of EDG at the C-2 and C-4 positions and there is a correlation between IP and BDE. Our results identified three different classes of new derivatives more potent than edaravone.

Exploring the coordination chemistry of isomerizable terpyridine derivatives for successful analyses of cis and trans isomers by travelling wave ion mobility mass spectrometry

The photochemical cis-trans isomerization of the 4-{4-[2-(pyridin-4-yl)ethenyl]phenyl}-2,2': 6',2''-terpyridine ligand (vpytpy) was investigated by UV-vis, NMR and TWIM-MS. Ion mobility mass spectrometry was performed pursuing the quantification of the isomeric composition during photolysis, however an in-source trans-to-cis isomerization process was observed. In order to overcome this inherent phenomenon, the isomerization of the vpytpy species was suppressed by complexation, reacting with iron(II) ions, and forming the [Fe(vpytpy)(2)](2+) complex. The strategy of "freezing" the cis-trans isomerizable ligand at a given geometric conformation was effective, preventing further isomerization, thus allowing the distinction of each one of the isomers in the photolysed mixture. In addition, the experimental drift times were related to the calculated surface areas of the three possible cis-cis, cis-trans and trans-trans iron(II) complex isomers. The stabilization of the ligand in a given conformation also allows us to obtain the cis-cis and cis-trans complexes exhibiting the ligand in the metastable cis-conformation, as well as in the thermodynamically stable trans-conformation.

Two-photon absorption in oxazole derivatives: An experimental and quantum chemical study

Experimental and theoretical studies on the two-photon absorption properties of two oxazole derivatives: 2,5-diphenyloxazole (PPO) and 2-(4-biphenylyI)-5-phenyl-1,3,4-oxadiazole (PBD) are presented. The two-photon absorption cross-section spectra were determined by means of the Z-scan technique, from 460 up to 650 nm, and reached peak values of 84 GM for PBD and 27 GM for PPO. Density Functional Theory and response function formalism are used to determine the molecular structures and the one- and two-photon absorption properties and to assist in the interpretation of the experimental results. The Polarizable Continuum Model in one-photon absorption calculations is used to estimate solvent effects. (C) 2011 Elsevier B.V. All rights reserved.

Photodynamic antimicrobial chemotherapy (PACT) using phenothiazine derivatives as photosensitizers against Leishmania braziliensis

Background and Objective Cutaneous and mucocutaneous leishmaniasis are diseases characterized by skin or mucosal manifestations. In the new world, Leishmania braziliensis is the main etiological agent of cutaneous leishmaniasis, condition that may evolve to the mucocutaneous form. The therapeutic arsenal routinely employed to treat infected patients is unsatisfactory, especially for pentavalent antimonials, treatment recommended by the WHO, as they are often highly toxic, poorly tolerated and of variable effectiveness. This work aimed to evaluate in vitro the effectiveness of photodynamic antimicrobial chemotherapy as a new approach for the treatment of leishmaniasis. Materials and Methods A laser (??=?660?nm, 40?mW, 4.2?J/cm2, and 8.4?J/cm2, CW) associated to phenothiazine's derivatives (5 and 10?mu g/ml, toluidine blue O, methylene blue, or phenothiazine) on the promastigote forms of L. braziliensis in a single session. Samples were removed and analyzed in a hemocytometer 72?hours after PACT and viability of the parasites was assessed in quadruplicates. Results An important decrease in the number of viable parasites on all treated groups in comparison to their controls was observed as all tested compounds lead to significant parasite lethality being the highest lethality achieved with 10?mu g/ml of TBO. No lethality was observed on groups treated with laser or with any of the compounds separately. Conclusions TBO presented higher parasite lethality in comparison to MB with impressive reduction from 1?hour to 5?minutes of pre-incubation time. Lasers Surg. Med. 44: 850855, 2012. (c) 2012 Wiley Periodicals, Inc.

Systematic UPLC-ESI-MS/MS Study on the Occurrence of Staurosporine and Derivatives in Associated Marine Microorganisms from Eudistoma vannamei

Former bioactivity-guided analysis of the marine invertebrate Eudistoma vannamei led to the isolation of staurosporine derivatives, which revealed strong cytotoxic activity against several human cancer cell lines. The occurrence of such alkaloids in E. vannamei may be correlated to the presence of associated biota, such as Streptomyces bacteria. In agreement to this hypothesis, marine microorganisms associated with E. vannamei were recovered and cultured, leading to a total of 84 isolated bacterial strains. Gas phase fragmentation reactions of staurosporine and derivatives were systematically studied and the analyzed results further supported by computational chemistry studies. The resulting fragment patterns were used to search for the presence of different derivatives in extracts of isolated microorganisms, thereby using LC-MS/MS analysis in MRM mode. These results evidenced that one isolated Streptomyces sp. was able to generate staurosporine, while none of the hydroxy-7-oxo derivatives were detected. Finally, significant cytotoxic activity against human cancer lines was observed for one of the extracts.

Conjugated Linoleic Acid: good or bad nutrient

Conjugated linoleic acid (CLA) is a class of 28 positional and geometric isomers of linoleic acid octadecadienoic.Currently, it has been described many benefits related to the supplementation of CLA in animals and humans, as in the treatment of cancer, oxidative stress, in atherosclerosis, in bone formation and composition in obesity, in diabetes and the immune system. However, our results show that, CLA appears to be not a good supplement in patients with cachexia.