Synthesis and biological evaluation of Hsp90/HDAC6 dual inhibitors bearing a 2-amino-pyrrolopyrimidine and purine scaffold as potential anticancer drugs to treat prostate cancer

Prostate cancer (PC) is the second common tumor diagnosed in men. Although current treatments are effective at the early stage of the disease, they lack efficacy in advanced stage and metastatic castrate-resistant prostate cancer (CRPC). HDAC6 and Hsp90 play a significant role in cellular processes and are involved in tumor genesis, metastasis and drug resistance.1-2 Therefore, the possibility to simultaneous inhibit HDAC6 and Hsp90 would represent a promising strategy to treat CRPC. Recently, we identified potent pyrrolo-pyrimidine/purine HDAC inhibitors with excellent antiproliferative activity and anti-migration properties on PC.3-4 The 2-amino-pyrrolopyrimidine scaffold is also present in potent Hsp90 inhibitors. Thus, in the search of Hsp90/HDAC6 dual inhibitors we designed two series of 2-amino-pyrrolopyrimidine and purine derivatives carrying an hydroxamate or 3 hydroxyisoxazole as Zinc Binding Group required to coordinate the catalytic zinc ion present in the small hydrophobic pocket of HDAC6, and a benzyl linker of variable length with different decorations (Figure 1). Two efficient synthetic routes were identified, allowing the obtainment of the desired products. The compounds were tested in vitro to assess their ability to inhibit recombinant HDAC6 and Hsp90. The results of the in silico design, chemical synthesis, and biological evaluation of the two series of compounds will be presented.