Rational design,synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

Heat shock protein 90 (Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin (GA) is the first identified Hsp90 inhibitor that exhibited potent anti-cancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1 (C6-ethyl) and 2 (C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds 1 and 2 bind to Hsp90 protein with the IC₅₀ of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.