Síntese de amidas graxas: uma nova família de lipídios biologicamente ativos

Amidas graxas são compostos orgânicos nitrogenados derivados de ácidos carboxílicos, as quais contém em sua estrutura uma longa cadeia carbônica (C16- C24), possuindo ou não insaturações. Estes compostos podem ser encontrados em vegetais terrestres ou aquáticos, microorganismos e animais. Já em meados do século passado, a identificação de duas amidas graxas: a N-araquidonoiletanolamina (AEA, 5) e a cis-oleamida (cOA, 6), membros mais conhecidos e estudados desta família, devido as suas propriedades como indutora do sono fisiológico e canabinomimética respectivamente; levantou o interesse para a investigação das propriedades, identificação, síntese e isolamento de novas amidas graxas. Atualmente as pesquisas acerca das amidas graxas se devem as suas atividades biológicas tais como: aumento da libido sexual, analgesia, inseticida ou agente redutor da fome. Neste contexto, objetivo desse trabalho foi desenvolver metodologias para a síntese de novas amidas graxas. As amidas foram produzidas a partir de ácidos graxos, via cloreto de ácido ou via ésteres metílicos graxos, em rendimentos compreendidos entre 44% e 88%. Todos os compostos sintetizados foram caracterizados por espectroscopia de Infravermelho e RMN de 1H e 13C. Ensaios citotóxicos em células eritroleucêmicas K562 para a série das pirrolidil amidas demonstraram atividade citotóxica e capacidade de inibir proliferação celular em menos de 72 horas na concentração máxima de 1000µg/mL.

Avaliação da atividade antitumoral de amidas graxas análogas de canabinóides

A atividade antiproliferativa in vitro de uma série de amidas graxas sintéticas, em sete linhagens de células tumorais foi investigada. Baseado em GI50, TGI e LC50, os ensaios preliminares mostraram que a maior parte dos compostos mostrou atividade antiproliferativa moderada a boa contra as linhagem de células tumorais testadas, principalmente em células de glioma humano (U251) e câncer de ovário humano com fenótipo de resistentencia a múltiplos fármacos (NCI-ADR/RES). A amida (R,S)-3d, derivada do ácido ricinoleico, mostrou uma elevada seletividade com potência de inibição do crescimento e morte celular para a linhagem de células de glioma. Além disso, as amidas (S)-3c e (S)-3e, derivadas dos ácidos oleico e linoleico respectivamente, foram especificas para glioma e ovário com fenótipo de resistência a múltiplos fármacos com inibição potente do crescimento celular. Estes resultados aliados a um perfil de segurança relativo quando analisado o efeito sobre as linhagens celulares não–tumorais, apontam para que estes compostos sirvam como modelos para o desenvolvimento de candidatos a fármacos para o tratamento de câncer, incluindo cânceres com fenótipo de resistência a múltiplos fármacos.

Síntese de ligantes Bis-amida e aplicação em reações de acoplamento Suzuki

As amidas constituem uma classe de moléculas com amplo perfil farmacológico e que despertam atenção também pela capacidade de coordenar metais de transição. Esta proposta de trabalho compreende, inicialmente, a síntese de 3 ligantes bis-amidas simétricas tendo como reagentes de partida etilenodiamina, orto-fenilenodiamina, salicilato de metila e cloreto de benzoíla. Esses compostos foram caracterizados por espectroscopia no infravermelho (IV), ressonância magnética nuclear de hidrogênio (RMN 1H) e difração de raios X em monocristal (DRX). Após sintetizar e caracterizar esses compostos, a outra etapa do trabalho foi a utilização dessas bis-amidas como ligante na reação catalítica de acoplamento Suzuki. O sistema catalítico otimizado à base destes ligantes na presença de paládio, foi capaz de promover a formação de bifenilas com rendimentos superiores a 90% à temperatura de 50 °C e tempo reacional de 1 h. Este sistema se mostrou eficiente para reagentes com diversos grupos substituintes (eletroretiradores e eletrodoadores) nos anéis aromáticos dos haletos de arila e ácidos arilborônicos.

Estudos de vias sintéticas catalíticas para benzociclo-alcanois e análogos: potenciais fármacos para doença de Alzhjeimer

A doença de Alzheimer constitui uma ameaça significativa a nível mundial. Estima-se que, mundialmente existam cerca de 35 milhões de pessoas afetadas por este tipo de demência. Os compostos contendo um esqueleto benzocicloalcanol (que incluem benzofuranos e di-hidrobenzofuranóis) mostram atividades biológicas significativas e possuem muito potencial no tratamento das doenças neurodegenerativas. Nos últimos anos têm havido avanços significativos no campo das reações catalisadas por metais. As reações de adição nucleófila intramolecular e a de Heck intramolecular constituem metodologias importantes para a síntese de benzocicloalcanóis. No âmbito deste trabalho, pretendia-se sintetizar uma biblioteca de compostos contendo um esqueleto benzocicloalcanol. A estratégia adotada para a síntese de dihidrobenzofuranóis envolveu um método de ciclização catalítica de cetonas aril-éteres e para a síntese de benzofuranos, um método de ciclização catalítico de enoatos e enamidas (amidas de Weinreb). Várias condições foram estudadas; Abstract: Studies on Synthetic Catalytic Pathways to Benzocycloalkanols and Derivatives – Potential Drugs for Alzheimer’s Disease Alzheimer's disease constitutes a significant threat worldwide. It is estimated that are about 35 million people worldwide suffering from this type of dementia. The compounds containing a benzocycloalkanol scaffold (including benzofurans and dihydrobenzofurans) show significant biological activity and have great potential in the treatment of neurodegenerative diseases. In recent years there have been many advances in the field of catalyzed reactions by transition-metals. The intramolecular nucleophilic addition and the intramolecular Heck reactions constitute important methods for the synthesis of benzocycloalkanols. Within this work, the main goal was to synthesize a library of compounds containing a benzocycloalkanol scaffold. The adopted strategy for the synthesis of dihydrobenzofurans was the catalytic cyclization of aryl ether ketones and for the synthesis of benzofurans, the catalytic cyclization of enoates and enamides (Weinreb amides). Several conditions were studied

Bis-Alkoxycarbonylation And Difunctionalization Of Alkenes Employing Palladium(II) Or Nickel(II) Complexes As Catalysts

Section 1 is focused on the bis-alkoxycarbonylation reaction of olefins, catalyzed by aryl α-diimine/Pd(II) complexes, for the synthesis of succinic acid ester derivatives, important compounds in many industrial fields. The opening chapter (Chapter 1) of this thesis presents an overview of the basic chemistry of organopalladium compounds and carbonylation reactions, focusing on oxidative bis-alkoxycarbonylation processes. In Chapter 2 the results obtained in the bis-alkoxycarbonylation of 1,2-disubstituted olefins are reported. The reaction proceeds under very mild reaction conditions, using an aryl α-diimine/Pd(II) catalyst and p-benzoquinone as oxidant, in the presence of a suitable alcohol. This process proved to be very efficient, selective and diastereospecific and various 2,3-disubstituted succinic esters have been obtained in high yields. In Chapter 3 the first bis-alkoxycarbonylation reaction of acrylic esters and acrylic amides, leading to the synthesis of 2-alkoxycarbonyl and 2-carbamoyl succinates respectively, is reported. Remarkably, the utilized aryl α-diimine/Pd(II) catalyst is able to promote the carbonylation of both the β- and the generally non-reactive α- positions of these alkenes. The proposed catalytic cycle is supported by DFT calculations. Section 2 is mainly focused on the Ni-catalyzed difunctionalization of unactivated alkenes tethered to unstabilized ketones. This reaction allows for a wide range of pharmaceutically useful cyclic architectures to be obtained. Chapter 4 consists of an introduction to the difunctionalization reactions of unactivated olefins. In particular, intramolecular reactions will be discussed in detail. In Chapter 5 the results obtained from the Ni-catalyzed difunctionalization of unactivated alkenes tethered to unstabilized ketones are reported. The reaction proceeds through the formation of a zinc-enolate compound, followed by a cyclization/cross-coupling reaction, which takes place in the presence of a phosphine/Ni(II) complex and an (hetero)aryl electrophile, leading to different cyclic and bicyilc architectures. In Chapter 6, preliminary results concerning the anionic cyclization of zinc enolates tethered to unactivated alkenes are presented.

β-lactams from their structural features to their biological applications

β-lactam compounds represent an important class of four-membered cyclic amides (azetidin-2-ones) thanks to their valuable and varied biological activities. The presence of a β-lactam ring in a series of bioactive molecules targeting different proteins, allows us to consider the azetidin-2-one a privileged structure. The constrained four-membered cyclic amide could easily undergo ring-opening reactions by nucleophilic residues in the active sites of enzymes and this is the mechanism suggested for antibacterial activity; moreover, the rigid core structure could favour and actually enhance directional noncovalent bonding for an effective ligand−receptor recognition. Nowadays monocyclic β-lactams are known as anticancer, antidiabetic, anti-tubercular, anti-inflammatory agents and as ligands of integrin receptors. In order to consider different facets of 4-azetidin-2-ones, this theis will be divided into two sections: the first one will be dedicated to the design, synthesis and characterization of biological active β-lactams (new β-lactam based integrin ligands and their different applications and novel N-thio-alkyl substituted azetidinones for the treatment of Tuberculosis); the second one instead, will be based on two projects which consider two different proprieties of β-lactams: stereochemistry, evaluated by biocatalytic methods and reactivity at C-4 position. In the first case we want to obtain enantiomerically pure 4-acetoxy-2-azetidinone, useful for synthesis of stereo-chemically defined bioactive β-lactams, while in the second case we want to study in which conditions the nucleophilic substitutions occur. A final section will be instead dedicated to the research project conducted in Philochem AG, Zurich, under the supervision of Prof. Dario Neri and Dr. Samuele Cazzamalli, based on the study of new cleavable disulfide linkers for small molecule drug conjugates targeting Fibroblast activation protein (FAP).

Strategies to hijack MTs dysfunction in neurodegenerative tauopathies: Design and synthesis of novel CNS-disease-modifying tools

Neuronal microtubules assembly and dynamics are regulated by several proteins including (MT)-associated protein tau, whose aberrant hyperphosphorylation promotes its dissociation from MTs and its abnormal deposition into neurofibrillary tangles, a common neurotoxic hallmarks of neurodegenerative tauopathies. To date, no disease-modifying drugs have been approved to combat CNS tau-related diseases. The multifactorial etiology of these conditions represents one of the major limits in the discovery of effective therapeutic options. In addition, tau protein functions are orchestrated by diverse post-translational modifications among which phosphorylation mediated by PKs plays a leading role. In this context, conventional single-target therapies are often inadequate in restoring perturbed networks and fraught with adverse side-effects. This thesis reports two distinct approaches to hijack MT defects in neurons. The first is focused on the rational design and synthesis of first-in-class triple inhibitors of GSK-3β, FYN, and DYRK1A, three close-related PKs, which act as master regulators of aberrant tau hyperphosphorylation. A merged multi-target pharmacophore strategy was applied to simultaneously modulate all three targets and achieve a disease-modifying effect. Optimization of ARN25068 by a computationally and crystallographic driven SAR exploration, allowed to rationalize the key structural modifications to maintain a balanced potency against all three targets and develop a new generation of quite well-balanced analogs exhibiting improved physicochemical properties, a good in vitro ADME profile, and promising cell-based anti-tau phosphorylation activity. In Part II, MT-stabilizing compounds have been developed to compensate MT defects in tau-related pathologies. Intensive chemical effort has been devoted to scaling up BL-0884, identified as a promising MT-normalizing TPD, which exhibited favorable ADME-PK, including brain penetration, oral bioavailability, and brain pharmacodynamic activity. A suitable functionalization of the exposed hydroxyl moiety of BL-0884 was carried out to generate corresponding esters and amides possessing a wide range of applications as prodrugs and active targeting for cancer chemotherapy.