Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach

Neganova, Margarita E.; Клочков, С. Г.; Petrova, L. N.; Shevtsova, Elena F.; Afanasieva, Svetlana V.; Chudinova, E. S.; Фисенко, Владимир Петрович; Bachurin, S. O.; Barreto, George E.; Aliev, Gjumrakch

doi:10.2174/1871527315666161107090525

Cited by 14 publications

(13 citation statements)

References 19 publications

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“…Очевидно, этот эффект связан с его антиоксидантной и митопротекторной активностью [54,55]. Кроме того, алломаргаритарин снижает агрегацию Аb [56]. Противосудорожная активность алломаргаритарина на моделях индуцированных пилокарпином судорог [57] также может быть отчасти связана с его способностью увеличивать устойчивость митохондрий к индукции МРТ.…”

Section: ингибиторы мрт как перспективная группа лекарственных препарunclassified

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Shevtsova

Vinogradova

Neganova

et al. 2018

BMCRM

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The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimer′s disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimer′s disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest – both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.

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Section: ингибиторы мрт как перспективная группа лекарственных препарunclassified

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Shevtsova

Vinogradova

Neganova

et al. 2018

BMCRM

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“…This ambiguity of action of melatonin and, to a larger extent, NAS and the non‐monotonic dependence on the concentration and MPT induction conditions are attributable and are in rather good agreement with the hypothesis that these compounds possess a multimodal capabilities 119,120 and play a special role as endogenous and local MPT regulators, and, hence, regulators of synaptic and neuronal viability. Tryptamine (as a pharmacophore) and securinine, a sesquiterpene lactone possessing a significant neurotropic potential, 121–123 were used to synthesize the adduct allomargaritarine (Figure 4, AM), which also had an antioxidant potential and increased the mitochondrial resistance to MPT, including that induced by the βA peptide 124–126 …”

Section: Mpt Inhibitorsmentioning

confidence: 99%

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Shevtsova

Maltsev

Vinogradova

et al. 2020

Medicinal Research Reviews

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The mitochondria‐targeting drugs can be conventionally divided into the following groups: those compensating for the energy deficit involved in neurodegeneration, including stimulants of mitochondrial bioenergetics and activators of mitochondrial biogenesis; and neuroprotectors, that are compounds increasing the resistance of mitochondria to opening of mitochondrial permeability transition (MPT) pores. Although compensating for the energy deficit and inhibition of MPT are obvious targets for drugs used in the very early stages of Alzheimer‐like pathology, but their use as the monotherapy for patients with severe symptoms is unlikely to be sufficiently effective. It would be optimal to combine targets that would provide the cognitive‐stimulating, the neuroprotective effects and the ability to affect specific disease‐forming mechanisms. In the design of such drugs, assessment of their potential mitochondrial‐targeted effects is of particular importance. The possibility of targeted drug design for simultaneous action on mitochondrial and neurotransmitter's receptors targets is, in particularly, based on the known interplay of various cellular pathways and the presence of common structural components. Of particular interest is directed search for multitarget drugs that would act simultaneously on mitochondrial calcium‐dependent functions, the targets (receptors, enzymes, etc.) facilitating neurotransmission, and the molecular targets related to the action of so‐called disease‐modifying factors, in particular, the formation and overcoming of the toxicity of β‐amyloid or hyperphosphorylated tau protein. The examples of such approaches realized on the level of preclinical and clinical trials are presented below.

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“…It also effectively suppresses it when Aβ35-25 is used as an inducer and, as a result, displays cyto(neuro)protector activity in models of excitotoxicity and toxicity mediated by trivalent iron ions and amyloid [ 41 , 42 , 168 ]. Moreover, allomargaritarine has the ability to reduce Aβ [ 169 ]. Therefore, mitochondria represent a promising target in the search for potential neuroprotective agents aimed at preventing or slowing down the development of neurodegenerative diseases: in particular, Alzheimer’s.…”

Section: Problems and Targets In The Treatment Of Neurodegeneative DImentioning

confidence: 99%

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

et al. 2020

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Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, -synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.

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Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach

Abstract: Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

Cited by 14 publications

References 19 publications

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

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