Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities

Abstract

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90–Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a–2d, 3a–3g, and 4a–4t, were designed and synthesized, and their Hsp90–Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90–Cdc37 disruption activity (IC50 = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90–Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.

Prodrug-inspired adenosine triphosphate–activatable celastrol-Fe(III) chelate for cancer therapy

“…In the Hsp90-Cdc37 complex [Protein Data Bank (PDB): 2K5B], key hydrogen bonds were identified between Gln 133 (Hsp90)–Arg 166 /Arg 167 (Cdc37) and Arg 46 /Glu 47 (Hsp90)–Asp170 (Cdc37) (fig. S8) ( 23 , 68 ). CEL disrupts these bonds by occupying the hydrophobic pocket ( 40 , 65 ).…”

Thiazolidinedione-Based Structure Modification of Celastrol Provides Thiazolidinedione-Conjugated Derivatives as Potent Agents against Non-Small-Cell Lung Cancer Cells through a Mitochondria-Mediated Apoptotic Pathway

“…A xenograft model is a well-studied and adopted in vivo model that is used for cancer research and drug discovery . The antitumor activity of compound 10b in vivo was further evaluated with a xenograft model generated by grafting A549 cells in nude mice.…”

Recent advances of N-heterocyclic carbenes in the applications of constructing carbo- and heterocyclic frameworks with potential biological activity

“…Cyclic organic frameworks, especially heterocyclic frameworks, are widely distributed motifs in numerous biologically active molecules, including natural products and pharmaceutical molecules, which occupy a crucial position in organic and medicinal chemistry. 1 The interest toward the discovery of novel and elegant approaches for the construction of these complex carbocycles and heterocycles has been enduring, due to their potential in the production of pharmaceutically active compounds. 2 Organocatalysts are tremendously attractive for assembling these bioactive cyclic compounds.…”