1133784-46-9

Upstream product

• 1133784-45-8 ethyl 5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxylate 

Relevant academic research and scientific papers

Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation

Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.

Optimized HSP90 mediated fluorescent probes for cancer-specific bioimaging

Cancer-specific bioimaging has been correlated with fluorescence-guided tumor therapy, garnering extensive interest from researchers. Herein, a highly efficient tumor-targeting fluorescent probe (NP-001), which is integrated with 4-hydroxy-1,8-naphthalimide and NVP-AUY922, for tumor imaging has been established. 4-Hydroxy-1,8-naphthalimide is a fluorescent molecule with remarkable imaging compatibility. NVP-AUY922 is a heat shock protein 90 (HSP90) inhibitor with preferential tumor selectivity that is conjugated to 4-hydroxy-1,8-naphthalimide as a tumor-targeting ligand. NP-002, a resorcinol-blocked probe which prevented binding with an amino acid residue of the HSP90 ATP binding pocket, was also synthesized as a control. In vitro and ex vivo assays showed that NP-001 could arrest cell proliferation, induce apoptosis and accumulate to inhibit HSP90. Confocal laser scanning microscopy (CLSM) also confirmed that NP-001 could be selectively internalized by tumor cells for cancer-specific bioimaging. Moreover, pharmacokinetic studies and histological analysis also indicated that NP-001 had a relatively longer retention time and showed no major organ-related toxicities. Overall, these encouraging data suggest that NP-001 is a promising new candidate for the early diagnosis of metastatic disease as well as targeted tumor imaging.

HSP90 INHIBITORS CONTAINING A ZINC BINDING MOIETY

The present invention relates to HSP90 inhibitors containing a zinc binding moiety and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.