Pteridine-Sulfonamide Conjugates as Dual Inhibitors of Carbonic Anhydrases and Dihydrofolate Reductase with Potential Antitumor Activity

Marques, Sérgio M. and Enyedy, Éva Anna and Supuran, Claudiu T. and Krupenko, Natalia I. and Krupenko, Sergey A. and Santos, M. Amélia (2010) Pteridine-Sulfonamide Conjugates as Dual Inhibitors of Carbonic Anhydrases and Dihydrofolate Reductase with Potential Antitumor Activity. BIOORGANIC & MEDICINAL CHEMISTRY, 18 (14). pp. 5081-5089. ISSN 0968-0896

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Abstract

Recent evidences suggest that cancer treatment based on combination of cytostatic and conventional chemostatic therapeutics, which are usually cytotoxic, can provide an improved curative option. On the sequence of our previous work on methotrexate (MTX) derivatives, we have developed and evaluated novel MTX analogues, containing a pteridine moiety conjugated with benzenesulfonamide derivatives, thus endowed with the potential capacity for dual inhibition of dihydrofolate reductase (DHFR) and carbonic anhydrases (CA). These enzymes are often overexpressed in tumors and are involved in two unrelated cellular pathways, important for tumor survival and progression. Their simultaneous inhibition may turn beneficial in terms of enhanced antitumor activity. Herein we report the design and synthesis of several diaminopteridine–benzenesulfonamide and -benzenesulfonate conjugates, differing in the nature and size of the spacer group between the two key moieties. The inhibition studies performed on a set of CAs and DHFR, revealed the activities in the low nanomolar and low micromolar ranges of concentration, respectively. Some inhibitors showed selectivity for the tumor-related CA (isozyme IX). Cell proliferation assays using two tumor cell lines (the non-small cell lung carcinoma, A549, and prostate carcinoma, PC-3) showed activities only in the millimolar range. Nevertheless, this fact points out the need of improving the cell intake properties of these new compounds, since the general inhibitory profiles revealed their potential as anticancer agents.

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