ILX-295501

Muscle-stripped piglet colon was used to evaluate changes in short-circuit current ( Isc) as an indicator of anion secretion. Mucosal exposure to Escherichia coli heat-stable (STa) or heat-labile enterotoxins (LT) stimulated Iscby 32 ± 5 and 42 ± 7 μA/cm2, respectively. Enterotoxin-stimulated Iscwas not significantly affected by either 4,4′-diaminostilbene-2,2′-disulfonic acid or CdCl2, inhibitors of Ca2+-activated Cl−channels and ClC-2 channels, respectively. Alternatively, N-(4-methylphenylsulfonyl)- N′-(4-trifluoromethylphenyl)urea (DASU-02), a compound that inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl−secretion, reduced Iscby 29 ± 7 and 34 ± 11 μA/cm2, respectively. Two additional diarylsulfonylurea (DASU)-based compounds were evaluated for their effects on enterotoxin-stimulated secretion. The rank order of potency for inhibition by these three closely related DASU structures was identical to that observed for human CFTR. The degree of inhibition by each of these compounds was similar for both STa and LT. The structure- and concentration-dependent inhibition shown indicates that CFTR mediates both STa- and LT-stimulated colonic secretion. Similar structure-dependent inhibitory effects were observed in forskolin-stimulated rat colonic epithelium. Thus DASUs compose a family of inhibitors that may be of therapeutic value for the symptomatic treatment of diarrhea resulting from a broad spectrum of causative agents across species.

Potent sulfonamide inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), derivatives of I ,3,4-thiadiazole-2-sulfonamide, possessing inhibition constants in the range of 10(-8)-10(-9) M against isozymes II and IV, were shown to act as efficient in vitro tumour cell growth inhibitors with GI(50) (molarity of inhibitor producing a 50% inhibition of tumour cell growth) values typically in the range of 0.1-30 microM against several leukaemia, non-small cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. The mechanism of antitumour action with the new sulfonamides reported here is unknown, but it might involve either inhibition of several CA isozymes (such as CA IX, CA XII, CA XIV) present predominantly in tumour cell membranes, acidification of the intracellular environment as a consequence of CA inhibition, uncoupling of mitochondria and/or strong CA V inhibition, or a combination of several such mechanisms. Such derivatives might lead to the development of effective novel types of anticancer agents/therapies. ¿ 2000 Editions scientifiques et m|dicales Elsevier SAS.