| Literature DB >> 30925064 |
Prashant Mujumdar1, Joanna Kopecka2, Silvia Bua3, Claudiu T Supuran3, Chiara Riganti2, Sally-Ann Poulsen1.
Abstract
The natural product primary sulfonamide, psammaplin C (1), when used in combination with clinically used chemotherapeutic drugs, including temozolomide, reverses multidrug resistance and increases survival in glioblastoma, a highly aggressive primary brain tumor. We showed previously that the mechanism of action of 1 is novel, acting to indirectly interfere with P-glycoprotein drug efflux activity as a consequence of carbonic anhydrase XII (CA XII) inhibition. To build structure-activity relationships, 45 derivatives of 1 were designed, synthesized, and evaluated against a panel of CA isoforms. Compound 55 was identified as a potent inhibitor of CA XII ( Ki = 0.56 nM) and was investigated in vitro and in vivo using samples from glioblastoma patients. The results strengthen the possibility that co-therapy of temozolomide with a CA XII inhibitor may more effectively treat glioblastoma by suppressing an important temozolomide resistance mechanism.Entities:
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Year: 2019 PMID： 30925064 DOI： 10.1021/acs.jmedchem.9b00282
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446