A series of diarylsulfonylureas with exceptionally broad-spectrum activity against syngeneic rodent solid tumors in vivo is described. Their discovery resulted from a program dedicated to in vivo screening for novel oncolytics in solid tumor models, rather than traditional ascites leukemia models. The structures, oral efficacy, side-effect profile, and mechanism of action of these sulfonylureas appear to be distinct from previously known classes of oncolytics. An extensive series of analogues was prepared to probe structure-activity relationships (SAR), with particular focus on the substituent patterns of each aryl domain. Quantitative analysis of these substituent SARs, using the method of cluster significance analysis, showed the lipophilicity of the substituents to be the dominant determinant of activity. One compound from the series, LY186641 (104, sulofenur), has progressed to Phase I clinical trials as an antitumor drug.

Vlndesine(VDS; deacetyl vinblastineamide sulfate) giveni.p. dailycompletelyinhibitedthe growthof boththe Ridgewayosteogenic sarcomaat 0.4mg/kgandthe Gard ncrIymphosarcóma at 0.25mg/kg.Incontrast,the parent alkaloid, vinbbastine (VLB), at 0.5 mg/kg was inactive againstthesetwotumors.VDScausedinhibition ofgrowth of the Meccalymphosarcoma thatwascomparableto the inhibitionby vincristine(VCR),(60versus68%)whileVLB caused 41% inhibition.The Ca115 Shlonogimammary carcinomadidnotrespondto VDS,butbothVLBandVCR causedinhibitions of 62and67%,respectively. TheCa755 mammaryadenocarcinoma showeda moderateresponse to VDS (46%)and VCR (39%),and no responseto VLB. The Sarcoma180 ascitestumor(solid,s.c.), the X5563 myeloma,and the C3H mammarycarcinomawere not responsive to VDS,VLB,or VCR. VDScauseda 113%prolongation of life in micewiththe B16melanoma(i.p.), and there were three of ten 45-day survivorsin one study,andten of ten 45-daysurvivorsin anotherstudy.VLBhadtwoof ten andeightof ten 45-day survivorsin the same studies.Animalsinoculatedwith the P388leukemiaandthe Walker256andEhrlichascites tumorshad greater than 100% prolongation of life with manyindefinitesurvivorswhentreatedwithVDS,VLB,or VCR. The L1210, AKR, L5178Y,and C1498 leukemias showsdnoresponseto VDSgivendailyat I.0 mg/kg. In tissueculturesof Chinesehamsterovarycells, the minimum effectiveconcentration of VDSthatcaused10to 15%accumulation of cellsin mitosiswas2.3 x 1O@N, for VLBit was 2.2 x 1O@M,andfor VCRft was 7.3 x 1O@M. The concentration of VDSneededfor 40 to 50%accumu lationof cells in mitosiswas 2.8 x 1O@M;for VLBit was 8.3 x 1O-@ M; and for VCR ft was 2.4 x 1O@N.