New Antineoplastic Naphthohydroquinones Attached to Labdane and Rearranged Diterpene Skeletons

Abstract

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.

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

“…Terpenylquinones, on their part, are mixed biogenetic secondary metabolites widespread in nature that have interesting pharmacological activities, such as antifungal, antiviral, antileishmanial, or antineoplastic, among others [ 191 ]. Our research group also has a great deal of experience in the semisynthesis of this type of compound from natural terpenoids [ 192 , 193 ].…”

Improving Properties of Podophyllic Aldehyde-Derived Cyclolignans: Design, Synthesis and Evaluation of Novel Lignohydroquinones, Dual-Selective Hybrids against Colorectal Cancer Cells

“…In previous work [ 38 ], we prepared hybrids, generically named lignohydroquinones (L-HQs), by linking cyclolignans (L) and a diterpenylnaphthohydroquinone (DHQ, Figure 2 ) through aliphatic and aromatic linkers. The DHQ was obtained by us from the natural diterpenoid myrceocommunic acid [ 40 ] and the cyclolignan scaffold was obtained by transforming podophyllotoxin ( 1 ) into the podophyllic aldehyde ( 2 ) ( Figure 2 ) [ 33 ].…”