Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer’s disease

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 22; pp. 7324 - 7331
• Main Authors: Chojnacki, Jeremy E., Liu, Kai, Saathoff, John M., Zhang, Shijun
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2015; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Biochemistry & Molecular Biology; Bivalent strategy; Caprospinol; Cell Line, Tumor; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Curcumin; Curcumin - chemistry; Curcumin - pharmacology; Curcumin - therapeutic use; Diosgenin; Diosgenin - chemistry; Diosgenin - pharmacology; Diosgenin - therapeutic use; Drug Design; Humans; Life Sciences & Biomedicine; Ligands; Natural products; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Pharmacology & Pharmacy; Physical Sciences; Reactive Oxygen Species - metabolism; Science & Technology; Thiazoles - chemistry; Thiazoles - metabolism; ThT; EDC; LR; MTT; TFA; Aβ; THF; DMAP; HOBt; Curcumin; DMF; DCFH; AβO; Caprospinol; AD; Alzheimer’s disease; DCC; TBST; DCM; TC; Bivalent strategy; DCFH-DA; TEA; PEG; Natural products; ROS; Diosgenin; OXIDATIVE STRESS; COPPER; IRON; DISCOVERY; DAMAGE; CELL-DEATH; LIPID RAFTS; HYPOTHESIS; A-BETA; OLIGOMERIZATION; Alzheimer's disease
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.10.032

[Display omitted] In an effort to combat the multifaceted nature of Alzheimer’s disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7±9.0nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.