A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

Abstract

Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.

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

“…As described in Ref. [ 46 ], we built a model for the tubulin-dimer based on the PDB 1SA1 [ 47 ] crystal structure, for which podophyllotoxin was resolved at the colchicine site, close to the dimerization interface of the tubulin-dimer. Coordinates of the hydrogen atoms were generated with CHARMM [ 48 ] using standard protonation states for all the titratable residues.…”

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

“…Our research group has been interested for many years in the design of podophyllotoxin derivatives lacking the lactone ring. In this regard, several podophyllic aldehyde derivatives hybridized with other bioactive compounds have been described, such as lignopurines [ 25 ] and more recently lignoquinones [ 187 ] and biscyclolignans [ 188 ].…”

“…Lignohydroquinones are a family of molecular hybrids formed by the junction of the podophyllotoxin derivative, the podophyllic aldehyde, and several diterpenylnapthohydroquinones (DNHQs) and monoterpenylhydroquinones (MNHQs) through aliphatic or aromatic linkers [ 187 , 194 ] ( Scheme 45 ). The first class of compounds were synthesized by attaching the linker to the DNHQ ( 160 ) through the carboxylic acid presented in myrceocommunic acid ( 157 ) [ 188 ]. In the case of lignohydroquinones derived from MNHQs, oxidation of the β-myrcene rest double bond to carboxylic acid was first accomplished before linker attachment [ 194 ].…”

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

“…Recently, another compound, 39, was identified via a similar approach (Figure 9). 94 It is a novel conjugate of podophyllotoxin (a tubulin polymerization inhibitor) and etoposide (a topo II inhibitor), exhibiting the inhibitory potency of microtubule polymerization and topo II. Moreover, compound 39 can perturb the cell cycle through a dual mechanism of action and showed superior antiproliferative activity compared to two parent compounds.…”