Synthesis and Biological Evaluation of Strong Cytotoxic Maleimide Derivatives with Potential Multidrug Resistance Reversal Activity in the Breast Cancer Therapy

Abstract

Maleimide core is a broadly used chemical-based scaffold for natural and new compounds synthesis. Several of them show anticancer and multidrug resistance (MDR) reversal activity. A new family of twelve 3,4-substituted N-benzyl and N-methyl maleimides were synthesized in a two-step sequence consisting of bromination and Suzuki cross-coupling or bromination–thiolation. We were able to obtain two groups of maleimide derivatives which were tested and determining their cytotoxicity. Following our previous work, the biological activity of these compounds as MDR reversal agents was tested with a cancerous cell line MCF-7 that has been exposed chronically to etoposide to achieve MDR. MCF-7 cell line resistant to etoposide (MCF-7R), was treated with a combination of etoposide and the synthetized compounds. The results presented strong effects in compounds 20, 21, 22, 23, 24, and 25 in no resistant and resistant cells, the IC₅₀ values for the proliferation inhibition ranged from 1.8–30.8 µM. The combination between etoposide and maleimide shows proliferation increase in most of the compounds except for compound 15 where it was shown a MDR low reversion degree. These findings suggest that maleimides tested in this work can be used in tumorigenic cancer cells before and after acquiring resistance. The combination with etoposide should be evaluated considering that an undesirable effect can be caused due to proliferation increase.