Dual-Functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-κB Activation

Abstract

Taxchinin A, with a 11(15→1)-abeo-taxane skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis. In our design of dual-functional antitumor abeo-taxane derivatives, two fragments from antitumor agents with different molecular targets (the N-acyl-3′-phenylisoserine side chain from the antimitotic agent paclitaxel and an α,β-unsaturated carbonyl system from NF-κB inhibitors) were incorporated into the scaffold of taxchinin A. The resulting compounds displayed broad inhibitory effects against proliferation of tumor cell lines, with notable selectivity towards colon cancer, melanoma and renal cancer, when evaluated in the NCI-60 human tumor cell line screening panel. Based on the NCI-60 assay data, structure-activity relationship (SAR) correlations were elucidated. Mechanistic studies indicated that this new compound type can both destabilize microtubules and inhibit NF-κB activation, thereby inducing tumor cell apoptosis. This first report of the dual-functional taxoid-core compounds thus provides new opportunities for future drug development based on natural taxoid scaffolds.

Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation

“…There are also a number of studies demonstrating a reduction in NF-κB activation together with microtubule destabilisation and cell death. For example, destabilising taxoid derivatives reduced TNFαinduced NF-κB activity in HEK293 cells by up to 6.5-fold (Zhao et al 2013) and Jackman et al (2009) showed that this effect likely involves a requirement for physical interaction between microtubules and the TNF-α receptor activation complex, as well as being able to occur directly, with activation of NF-κB being induced directly by microtubule stabilisers without the presence of TNFα.…”

A One-Pot Three-Component Synthesis and Investigation of the In Vitro Mechanistic Anticancer Activity of Highly Functionalized Spirooxindole-Pyrrolidine Heterocyclic Hybrids

“…The prominent advantage of employing the molecular hybridization approach is to trigger diverse targets by a sole molecule, thus increasing the therapeutic effectiveness and bioavailability profiles. Promisingly, noteworthy results with a diverse group of heterocyclic hybrids have been elegantly recognized as a result of this approach [11][12][13][14][15][16][17][18].…”

New Cytotoxic Naphthohydroquinone Dimers from Rubia alata

“…Compounds 1 and 2 were also evaluated for their effects on the NF-κB pathway (Figure 5). 20 Only compound (+)-1 could inhibit TNF-α induced NF-κB activation at 40 μM (Figure 5A). But 2 could activate the NF-κB pathway with the existence of TNF-α, which revealed the synergistic effect of 2 with TNF-α on NF-κB activation (Figure 5B).…”

“…Compounds 1 and 2 were also evaluated for their effects on the NF-κB pathway (Figure ) . Only compound (+)- 1 could inhibit TNF-α induced NF-κB activation at 40 μM (Figure A).…”