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      Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates

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          A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer’s disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC 50=4.0–30.0 μΜ) and moderate ability for inhibition of Aβ 1–42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ 42 aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ 1–42 induced toxicity. Structure–activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.

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          Most cited references 43

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          Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays

          A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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            Alzheimer's disease.

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              Free radicals, metals and antioxidants in oxidative stress-induced cancer.

              Oxygen-free radicals, more generally known as reactive oxygen species (ROS) along with reactive nitrogen species (RNS) are well recognised for playing a dual role as both deleterious and beneficial species. The "two-faced" character of ROS is substantiated by growing body of evidence that ROS within cells act as secondary messengers in intracellular signalling cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. The cumulative production of ROS/RNS through either endogenous or exogenous insults is termed oxidative stress and is common for many types of cancer cell that are linked with altered redox regulation of cellular signalling pathways. Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer. It appears that the DNA damage is predominantly linked with the initiation process. This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process. Attention is focused on structural, chemical and biochemical aspects of free radicals, the endogenous and exogenous sources of their generation, the metal (iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel)-mediated formation of free radicals (e.g. Fenton chemistry), the DNA damage (both mitochondrial and nuclear), the damage to lipids and proteins by free radicals, the phenomenon of oxidative stress, cancer and the redox environment of a cell, the mechanisms of carcinogenesis and the role of signalling cascades by ROS; in particular, ROS activation of AP-1 (activator protein) and NF-kappaB (nuclear factor kappa B) signal transduction pathways, which in turn lead to the transcription of genes involved in cell growth regulatory pathways. The role of enzymatic (superoxide dismutase (Cu, Zn-SOD, Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic antioxidants (Vitamin C, Vitamin E, carotenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium and others) in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors, including Ref-1, NF-kappaB, AP-1 are also reviewed.

                Author and article information

                J Enzyme Inhib Med Chem
                J Enzyme Inhib Med Chem
                Journal of Enzyme Inhibition and Medicinal Chemistry
                Taylor & Francis
                30 August 2018
                : 33
                : 1
                : 1212-1224
                [a ] Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa , Lisbon, Portugal;
                [b ] Dipartimento di Farmacia–Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Consortium C.I.N.M.P.I.S , Bari, Italy;
                [c ] CNC–Center for Neuroscience and Cell Biology, University of Coimbra , Coimbra, Portugal;
                [d ] Institute of Molecular and Cell Biology, Faculty of Medicine, University of Coimbra , Coimbra, Portugal
                Author notes

                Supplemental data for this article can be accessed here .

                CONTACT M. Amélia Santos masantos@ Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa , Av. Rovisco Pais 1, Lisbon1049-001, Portugal
                © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 13, Words: 8960
                Research Paper


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