Design, synthesis and biological profile of new inhibitors of multidrug resistance associated proteins carrying a polycyclic scaffold

作者：Bisi Alessandra^*; Gobbi Silvia; Merolle Lucia; Farruggia Giovanna; Belluti Federica; Rampa Angela; Molnar Joseph; Malucelli Emil; Cappadone Concettina

来源：European Journal of Medicinal Chemistry, 2015, 92: 471-480.

DOI：10.1016/j.ejmech.2015.01.004

• P-glycoprotein
• MDR-1
• MDR modulators
• Chemosensitizers
• Anticancer
• Drug design

Following the identification of a novel polycyclic scaffold, leading to the previously reported potent P-gp modulator 1, a small series of easily affordable derivatives bearing a properly selected nitrogen-containing but-2-ynyl side chain was now synthesized and tested to evaluate the MDR reverting activity on two different experimental models. All compounds proved not to be cytotoxic when tested alone and more potent chemosensitizers than the reference verapamil. Some of them showed remarkable effects in combination with doxorubicin, being able to induce apoptotic cell death due to their reverting activity. In particular, 2a and 2c could be regarded as non-toxic new potential chemosensitizers, being able to interfere with different ABC proteins. Moreover, the intrinsic cytotoxicity of compound 1 could broaden its employment as MDR modulator. These results also seem to confirm the polycyclic core of these compounds as a potential new pharmacophoric carrier in medicinal chemistry.

• 出版日期2015-3-6
• 单位河北医科大学