Synthesis and Characterization of New Galanthamine Derivatives Comprising Peptide Moiety

Vezenkov, L.; Georgieva, Maria G.; Danalev, Dancho; Ivanov, Tchavdar B.; Ivanova, Galya

doi:10.2174/092986609789055412

Cited by 16 publications

(6 citation statements)

References 9 publications

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“…Inhibiting Aβ release by γ-secretase is also a widely sought approach against AD. Peptides such as N -(3,4-dichlorophenyl)- d , l -Ala-OH have been shown to inhibit γ-secretase, so researchers hypothesized that by conjugating peptides containing this moiety with galantamine, compounds would exhibit joint AChE and γ-secretase inhibition . Conjugates were designed to link several di- or tripeptides with the N -(3,4-dichlorophenyl)- d , l -Ala-OH sequence linked to position 6 or 11 of galantamine through ester or amide bonds ( 10 , Figure A).…”

Section: Peptide–drug Conjugates For Cns Targetsmentioning

confidence: 99%

“…Cartoon representations of protein targets are displayed on the right with target names below. (A) Example of a galantamine-peptide drug conjugate where galantamine (shown in red) is covalently linked through an ester bond to a tripeptide comprising N-(3,4-dichlorophenyl)-D,L-Ala-OH (shown in blue) at position 6 110. (B) Example of a galantamine-peptide drug conjugate with a shortened sequence of OM 99−2 covalently linked at position 11 through an amide bond to an Asp residue, which is also linked to a nicotinic residue 115.…”

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confidence: 99%

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Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Dean,

Jelú-Reyes,

Allen

et al. 2024

J. Med. Chem.

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Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide−drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide−drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody−drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide−drug conjugate design and optimization, such as peptide/smallmolecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide−drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms. ■ SIGNIFICANCE• Juxtaposition of peptide−drug conjugates and antibody−drug conjugates with a focus on challenges that can be overcome with peptide−drug conjugate strategies. • Considerations for the design and optimization of peptide−drug conjugates. • Analysis of several peptide−drug conjugate series that demonstrate effectiveness toward drug-resistant infections and complex disease states.

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Section: Peptide–drug Conjugates For Cns Targetsmentioning

confidence: 99%

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confidence: 99%

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Dean,

Jelú-Reyes,

Allen

et al. 2024

J. Med. Chem.

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“…We previously described the [11]. Here we report on the inhibitory spectrum of a series of dipeptides and tripeptides-containing galantamine derivatives towards cholinesterases andsecretase activities that should thus prove useful to interfere with distinct biochemical alterations taking place in AD.…”

Section: Introductionmentioning

confidence: 96%

Galantamine-based Hybrid Molecules with Acetylcholinesterase, Butyrylcholinesterase and γ-Secretase Inhibition Activities

Vezenkov¹,

Sévalle²,

Danalev³

et al. 2012

CAR

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We previously designed novel peptides-containing galantamine analogues. These compounds we analyzed for their putative inhibitory effect towards acetylcholinesterase, butyrylcholinesterase and γ-secretase, three activities of which could be central to various neurodegenerative pathologies including Alzheimer's disease. These pharmacological agents were virtually equipotent on acetylcholinesterase activity but display drastically higher inhibitory activities towards butyrylcholinesterase with several compounds displaying an about 100-fold higher activity than that harboured by galantamine. Strikingly, two of the galantamine amides that displayed low activity towards acetylcholinesterase exhibited the highest inhibitory potency towards butyrylcholinesterase (106 to 133 times more active than galantamine). Interestingly, five compounds show a rather good γ-secretase inhibitory potency while they retain their ability to inhibit AChE and/or BuChE activity. Thus, we have been able to design novel compounds with significant inhibitory activity against several of the enzymes responsible for key dysfunctions taking place in several neurodegenerative diseases. These mixed inhibitors could therefore be envisioned as potential pharmacological tools aimed at circumventing the degenerative processes taking place in these major pathologies.

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“…In this paper we will report the results of quantum chemical calculations of the enthalpies of dissociation of O-H and C-H bonds in galantamine (see Figure 1 and the Schemes 1-5 below) аnd norgalantamine -an analogue of galantamine without the methyl group at N11. Norgalantamine is widely used in synthetic chemistry instead of galantamine [13,14].…”

Section: Introductionmentioning

confidence: 99%

Computational Radical-Scavenging Activity Investigation of Galantamine

Karadjova

Saso

Velkov

2022

Preprint

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Galantamine is a natural alkaloid witha proved antioxidant activity, which easily passes the blood-brain barrier. This makes it a reliable drug for the treatment of many human brain diseases.In this paper we report the results of quantum chemical calculations of the dissociationenthalpies of O-H and C-H bonds in galantamine. The results clearly show the propensity of galantamine to react with radicals in the living organisms.This includes an assessment of the stability of O-H and C-H bonds in it, as well as their acidity.In addition, hydride ion abstraction reactions such as occur with nicotine-amid-adenine-dinucleotide (NAD) are discussed here.

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Synthesis and Characterization of New Galanthamine Derivatives Comprising Peptide Moiety

Cited by 16 publications

References 9 publications

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Galantamine-based Hybrid Molecules with Acetylcholinesterase, Butyrylcholinesterase and γ-Secretase Inhibition Activities

Computational Radical-Scavenging Activity Investigation of Galantamine

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