NEWSLETTER 26

Annals of the Brazilian Academy of Sciences

AABC - Volume 90 (1 Suppl. 2) - May 2018

I am very pleased to present this special issue of the AABC! Entitled “Chemistry and Health: Past, Present and Future“. This splendid issue was organized by the colleague Dr. José A. S. Cavaleiro (Department of Chemistry and Organic Chemistry, University of Aveiro, Portugal) and includes 15 papers in a variety of fields specifically: addressing the question what Chemistry can do in order to provide the overall quality of health. Topics range from therapies concerning cancer to pharmacological evaluation of compounds that might have pharmacological applications.
As pointed out before, this volume is part of a project that started in 2016. The purpose was to produce special issues of the AABC to commemorate the centenary of the Brazilian Academy of Sciences.

Please keep in mind that since 2000, all papers published by the AABC can be downloaded free of charge at the SciELO site and previous editions of the Newsletter are available at the ABC website.

We are now inviting you to scroll through the text and click on the title of the article that interests you!

Alexander W. A. Kellner
Editor-in-Chief

CHEMISTRY AND HEALTH: PAST, PRESENT AND FUTURE

1 - Cancer, Photodynamic Therapy and Porphyrin-Type Derivatives
Authors: Ana T.P.C. Gomes, Maria G.P.M.S. Neves and José A.S. Cavaleiro

Among all lethal diseases, cancer is the second leading cause of death in the world. Photodynamic Therapy of Cancer (PDT), a therapy which uses the in vivo oxygen, adequate long wavelength radiations and sensitizers, has already demonstrated its efficiency against several oncologic diseases. This review presents the historical perspective of the evolution of PDT, showing important remarks in the development of photosensitizers since the beginning of the last century and highlights all the clinical already approved photosensitizers. It also emphasizes certain progresses in the synthesis and in the photodynamic action of new photosensitizers developed at the authors University in Aveiro.

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2 - Synthesis and Cytotoxic Evaluation of 1H-1,2,3-Triazol-1-ylmethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-diones
Authors: Ingrid C. Chipoline, Evelyne Alves, Paola Branco, Leticia V. Costa-Lotufo, Vitor F. Ferreira and Fernando C. da Silva

A series of eleven 1,2-naphthoquinones tethered in C2 to 1,2,3-1H-triazoles were designed, synthesized and their cytotoxic activity evaluated using HCT-116 (colon adenocarcinoma), MCF-7 (breast adenocarcinoma) and RPE (human nontumor cell line from retinal epithelium). Compounds containing aromatic group linked to 1,2,3-triazole ring presented superior cytotoxic activity against cancer cell lines with IC₅₀ in the range of 0.74 to 4.4 µM indicating that the presence of aromatic rings substituents in the 1,2,3-1H-triazole moiety is probably responsible for the improved cytotoxic activity.

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3 - Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring
Authors: Silvina Eduardo-Canosa, María Marco, Rita Sigüeiro and Antonio Mouriño

This work describes our studies on the synthesis of novel 1,25-dihydroxyvitamin D₃ analogs with a benzene ring in place of the natural 5-membered D-ring by the Wittig-Horner and Dienyne approaches. A key feature is the synthesis of a Cr(CO)₃-complexed previtamin D derivative that facilitates the access to vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)₃ type moieties for specific molecular recognition and drug research and development.

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4 - Synthesis and antimicrobial activity of new amino derivatives of pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
Authors: Samvel N. Sirakanyan, Athina Geronikaki, Domenico Spinelli, Elmira K. Hakobyan, Viktor G. Kartsev, Anthi Petrou and Anush A. Hovakimyan

The aim of the paper is the synthesis and study of properties of compounds containing fused thieno[2,3-b]pyridine and tetrazolo[1,5-c]pyrimidine heterocycles. Thus, as a result of fine and multi-stage synthesis, 8-amino derivatives of tetracyclic pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidines as well as the condensed pentaheterocyclic system: thieno[2,3-e]tetrazolo[1,5-c]pyrimidine were synthesized. The azide/tetrazole equilibrium in thieno[2,3-e]tetrazolo[1,5-c]pyrimidines has been examined as a function of solvent and its structure. Biological tests of new 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidines evidenced that some of them showed promising antimicrobial activity and according to predicted docking studies could be DnaG inhibitors.

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5 - Synthesis of Chiral 1,3-Dienes through Ring-Closing Metathesis of Enantioenriched Enynes: Potential Precursors of Morphane Analogs
Authors: María Jesús García-Muñoz, Ana Sirvent, Francisco Foubelo and Miguel Yus

Enantioenriched enynes were easily accessible by an indium mediated diastereoselective allylation with allyl bromide of aromatic N-tert-butanesulfinyl imines bearing alkynyl groups at ortho-position. These enynes were efficiently converted into 1,3-dienes through a ruthenium-catalyzed ring-closing metathesis with second generation Grubbs catalyst. The resulting chiral dienes are of synthetic interest because cycloaddition reactions with different dienophiles will lead to morphane-like polycyclic amino functionalized compounds with potential pharmacological activity.

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6 - Synthesis, X-ray diffraction study and pharmacological evaluation of 3-amino-4-methylthiophene-2-acylcarbohydrazones
Authors: Sonja Herrmann, Tabea Schübel, Fanny N. Costa, Maria Letícia C. Barbosa, Fabio F. Ferreira, Thays L.M.F. Dias, Morgana V. Araújo, Magna S. Alexandre-Moreira, Lídia M. Lima, Stefan Laufer and Eliezer J. Barreiro

This manuscript describes the design, synthesis, structural characterization and pharmacological evaluation of a novel series of N-acylhydrazone (NAH) derivatives (8a-t) as analgesic drug candidates. The NAH scaffold has been widely recognized as a privileged structure for different pharmacological applications. In this context, substances described herein were designed by molecular modifications of known analgesic and anti-inflammatory NAHs. Particularly, derivatives 8j and 8l displayed relative potency similar to dipyrone, highlighting them as promising analgesic lead-candidates for further investigation.

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7 - Deacylative alkylation (DaA) of N-methyl-3-acetyl-2-oxindole for the synthesis of symmetrically 3,3-disubstituted 2-oxindoles. An access gate to anticancer agents and natural products
Authors: Cristina Moreno-Cabrerizo, Aitor Ortega-Martínez, Cynthia Molina, Carmen Nájera and José M. Sansano

A key for the synthesis of antitumoral agents and bioactive products consists in the preparation of 3,3-disubstituted N-methyloxindoles employing a sequential one-pot synthesis involving deacylative alkylations.

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8 - An insight on the role of photosensitizer nanocarriers for Photodynamic Therapy
Authors: Mariana Q. Mesquita, Cristina J. Dias, Sara Gamelas, Margarida Fardilha, Maria G.P.M.S. Neves and Maria Amparo F. Faustino

Photodynamic Therapy (PDT) is a modality of cancer treatment in which tumor cells are destroyed by reactive oxygen species (ROS) produced by photosensitizers following  their activation with visible or near infrared light.  The PDT success is dependent on different factors namely on the efficiency of the photosensitizer deliver and targeting ability. In this review a special attention was given to the role of some drug delivery systems like liposomes, silica nanoparticles, gold nanoparticles and polymeric micelles to improve the PDT efficiency of tetrapyrrolic photosensitizers.

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9 - Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients
Authors: Juliana M. de Souza, Renan Galaverna, Aline A.N. de Souza, Timothy J. Brocksom, Julio C. Pastre, Rodrigo O.M.A. de Souza and Kleber T. de Oliveira

In this review we present the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and APIs, which are definitely responsible for a revolution in modern healthcare. We describe the beginnings of the modern drug era, and the large-scale batch mode of production, both chemical and microbiological. Subsequently, we comprehensively discussed the introduction of continuous flow chemistry, both as a technological tool for enabling organic chemistry, and as a fundamental research endeavor. Our main perspective is that continuous flow chemistry/processes are not a promise, but the present and the future of the big-Pharma.

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10 - Evaluation of meso-substituted cationic corroles as potential antibacterial agents
Authors: Teresa A.F. Cardote, Joana F.B. Barata, Carolina Amador, Eliana Alves, Maria Graça P.M.S. Neves, José A.S. Cavaleiro, Ângela Cunha, Adelaide Almeida and Maria Amparo F. Faustino

Tetrapyrrolic derivatives of the corrole type compounds are calling the attention of the scientific community due to their interesting and unique properties. The development of synthetic approaches is allowing great flexibility on the preparation of new corroles with adequate properties for certain applications. Their therapeutic potential as photosensitizers has been recently disclosed. Looking for corrole derivatives with antibacterial activity, this manuscript describes studies on the synthesis of cationic derivatives of the gallium(III) complex of 5,10,15- trispentafluorophenylcorrole. Such compounds have exhibited antibacterial activity at micromolar concentrations against the naturally bioluminescent Gram-negative bacterium Allivibrio fischeri.

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11 - The Antifungal Activity of Naphthoquinones: An Integrative Review
Authors: Débora O. Futuro, Patricia G. Ferreira, Caroline Nicoletti, Luana P. Borba-Santos, Fernando C. da Silva, Sonia Rozental and Vitor Francisco Ferreira

Naphthoquinones are the most common type of quinines in nature. They are a family of secondary metabolites that occur in plants, lichens and various microorganisms. Interest in quinines and the search for new biological activities within members of this class have intensified in recent years, as evidenced by the evaluation of potential antimicrobial activities of quinines. The objective of this review is to describe the development of naphthoquinones as antifungals against Candida species and to observe the most promising compounds. Using certain criteria for the selection of publications, 68 reports involving synthetic and natural naphthoquinones are discussed.

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12 - 2,3,8-Trisubstituted Quinolines with Antimalarial Activity
Authors: Pablo D.G. Martinez, Susann H. Krake, Maitia L. Poggi, Simon F. Campbell, Paul A. Willis and Luiz C. Dias

Although medicines are available for Malaria treatment since the XVII century, like quinine, this disease still displays resistance even with recently developed treatments. We investigated a series of compounds containing a trisubstituted quinoline unit. This heterocycle was chosen as it constantly appears in many antimalarial drugs. After a careful evaluation of SAR we found highly active compounds with a different mode of action. However, we also observed resistance of this chemical space in some Pf strains. In view of these results it is important to verify this effect in early stages of drug development.

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13 - Recent Advances and Perspectives in Cancer Drug Design
Authors: Luma G. Magalhães, Leonardo L.G. Ferreira and Adriano D. Andricopulo

Cancer drug discovery is a challenging field given the complexity of the disease and the consequent striking hurdles to be overcome in developing compounds that selectively target neoplastic tissues. Despite the significant achievements of the last decades and the substantial number of new drugs approved, the clinical outcome of cancer therapies still need to be considerably improved. This perspective explores some of the main molecular targets in cancer research and development, with a special focus on the discoveries made in the past five years. In addition, state-of-the art medicinal chemistry strategies applied in cancer pharmaceutical research are highlighted, providing a brief update on breakthrough drugs featuring innovative mechanisms of action.

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14 - Current Antimalarial Therapies and Advances in the Development of Semi-Synthetic Artemisinin Derivatives
Authors: Luiz C.S. Pinheiro, Lívia M. Feitosa, Flávia F. da Silveira and Nubia Boechat

According to the World Health Organization (WHO), malaria remains one of the biggest public health problems in the world. The development of resistance is a current concern, mainly because the number of safe drugs for this disease is limited. Artemisinin-based combination therapy is recommended by the WHO to prevent or delay the onset of resistance. Thus, the need to obtain new drugs makes artemisinin the most widely used scaffold to obtain synthetic compounds. This review describes the drugs based on artemisinin and its derivatives, including hybrid derivatives and dimers, trimers and tetramers.

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15 - New Palladacycle-Derived Acylhydrazones as Pre-catalysts in Mirozoki-Heck Coupling and Oxyarylations
Authors: Raquel A.C. Leão, Vagner D. Pinho, Artur S. Coelho, Arthur E. Kümmerle and Paulo R.R. Costa

Palladacycles are a source of in situ formed Pd (0) nanoparticles that have been successfully used in various coupling reactions for the formation of carbon-carbon bonds. Indeed, palladacycles have been widely used as pre-catalysts in various palladium- catalyzed cross-coupling reactions, allowing access to many complex molecular structures. Here we describe the synthesis of novel acylhydrazone-based palladacycles and their application as efficient pre-catalysts in Mirozoki-Heck and oxyarylation reactions at reasonable to good yields with low catalytic loading.

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