New Antineoplastic Naphthohydroquinones Attached to Labdane and Rearranged Diterpene Skeletons

© 2021 by the authors.
Terpenylquinones are mixed biogenesis primary or secondary metabolites widespread in Nature with many biological activities, including the antineoplastic cytotoxicity, that have inspired this work. Here, we present a cytotoxic structure-activity relationship of several diterpenylhydroquinone (DTHQ) derivatives, obtained from the natural labdane diterpenoid myrceocommunic acid used as starting material. Different structural modifications, that changed the functionality and stereochemistry of the decalin, have been implemented on the bicyclic core through epoxidation, ozonolysis or decarboxylation, and through induction of biomimetic breaks and rearrangements of the diterpene skeleton. All the isomers generated were completely characterized by spectroscopic procedures. The resulting compounds have been tested in vitro on cultured cancer cells, showing their relevant antineoplastic cytotoxicity, with GI50 values in the μM and sub-μM range. The rearranged compound 8 showed the best cytotoxic results, with GI50 at the submicromolar range, retaining the cytotoxicity level of the parent compounds. In this report, the versatility of the labdane skeleton for chemical transformation and the interest to continue using structural modifications to obtain new bioactive compounds are demonstrated.
This research was funded by Spanish MINECO (CTQ2015-68175-R, AGL2016-79813-C2-2-R), Junta de Castilla y Leo ´n (SA076P20) and ISCIII-RICET Network (RD16/00270018) cofinanced by the Fondo Social Europeo of the European Union (Fondos FEDER—EU) and USAL (Financiación GIR).