Synthesis and Biological Evaluation of Hydroxylated Monocarbonyl Curcumin Derivatives as Potential Inducers of Neprilysin Activity

Abstract

Background: Alzheimer’s disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Aims: Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and evaluated for their NEP upregulating potential using sensitive fluorescence-based Aβ digestion and inhibition assays. Results: Compound 4 was the most active one, resulting in a 50% increase in Aβ cleavage activity. Cyclohexanone-bearing derivatives exhibited higher activity enhancement compared to their acetone counterparts. Inhibition experiments with the NEP-specific inhibitor thiorphan resulted in dramatic cleavage reduction. Conclusion: The increased Aβ cleavage activity and the ease of synthesis of 4 renders it an extremely attractive lead compound.

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer’s Disease

“…Гидроксилированные производные монокарбонилкуркумина, содержащие циклогексанон, повышают уровень NEP [180]. В совокупности эти данные позволяют предположить, что куркумин обладает многоцелевой активностью и требует дальнейшего изучения.…”

“…In vivo and in vitro experiments revealed another mechanism of curcumin-induced reduction of Aβ accumulation and deposition: suppression of BACE1 expression [ 178 , 179 ]. Hydroxylated derivatives of monocarbonyl curcumin containing cyclohexanone increase NEP levels [ 180 ]. Taken together, these data suggest that curcumin exhibits multi-targeted activity and warrants further study.…”

The Multi‐Biological Targeted Role of Dehydrozingerone and its Analogues

“…Dimitris Matisdis synthesised numerous hydroxyl-bearing DZG derivatives and described them as good stimulants of the NEP enzyme. [55] Each analogue was evaluated for its ability to induce NEP expression at a maximum dose of 5 μM using two synthesised peptides qf-Aβ(1-7)C and qf-Aβ(12-16)AAC assay. Compound 80 (Figure 14) demonstrated the highest activity percentage (150.08) in the qf-Aβ(1-7)C assay, whereas compounds 81 and 82 (Figure 14) displayed the highest potency in the qf-Aβ(12-16)AAC-EDANS assay, with activity percentages of 124.48 and 125.10, respectively.…”

“…Amyloid plaques (Aβ) have been one of the major causes of Alzheimer's disease, and some studies suggested that the Neprilysin (NEP) enzyme reduces the Aβ peptide level. Dimitris Matisdis synthesised numerous hydroxyl‐bearing DZG derivatives and described them as good stimulants of the NEP enzyme [55] . Each analogue was evaluated for its ability to induce NEP expression at a maximum dose of 5 μM using two synthesised peptides qf‐Aβ(1‐7)C and qf‐Aβ(12‐16)AAC assay.…”

Curcumin Derivatives as Potential Mosquito Larvicidal Agents against Two Mosquito Vectors, Culex pipiens and Aedes albopictus

“…(1E,4E)-1,5-bis (4-hydroxy-3-methoxyphenyl) penta-1,4-dien-3-one 6f [52] Orange solid, Yield: 2.15 g (66%), 1…”