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

Abstract

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 (K_i = 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.