Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer's disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 mu M. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 x 10(-6) cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.

Automated summary

Nowadays, Se-containing molecules, such as ebselen, have demonstrated well-established preventive effects against cancer and Alzheimer's disease. In this study, a total of 39 Se-derivatives were synthesized and tested for their antioxidant and antiproliferative activities. Compound 13a showed concentration- and time-dependent radical scavenging activity, while compounds 14a and 17a exhibited high activity in certain cancer cell lines. Compound 14a also showed promising potential as an anti-Alzheimer agent.