Discovery of Novel Hsp90 Inhibitor-Evodiamine Derivative Conjugates as Potent and Orally Active Antitumor Agents for Colon Cancer Therapy

Natural products (NPs) and their derivatives have long been important components of antitumor drugs. Nevertheless, traditional natural product derivatives are generally limited by tumor-targeting deficiency and toxicity to normal tissue. Particularly, there remains a lack of effective strategies to improve in vivo antitumor efficacy and reduce the toxicity of natural product derivatives. Herein, a series of heat shock protein 90 (Hsp90) inhibitor-evodiamine (an NP from Evodiae fructus) conjugates were rationally designed, binding extracellular Hsp90 (eHsp90), which could mediate endocytosis to improve the antitumor efficacy of evodiamine derivatives. Notably, conjugate 5a demonstrated a potent antitumor efficacy. It exhibited significant in vitro antiproliferative activity (IC50 = 7.7 nM) and high Hsp90 inhibitory activity (IC50 = 19.4 nM). Furthermore, conjugate 5a achieved excellent in vivo tumor growth inhibition upon intraperitoneal injection (12 mg/kg; TGI = 72.9%) and oral administration (24 mg/kg; TGI = 61.2%).