Distribution Studies with Sulfur 35-Labeled Disulfonamides in Tumor-bearing and Tumor-free Mice

Abstract

THE desirability of finding a radioactive compound that would localize in tumor tissue and which could be used in the diagnosis and therapy of internal cancer has long been recognized. Previous studies carried out in our Laboratory have shown that with certain sulfur 35-labeled derivatives of fluorene, localization in tumor tissue is favorable compared to liver, kidneys, spleen, blood and muscle. The first of these promising compounds was disodium fluorene-2,7-disulfonate-S35 (Argus, 1953). This compound was then used as the basis for the synthesis of a number of related substances which could be used for investigating the relation of chemical structure to tumor localizing properties in the hope of obtaining compounds of improved characteristics. Of those tested, sulfonated fluorene-2,7-di-(sulfonamido-2'-naphthalene)-S35 showed the best tumor localization. Two compounds without free sulfonic acid groups, fluorene-2,7-disulfonamide-S35 and fluorene-2,7-di-(sulfonamido-2'-naphthalene)-S35, did not selectively concentrate in tumor tissue (Argus and Hewson, 1954). There seemed to be some indication at 8 hours, however, that the latter compound showed a differential in the blood between tumor-bearers and non-tumor-bearers. This difference was not large but if real could be of considerable diagnostic importance since there was the possibility that the effect could be enhanced in a new compound of suitable structure.In the present study three new substances were investigated in tumor-bearing and tumor-free mice. These were fluorene-2,7-di-(sulfonamidobenzene)-S35 (I), a disulfonamido derivative of fluorene with molecular weight falling between the compounds previously tested; and two related biphenyl derivatives, biphenyl-4, 4'-di-(sulfonamidobenzene-4-carboxylic acid)-S35 (II) and biphenyl-4,4'-di-(sulfonamidobenzene-S35-4-sulfonamide) (III Biphenyl-4,4'-di-(sulfonamidobenzene-4-carboxylic acid)-S35 (II).-Biphenyl-4, 4'-disulfonyl chloride-S35, 1-7 g. (0-005 moles), was finely powdered and slowly added to a solution of p-aminobenzoic acid, 2-8 g. (0-020 moles), in 30 ml. anhydrous acetone. The mixture was stirred for 30 minutes at reflux temperature and for 10 hours at room temperature. The light gray precipitate was collected, washed with 750 ml. hot water and dried over phosphorus pentoxide. The yield was 2-6 g. (82-6 per cent of theory); the compound melted at 3200. Recrystallization by dissolving in 70 ml. of a 2: 5 mixture of water: dimethylformamide and precipitating with 30 ml. of water gave a white product melting at 3270 and having a specific activity of 16,000 disintegrations per second per mg. Analyses gave 56-15 and 56-20 per cent C, 4-96 and 5-03 per cent N, and 11-26 and 11-28 per cent S; the calculated values are 56-51 per cent C, 5-07 per cent N, and 11-61 per cent S.Biphenyl-4,4'-di-(sulfonamidobenzene-S35-4-sulfonamide) (111).-Biphenyl-4,4'-disulfonyl chloride-S35, 3 g. (0-0085 moles), dissolved in 35 ml. of anhydrous acetone was added with stirring to a solution of sulfanilamide, 7-35 g. (0-42 mole...