The Design, Synthesis, and Evaluation of Coumarin Ring Derivatives of the Novobiocin Scaffold that Exhibit Antiproliferative Activity

Abstract

Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Cterminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at ~700 μM in breast cancer cells (SkBr3). Although many analogues of novobiocin have been synthesized, it was only recently demonstrated that monomeric species can exhibit anti-proliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated for elucidation of structure-activity relationships for novobiocin as an anti-cancer agent. Results obtained from these studies have produced novobiocin analogues that manifest low micromolar activity against several cancer cell lines.

KU135, a Novel Novobiocin-Derived C-Terminal Inhibitor of the 90-kDa Heat Shock Protein, Exerts Potent Antiproliferative Effects in Human Leukemic Cells

“…However, the potential clinical utility of several of the N-terminal inhibitors as anticancer drugs has been dampened significantly due to concerns about their adverse hepatotoxic effects (Egorin et al, 1998) and tendency to induce expression of cytoprotective Hsp90 and Hsp70 proteins (Chiosis et al, 2003;Whitesell et al, 2003;Powers and Workman, 2007;Schmitt et al, 2007). More recently, the observation was made that Hsp90 contains a previously unrecognized C-terminal ATP-binding domain (Marcu et al, 2000a,b), which has led several groups to pursue the development of specific C-terminal Hsp90 inhibitors as potential anticancer drug modalities (Burlison et al, 2006Le Bras et al, 2007;Donnelly et al, 2008;Radanyi et al, 2009). Both N-terminal and C-terminal Hsp90 inhibitors can exert an antiproliferative response, in some instances, by stimulating apoptosis (Isaacs et al, 2003;Georgakis and Younes, 2005;Whitesell and Lindquist, 2005), although the underlying mechanisms are not well understood.…”

Induction of Suicidal Erythrocyte Death by Novobiocin

“…Those concentrations have been shown for instance to decrease viability of nucleated cells [76], to enhance NO accumulation [77] and to induce metazoan apoptosis [78]. Even higher concentrations of novobiocin have been employed to stimulate degradation of Hsp90-dependent client proteins [79,80,81], to inhibit self-splicing of primary transcripts of the phage T4 thymidylate synthase gene [82] and to inhibit intestinal secretion [83]. However, at lower concentrations, novobiocin may exert a variety of effects, including inhibition of the organic anion transporters hOAT1, hOAT3, and hOAT4 [84] and neurotoxicity [85].…”

Efficient Synthesis of Novel 3-Substituted Coumarin-3-carboxamide

“…15 According to these results, the number of amide bonds and also their position in the structure of coumarin scaffold could affect the type of biological activity. 16−20 Meanwhile, coumarins are the largest class of laser dyes and highly sensitive for the blue-green region, include commercially available fluorescent derivatives of extended spectral range, high emission quantum yield, photostability and good solubility in many solvents.…”