Synthesis and Biological Evaluation of NO-Donor-Tacrine Hybrids as Hepatoprotective Anti-Alzheimer Drug Candidates

Fang, Lei; Appenroth, Dorothea; Decker, Michael; Kiehntopf, Michael; Roegler, Carolin; Deufel, Thomas; Fleck, Christian; Peng, Sixun; Zhang, Yihua; Lehmann, Jochen

doi:10.1021/jm701491k

Cited by 110 publications

(63 citation statements)

References 34 publications

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“…There are several reports in the literature on nitrate hybrid molecules: nicorandil, a potassium channel opener with nitrate function [10,11]; 2NTX-99, a thromboxane synthase inhibitor and thromboxane receptor antagonist and NO-releasing group [12]; GT-094, a nonsteroidal anti-inflammatory drug with NO function [13]; the antifungal drug ketoconazole with a diazen-1-ium-1,2-diolate or an organic nitrate moiety [14]; NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates [15]; the NicOx compound nitroaspirin, reviewed in Gresele and Momi [16]; NO-releasing celecoxib analogs, inhibitors of inducible cyclooxygenase [17]; a vitamin E analog with NO donor function [18]. Probably we could not list all examples that have been published during the last few years but our list provides an overview of the diversity of NO hybrids.…”

Section: Characterization Of New Organic Nitrate Hybrid Drugs Covalenmentioning

confidence: 99%

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

et al. 2012

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Background and Purpose: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized new organic nitrate hybrid molecules. Compounds CLC-1265 (valsartan mononitrate) and CLC-1280 (valsartan dinitrate) are derivatives of the angiotensin receptor blocker valsartan, with CLC-1265 containing a single organic nitrate linker and CLC-1280 also containing a second, different linker. Compounds CLC-2000 (cilostazol mononitrate) and CLC-2100 (cilostazol dinitrate) are nitrate derivatives of the phosphodiesterase III inhibitor cilostazol. All compounds are designed as hybrid molecules, potentially combining the NO-donating properties of organic nitrates with the AT1-blocking activity of valsartan or the phosphodiesterase-III–inhibiting effect of cilostazol. Experimental Approach: The properties of new drugs were assessed by isometric tension recording, inhibition of platelet aggregation and formation of mitochondrial reactive oxygen and nitrogen species. Key Results: In this report, all new nitrate compounds are shown, in vitro, to induce vasodilation in the range of other, classical organic nitrates, without inducing oxidative stress or classical nitrate tolerance. In addition, the new hybrid nitrate molecules displayed superior antiaggregatory properties over classical mono- and dinitrates. Conclusions and Implications: Our results demonstrate that organic nitrates can be successfully linked to existing therapeutic molecules to create a new class of molecular entities with a potential dual mechanism of action via combining the established pharmacological properties of valsartan or cilostazol with the vasodilating properties of organic nitrates. Future experimental studies have to demonstrate whether the combined action of these compounds translates to superior therapeutic effects.

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Section: Characterization Of New Organic Nitrate Hybrid Drugs Covalenmentioning

confidence: 99%

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

et al. 2012

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“…Concerns about hepatotoxicity, due to oxidative damage from metabolism of tacrine (Osseni et al 1999;Dogterom et al 1988 ) , prompted the search for newer compounds that would have the same or better effects on A b aggregation, without toxicity. Among the newer agents are tacrine-antioxidant hybrid molecules, such as lipocrine, which contains a lipoic acid moiety (Rosini et al 2005), and tacrine hybrids that contain NO donors (Fang et al 2008 ) . Another source of concern was inhibition of butyrylcholinesterase (BuChE) activity outside of the CNS by AChE inhibitors.…”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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“…30 Simultaneous modulation of several pathological events of the ongoing disease may then contribute to therapeutic effect of progressing AD. 31 The MTDL approach has been employed by many research groups [32][33][34][35] and has shown success, for example in the case of the compound ladostigil 36 which has reached clinical trials. 37 Exploiting the advantage of conjunctive approach, we designed a series of compounds combining known scaffolds of MAO and ABAD inhibitors to introduce MAO inhibitory activity into frentizole moiety and explore structural inhibitory features of both MAO and ABAD scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

Hroch

Guest

Benek

et al. 2017

Bioorganic & Medicinal Chemistry

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Synthesis and Biological Evaluation of NO-Donor-Tacrine Hybrids as Hepatoprotective Anti-Alzheimer Drug Candidates

Cited by 110 publications

References 34 publications

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

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