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Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease.
Bioorg Med Chem. 2014 Nov 01; 22(21):6089-104.BM

Abstract

A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu(2+)-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment.

Authors+Show Affiliations

State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25282654

Citation

Lan, Jin-Shuai, et al. "Design, Synthesis and Evaluation of Novel Tacrine-(β-carboline) Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease." Bioorganic & Medicinal Chemistry, vol. 22, no. 21, 2014, pp. 6089-104.
Lan JS, Xie SS, Li SY, et al. Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. Bioorg Med Chem. 2014;22(21):6089-104.
Lan, J. S., Xie, S. S., Li, S. Y., Pan, L. F., Wang, X. B., & Kong, L. Y. (2014). Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. Bioorganic & Medicinal Chemistry, 22(21), 6089-104. https://doi.org/10.1016/j.bmc.2014.08.035
Lan JS, et al. Design, Synthesis and Evaluation of Novel Tacrine-(β-carboline) Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease. Bioorg Med Chem. 2014 Nov 1;22(21):6089-104. PubMed PMID: 25282654.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. AU - Lan,Jin-Shuai, AU - Xie,Sai-Sai, AU - Li,Su-Yi, AU - Pan,Long-Fei, AU - Wang,Xiao-Bing, AU - Kong,Ling-Yi, Y1 - 2014/09/15/ PY - 2014/07/09/received PY - 2014/08/27/revised PY - 2014/08/28/accepted PY - 2014/10/6/entrez PY - 2014/10/6/pubmed PY - 2015/7/17/medline KW - Alzheimer’s disease KW - Antioxidant KW - Metal chelator KW - Tacrine KW - β-Amyloid aggregation KW - β-Carboline SP - 6089 EP - 104 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 22 IS - 21 N2 - A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu(2+)-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25282654/Design_synthesis_and_evaluation_of_novel_tacrine__β_carboline__hybrids_as_multifunctional_agents_for_the_treatment_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00631-2 DB - PRIME DP - Unbound Medicine ER -