Synthesis of Di(Hetero)Arylamines and Ethers in the Thieno[3,2-b]Pyridine series by Metal-Catalyzed couplings

Foundation for the Science and Technology (FCT–Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER (European Fund for Regional Development)-COMPETE/QREN/EU for financial support the research unity PEst-C/QUI/UI686/2011 and the research project PTDC/QUI- QUI/111060/2009

Synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines from 2,3-dihalopyridines, (hetero)arylalkynes and Na2S. Further functionalizations

A simple and efficient three-step methodology is described for the first time for the synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines. The first step is a Sonogashira coupling from 3-bromo-2-chloropyridine or 2-bromo-3-chloropyridine with several (hetero)arylalkynes to obtain the corresponding 2- or 3-chloro(hetero)arylethynylpyridines. These were cyclized by treatment with Na2S affording the expected 2-(hetero)arylthienopyridines. As an improvement, these reactions were also performed in one-pot, without the isolation of the Sonogashira product, giving the thienopyridines in similar or better yields, reducing significantly the reaction time after the addition of Na2S. Further functionalizations were achieved in the thienopyridine system either by bromination in the thiophene ring or chlorination in the pyridine ring via a N-oxide intermediate, allowing metal-catalyzed coupling reactions and/or nucleophilic substitutions. The functionalization of some substituents is also possible and as an example a 1,3-diarylurea was obtained from the reaction of an aniline derivative with an arylisocyanate.Foundation for the Science and Technology (FCT – Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER -COMPETE/QREN/EU for financial support through the research unity CQ/UM(686) PEst-C/QUI/UI686/2011, the research project PTDC/QUI-QUI/111060/2009 and through the post-doctoral grant attributed to A. Begouin (SFRH/BPD/36753/2007) also financed by POPH and FSE

Synthesis of Tetracyclic systems and (Thio)Ureas from Aminodi(Hetero)Arylamines in the Thieno[3,2-b]Pyridine series

Foundation for the Science and Technology (FCT–Portugal) for financial support through the Portuguese NMR network (Bruker 400 Avance III-Univ Minho). FCT and FEDER (European Fund for Regional Development)-COMPETE/QREN/EU for financial support through the research centre PEst-C/QUI/UI686/2011, the research project PTDC/QUI-QUI/111060/2009 and the post-doctoral grant of R.C.C. SFRH/BPD/68344/2010

Effects of two new di(hetero)arylamines on prevention of oxidative stress induced in two different biological models

We investigated the antioxidant properties of two new diarylamines from organic synthesis (MJQ1 and MJQ2), whose basic structure is similar to others, with reported antioxidant capacity, assessed by chemical tests, and biological activity against microorganisms. In this study we induced lipid peroxidation, in isolated rat liver mitochondria with ADP/Fe2+, and the diarylamine effects were examined by oxygen consumption and by TBARS method. The anti-peroxidative effect was maximal for MJQ1 at 50 nM (higher than the one reported for trolox) and for MJQ2 at 60 μM. At these same concentrations none of them depressed the transmembrane potential (ΔΨ) developed by mitochondria, neither the RCR nor the ADP/O ratio values. For 2-fold these concentrations both diarylamines were effective in the prevention of mitochondrial ΔΨ collapse observed on respiring mitochondria, with the TPP+ electrode, which means a stabilization action on mitochondrial inner membrane. The results obtained were confirmed in whole cells. The compounds did not show toxicity to the L929 cell line, evaluated by the MTT reducing test and clearly protected from lipid peroxidation, induced by the oxidant pair ascorbate/Fe2+, to the PC12 cell model, at the concentrations where maximal antioxidant effect was observed in mitochondria. The new diarylamines revealed as very good antioxidants at very low concentrations, both in mitochondria and in whole cells. The results suggest a specific action site, for MJQ2, at mitochondrial complex I level. We are further exploring other intracellular targets for these new compounds that seems very promising against pathologies where oxidative stress is involved.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/17174/2004 - JP

Fluorescence of a benzothienopyridopyrimidone in solution and in lipid vesicles

Fluorescence properties of a biologically active benzothienopyridopyrimidone in solution and in lipid vesicles are reported. Assays at different pH values (0.5–10) allowed the determination of pKa = 2.0, showing that this compound may be useful as a pH indicator for pH ≤ 4. In lipid vesicles, benzothienopyridopyrimidone locates in a water-rich environment, indicating that it can be carried in the hydrophilic region of liposomes for drug delivery applications.Fundação para a Ciência e a Tecnologia (FCT

New synthetic raloxifen-like di(hetero)arylamines induce apoptosis and inhibit the estrogen receptor in breast cancer cells

Breast cancer is the most common form of cancer in women in the western world, and in spite of some decline in death rates in recent years it is still the second most common cause of death from cancer, in women (1). For more than three decades, the estrogen receptor (ER) has been the most important biomarker of breast cancer, largely due to the substantial benefit that endocrine therapy provides in the treatment of ER positive tumors, in women of all ages (2). Endocrine therapies currently available include selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene (3). Raloxifene acts as an estrogen antagonist in the breast by competitive binding to the ER, inhibiting estrogen-induced breast tissue proliferation and preventing the growth of mammary tumors. In addition, it shows no increase in incidence of endometrial cancer, which is an advantage compared to tamoxifen (4). The successes of these endocrine therapies, however, are often limited. So, it is important to continue searching for new strategies and/or drugs that overcome resistance problems and that can be potent enough with fewer adverse effects. In this work, we studied the effect of two new synthetic di(hetero)arylamines, named MJQ2 and MJQ3 (which have in common with raloxifene a benzothiophene ring), in cell proliferation and apoptosis of two different cell lines from breast cancer: MCF-7 (ER positive) and MDA-MB-231 (ER negative). Our results showed that both diarylamines induce apoptosis without significant necrosis (evaluated by Hoechst-PI staining), at the IC50 concentration that inhibits cell proliferation (evaluated by the SRB assay). The results obtained with TMRM, a marker of mitochondrial membrane potential, suggest that mitochondrial disruption can be involved in this apoptotic process. These effects are more pronounced in the MCF-7 cell line (ER positive), suggesting that the presence of the ER might be important in the response to these compounds. Confirmation of their interaction with the ER was obtained in the E-Screen assay, where a clear antagonism of the proliferative effects of the hormone 17β-estradiol was observed with both compounds, at non-toxic concentrations. The overall results suggest that these new synthetic “raloxifene-like” drugs might have potential to be further developed as alternative hormonal or adjuvant therapies for breast cancer.Fundação para a Ciência e a Tecnologia (FCT) research project PTDC/QUI/68382/2006 (FCOMP-01-0124-FEDER 007441)

Biodegradation of textile azo dyes by Phanerochaete chrysosporium

Instituto de Biotecnologia e Química Fina / Universidade do Minho (IBQF/UM) - Praxis XXI, Praxis XXI 2/2.1/QUI/44/94, Praxis XXI/BD/9120/96

Bioactivity of phenolic acids: Metabolites versus parent compounds: A review

Phenolic acids are present in our diet in different foods. In particular, mushrooms are a good source of these molecules. Due to their bioactive properties, phenolic acids are extensively studied and there is evidence of their role in disease prevention. Nevertheless, in vivo, these compounds are metabolized and circulate in the organism as glucuronated, sulfated and methylated metabolites, displaying higher or lower bioactivity. To clarify the importance of the metabolism of phenolic acids, the knowledge about the bioactivity of the metabolites is extremely important. In this review, chemical features, biosynthesis and bioavailability of phenolic acids are discussed as well as the chemical and enzymatic synthesis of their metabolites. Finally, the metabolites bioactive properties are compared with that of the corresponding parental compounds.The authors are grateful to Fundação para a Ciência e a Tecnologia (FCT, Portugal) and FEDER-COMPETE/QREN/EU for the financial support through the research centres (PEst-C/QUI/UI0686/2011 and PEst-OE/AGR/UI0690/2011). S.A. Heleno (BD/70304/2010) also thanks FCT, POPH-QREN and FSE for her grant

Synthesis of bis-amino acid derivatives by Suzuki cross-coupling, Michael addition and substitution reactions

Several bis-amino acids were prepared using a bis-Suzuki coupling (compounds 4-8, 10), a sequential Michael addition and bis-Suzuki coupling (compounds 12, 13) and a Michael addition followed by a substitution reaction (compounds 18, 19). Thus, the pure stereoisomer of the methyl esters of N-(tert-butoxycarbonyl)-beta-bromodehydroaminobutyric acid and dehydrophenylalanine and of N-benzyloxycarbonyl-beta-bromodehydroaminobutyric acid were reacted with 1,4-phenylene-bis-boronic acid or 9,9-dioctyl-9H-fluorene-2,7-bis-boronic acid using modified Suzuki coupling conditions. The corresponding bis-dehydroamino acid derivatives were obtained in good to high yields maintaining the stereochemistry of the starting materials. This reaction was also applied successfully to a brominated dehydrodipeptide and 1,4-phenylene-bis-boronic acid showing that it could be used to create cross-links in peptide chains. An N,N-diacyldehydroalanine derivative was used in a sequential Michael addition and bis-Suzuki coupling giving a p-terphenyl bis-amino acid and a fluorenyl bis-amino acid in good yields. Two bis-alpha,beta-diamino acids were obtained by a Michael addition of 1,2,4-triazole to the methyl esters of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl) dehydroamino acids followed by treatment with ethylenediamine.We acknowledge the Foundation for Science and Technology (FCT), Portugal and the Fundo Europeu de Desenvolvimento Regional (FEDER) for financial support through the Centro de Quimica of University of Minho and through the project POCI/QUI/59407/2004

Two-dimensional PCA highlights the differentiated antitumor and antimicrobial activity of methanolic and aqueous extracts of Laurus nobilis L. from different origins

"Article ID 520464"Natural matrices are important sources of new antitumor and antimicrobial compounds. Species such as Laurus nobilis L. (laurel) might be used for this purpose, considering its medicinal properties. Herein, in vitro activity against human tumor cell lines, bacteria, and fungi was evaluated in enriched phenolic extracts. Specifically, methanol and aqueous extracts of wild and cultivated samples of L. nobilis were compared considering different phenolic groups. Principal component analysis (PCA) was applied to understand how each extract acts differentially against specific bacteria, fungi, and selected human tumor cell lines. In general, the extract type induced the highest differences in bioactivity of laurel samples. However, from the PCA biplot, it became clear that wild laurel samples were higher inhibitors of tumor cell lines (HeLa, MCF7, NCI-H460, and HCT15). HepG2 had the same response to laurel from wild and cultivated origin. It was also observed that methanolic extracts tended to have higher antimicrobial activity, except against A. niger, A. fumigatus, and P. verrucosum. The differences in bioactivity might be related to the higher phenolic contents in methanolic extracts. These results allow selecting the extract type and/or origin with highest antibacterial, antifungal, and antitumor activity.The authors are grateful to Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) for the financial support to CIMO (strategic project PEst-OE/AGR/UI0690/2011) and REQUIMTE (PEst-C/EQB/LA0006/2011). M. I. Dias, R. Calhelha, and J. C. M. Barreira also thank FCT, POPHQREN, and FSE for their Grants (SFRH/BD/84485/2012, SFRH/BPD/ 68344/2010, and BPD/72802/2010). The authors also thank to Serbian Ministry of Education and Science for financial support (grant number 173032)