The pK_a values of a dataset of PROTACs and PROTAC precursors have been analyzed in order to show how a fine modulation of piperazine-containing linkers can impact their protonation state.

Background/Objectives: Salvia officinalis L. is widely used in food supplements, particularly those intended to support women’s health and alleviate menopausal vasomotor symptoms. However, the extent to which estrogen receptor signaling contributes to its reported clinical benefits remains unclear. Therefore, evaluating its potential endocrine activity is a key aspect of its toxicological characterization and overall safety assessment. The present study aimed to investigate the potential estrogenic effects of a standardized Italian Salvia officinalis L. extract (Salvira™), as well as its biological effects on estrogen-responsive breast cancer cells (MCF-7). Methods: In vitro enzymatic assays and estrogen receptor alpha (ERα) agonist- and antagonist-mode experiments were performed to assess its ability to modulate ERα signaling. Moreover, cell viability, proliferation, and clonogenic capacity were assessed in MCF-7 cells following exposure to increasing concentrations of the extract. Results: The extract did not exhibit estrogenic activity in all experimental dose–response assays. In MCF-7 cells, treatment with the sage extract did not produce an overall effect on cell viability or proliferative capacity. Moreover, no impairment of long-term clonogenic potential was observed at the tested concentrations. Conclusions: Under the experimental conditions investigated, the present findings suggest that the standardized Salvia officinalis L. extract showed no evidence of estrogenic activity and did not induce relevant ERα-mediated biological effects in estrogen-responsive MCF-7 cells. These findings contribute to the characterization of the endocrine safety profile of the extract, supporting its safe use as an ingredient in food supplements.