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Design, Synthesis and Biological Evaluation of Carboline Derivatives

Author: ZhuJiangWei
Tutor: ShengRong
School: Zhejiang University
Course: Medicinal Chemistry
Keywords: Alzheimer’s disease AChE inhibitors carbolines Winterfeldt oxidation
CLC: R914
Type: Master's thesis
Year: 2012
Downloads: 135
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Abstract

Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain characterized by loss of memory and cognition. The AChE inhibitors were the most important treatment for AD in clinic. Dimebon has been introduced into PhaseⅢclinical trial for AD therapy because of its unique multi-target effect, such as inhibition of AChE and BChE, protection of mitochondria and neuroprotection. The key structure of biological activity in dimebon is tetrahydro-γ-carboline. Based on the structure features of AChE, the modification of tetrahydro-γ-carboline will provide a series of novel compounds for the treatment of AD.There were two binding sites in the active gorge of AChE (peripheral anion site and central site) and bis-tacrine derivative showed 1000 time improvement in binding affinity compared with monomer tacrine. Thus 27 bivalent tetrahydro-γ-carbolines andγ-carbolines were designed and synthesized through linking monomer carboline with different sorts and length linkage to improve AChE inhibitory activities. Most of them showed moderate to good AChE inhibitory activities in vitro, especially the dimmer derivatives with 8 or 10 carbon chains. Four compounds displayed potent AChE inhibitory activities in vitro with IC50 values similar to Donepezil.Our group has reported a phenoxy-indanone derivative BYYT-25 as a potent AChE inhibitor with an IC50 value of 50 nM. The molecular docking study showed that the benzyl amine moiety binding to the catalytic sites of AChE. As a fused aromatic ring, the tetrahydro-y-carboline can interact with Trp279 of the peripheral sites of AChE. Thus 14 new tetrahydro-y-carboline derivatives and analogues were designed and synthesized as AChE inhibitors. Among them,2-25 exhibited a moderate AChE inhibitory activity with an IC50 value of 0.7μM. The molecular docking study shows that it binds to both the peripheral and central sites of AChE simultaneously.Among all the reported synthetic methods for the construction of fused quinolones scaffold, the Winterfeldt biomimetic oxidation has attracted much interest because of its simple procedure and widely available substrates. The Winterfeldt oxidation (NaOH, DMF, air, rt) of substituted 1,2,3,4-tetrahydro-y-carbolines has been developed, which provides a convenient and efficient method for the synthesis of the corresponding dihydropyrrolo[3,2-b]quinolones in moderate to excellent yields. The generality and substrate scope of this reaction are explored and a possible mechanism is proposed. The results imply that electron-withdrawing groups on N2 of tetrahydro-y-carbolines and N5-H are necessary. The synthesis of 5 or 7-substituted pyrrolo[3,2-b]quinolones in near quantitative yields has also been achieved through deprotection and aromatization of N2-Boc-dihydropyrrolo[3,2-b]quinolones.

Design, Synthesis and Biological Evaluation of Carboline Derivatives

Abstract

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