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

Long term performance evaluation of small-diameter vascular grafts based on polyvinyl alcohol hydrogel and dextran and MSCs-based therapies using the ovine pre-clinical animal model.

The functional and structural performance of a 5 cm synthetic small diameter vascular graft (SDVG) produced by the copolymerization of polyvinyl alcohol hydrogel with low molecular weight dextran (PVA/Dx graft) associated to mesenchymal stem cells (MSCs)-based therapies and anticoagulant treatment with heparin, clopidogrel and warfarin was tested using the ovine model during the healing period of 24 weeks. The results were compared to the ones obtained with standard expanded polyetetrafluoroethylene grafts (ePTFE graft). Blood flow, vessel and graft diameter measurements, graft appearance and patency rate (PR), thrombus, stenosis and collateral vessel formation were evaluated by B-mode ultrasound, audio and color flow Doppler. Graft and regenerated vessels morphologic evaluation was performed by scanning electronic microscopy (SEM), histopathological and immunohistochemical analysis. All PVA/Dx grafts could maintain a similar or higher PR and systolic / diastolic laminar blood flow velocities were similar to ePTFE grafts. CD14 (macrophages) and α-actin (smooth muscle) staining presented similar results in PVA/Dx/MSCs and ePTFE graft groups. Fibrosis layer was lower and endothelial cells were only detected at graft-artery transitions where it was added the MSCs. In conclusion, PVA/Dx graft can be an excellent scaffold candidate for vascular reconstruction, including clinic mechanically challenging applications, such as SDVGs, especially when associated to MSCs-based therapies to promote higher endothelialization and lower fibrosis of the vascular prosthesis, but also higher PR values.

NEW METAL-BASED MICELLES AS ANTICANCER AGENTS

Cancer is a leader cause of death worldwide. One of the problems associated with the current chemotherapeutic options is the noxious side effects caused by the lack of selectivity. In this frame, our research group has been committed to the development of a new Ru and Fe macrometallodrugs.[1] The data obtained so far shows that these compounds present an intrinsic selectivity towards cancer cells (relatively to healthy cells) due to the incorporation of polymeric ligands that promote a passive targeting through the cancer cell membrane. These results prompted us to the development of new macrometallodrugs bearing bioessential metals such as Fe, Zn and Co. We used a ‘M(bipy) 3 ’ scaffold (bipy = 2,2’-bipyridine derivatives) for the synthesis of the new compounds due to the promising cytotoxicity results observed for related compounds.[2] As polymeric ligands we have chosen the polylactide-co-polyethylene glycol amphiphilic copolymer that is able to self-assemble into micelles in water, keeping the metal center hidden, like a Trojan horse. We will present the synthesis and characterization of the new compounds and some preliminary data on their ability to form stable micelles (Figure 1).