Synthesis of novel conformationally restricted sulfonamides as antiproliferative agents

GUERRA, WALTER D.; ROSSI ROBERTO A.; JOSE M. PADRÓN; BAROLO, SILVIA M.

Vitoria-Gasteiz

Congreso; 19th National meeting of the Spanish Society of Medicinal Chemistry: New Challenges in Drug Discovery; 2019

Sociedad Española de Química Terapéutica

Sulfonamides have been largely explored for diverse pharmacological applications like antibacterial, diuretic, hypoglycemic and antitumoral. Sulfonamides E7010, E7070 and ER-34410 are well established examples that exhibit interesting antitumor activity. In most cases, the sulfonamide is used as a bridge to connect aromatic or heteroaromatic systems. However, the inclusion of the sulfonamide in a ring resulting in tricyclic systems has been scarcely explored. This approach perfectly fits the concept of molecular conformational restriction that has wide applications in medicinal chemistry. Our research group developed a synthetic strategy to obtain fused sulfonamides by photoinduced intramolecular arylation of N-aryl-2-halobenzenesulfonamides. As a result, we have transformed the diaryl sulfonamides into structurally rigid tricyclic analogues, and we have now extended this methodology to a wider series of substrates. Thus, we have prepared three different families: i) non-fused sulfonamides, family 1; ii) fused sulfonamides, family 2; and iii) N-substituted fused sulfonamides, family 3, in many cases in excellent yields (up to 98%, Scheme 1). We have explored the nature and position of the substituents on the aromatic rings (A and B) and the substitution on the free NH of the sulfonamide cores in order to study their influence on the antitumor activity.The biological evaluation of these compounds was performed by measuring their antiproliferative activity against six human cancer cell lines. We report herein the results obtained and the structure-activity relationship (SAR) studies, that support the interest of these compounds as a new scaffold for anticancer compounds.