Elaboration of the Effective Multi-Target Therapeutic Platform for the Treatment of Alzheimer's Disease Based on Novel Monoterpene-Derived Hydroxamic Acids

被引：7

作者：

Aleksandrova, Yulia ^{[1
]}

Munkuev, Aldar ^{[2
]}

Mozhaitsev, Evgenii ^{[2
]}

Suslov, Evgenii ^{[2
]}

Tsypyshev, Dmitry ^{[2
]}

Chaprov, Kirill ^{[1
]}

Begunov, Roman ^{[3
]}

Volcho, Konstantin ^{[2
]}

Salakhutdinov, Nariman ^{[2
]}

Neganova, Margarita ^{[1
]}

机构：

[1] Russian Acad Sci, Inst Physiol Act Cpds, Fed Res Ctr Problems Chem Phys & Med Chem, Severnij Pr 1, Chernogolovka 142432, Russia

[2] Russian Acad Sci, NN Vorozhtsov Novosibirsk Inst Organ Chem, Dept Med Chem, Siberian Branch, Lavrentiev Ave 9, Novosibirsk 630090, Russia

[3] PG Demidov Yaroslavl State Univ, Biol & Ecol Fac, Matrosova Ave 9, Yaroslavl 150003, Russia

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2023年 / 24卷 / 11期

关键词：

hydroxamic acids; Alzheimer's disease; transgenic mice model; molecular target; docking study; histone deacetylase 6; radical scavenging; amyloid beta-protein; learning and memory; TRANSGENIC MOUSE MODEL; HISTONE DEACETYLASE INHIBITORS; AMYLOID BETA-PROTEIN; THIOFLAVIN T; OXIDATIVE STRESS; COGNITIVE DEFICITS; ACCURATE DOCKING; BRAIN; HDAC6; TRICHOSTATIN;

D O I：

10.3390/ijms24119743

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 +/- 0.01 mu M to 0.74 +/- 0.02 mu M. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO(circle) radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R-2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological fi-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer's disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer's disease.

引用

页数：36

共 167 条

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