McColl G

References (3)

Title : Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model. - Dighe_2019_Commun.Chem_2_35
Author(s) : Dighe SN , De la Mora E , Chan S , Kantham S , McColl G , Miles JA , Veliyath SK , Sreenivas BY , Nassar ZD , Silman I , Sussman JL , Weik M , McGeary RP , Parat MO , Brazzolotto X , Ross BP
Ref : Communications chemistry , 2 :35 , 2019
Abstract : The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (Abeta) fibrillation, protect against Abeta42-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Abeta42, with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.
ESTHER : Dighe_2019_Commun.Chem_2_35
PubMedSearch : Dighe_2019_Commun.Chem_2_35
Gene_locus related to this paper: human-BCHE , torca-ACHE

Title : Effect of the Biphenyl Neolignan Honokiol on Abeta42-Induced Toxicity in Caenorhabditis elegans, Abeta42 Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation - Kantham_2017_ACS.Chem.Neurosci_8_1901
Author(s) : Kantham S , Chan S , McColl G , Miles JA , Veliyath SK , Deora GS , Dighe SN , Khabbazi S , Parat MO , Ross BP
Ref : ACS Chem Neurosci , 8 :1901 , 2017
Abstract : The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Abeta) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Abeta42 as a convenient in vivo system for examining the effect of honokiol against Abeta-induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Abeta42 oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron(II). Honokiol displayed activity similar to that of resveratrol and (-)-epigallocatechin gallate (EGCG) in delaying Abeta42-induced paralysis in C. elegans, and it exhibited moderate-to-weak ability to inhibit Abeta42 on-pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered.
ESTHER : Kantham_2017_ACS.Chem.Neurosci_8_1901
PubMedSearch : Kantham_2017_ACS.Chem.Neurosci_8_1901
PubMedID: 28650631

Title : Multifunctional Analogs of Kynurenic Acid for the Treatment of Alzheimer's Disease: Synthesis, Pharmacology, and Molecular Modeling Studies - Deora_2017_ACS.Chem.Neurosci_8_2667
Author(s) : Deora GS , Kantham S , Chan S , Dighe SN , Veliyath SK , McColl G , Parat MO , McGeary RP , Ross BP
Ref : ACS Chem Neurosci , 8 :2667 , 2017
Abstract : We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer's disease (AD). Synthesized KYNA analogs were tested for their N-methyl-d-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, interference with the amyloid beta peptide (Abeta) fibrillation process, and protection against Abeta-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Abeta42. Molecular modeling studies were also performed to predict the binding modes of most active compounds with NMDAR, mGluR5, and Abeta42. Among the synthesized analogs, 3c, 5b, and 5c emerged as multifunctional compounds that act via multiple anti-AD mechanisms including AChE inhibition, free radical scavenging, NMDA receptor binding, mGluR5 binding, inhibition of Abeta42 fibril formation, and disassembly of preformed Abeta42 fibrils. Interestingly, 5c showed protection against Abeta42-induced toxicity in transgenic C. elegans strain GMC101. Moreover, 5b and 5c displayed high permeability in an MDR1-MDCKII cell-based model of the blood-brain barrier (BBB). Compound 3b emerged with specific activity as a micromolar AChE inhibitor, however it had low permeability in the BBB model. This study highlights the opportunities that exist to develop analogs of endogenous molecules from the kynurenine pathway for therapeutic uses.
ESTHER : Deora_2017_ACS.Chem.Neurosci_8_2667
PubMedSearch : Deora_2017_ACS.Chem.Neurosci_8_2667
PubMedID: 28825789