Sideroxylonal B: A Dimeric Phloroglucinol From Eucalyptus cinerea With In Vitro Carbonic Anhydrase Inhibition and Evaluation of Cytotoxicity and Antiviral Potential

Sideroxylonal B, a natural dimeric acylphloroglucinol, demonstrates promising anticancer potential through a dual mechanism of action involving both cytotoxicity and selective enzyme inhibition. In preliminary screening against the NCI 60 human tumor cell line panel at a concentration of 10–5M, sideroxylonal B exhibited moderate but selective antiproliferative activity, particularly against leukemia (CCRF-CEM, RPMI-8226), breast (MCF7), and renal (CAKI-1) cancer cell lines. Notably, sideroxylonal B selectively inhibits tumor-associated carbonic anhydrase isoforms hCA IX and XII (Ki = 28.1 and 44.4 µM), with minimal inhibition of isoforms hCA I and II. Molecular docking and MM-GBSA binding energy simulations corroborated its selective interaction profile, highlighting its preferential binding to the more accommodating active sites of hCA IX and XII via hydrogen bonds and π–π interactions. The compound showed no antiviral activity against coxsackievirus B3 (CVB3) or Human Herpes virus type 1 (HHV-1). These findings suggest sideroxylonal B as a novel and selective natural carbonic anhydrase inhibitor with a unique structural scaffold, to be further explored for its potential application in targeted cancer therapy.