Synthesis and evaluation of some nitrobenzenesulfonamides containing nitroisopropyl and (ureidooxy)methyl groups as novel hypoxic cell selective cytotoxic agents.
Basic nitrobenzenesulfonamides containing nitroisopropyl and (ureidooxy)methyl groups were prepared and evaluated as novel hypoxic cell selective cytotoxic agents. In vitro, N-(2-aminoethyl)-N-methyl-3-nitro-4-(1-methyl-1-nitroethyl)benzene sulfonamide hydrochloride (11) proved to be preferentially toxic to hypoxic EMT6 mammary carcinoma cells. At 1 mM concentration in vitro, 11 reduced the surviving fraction of these hypoxic cells to 3 x 10(-3) with no effect on aerobic cells. In radiation experiments, 11 appeared to function as a hypoxic cell radiosensitizer as well as a selective cytotoxic agent. However, administration of 11 at 200 mg/kg ip or 100 mg/kg iv to BALB/c mice implanted with solid EMT6 tumors produced no evidence of significant in vivo cytotoxic or radiosensitizing activity. N-Methyl-N-[2-(methylamino)ethyl]-3-nitro-4- [(ureidooxy)methyl]benzenesulfonamide hydrochloride (20) showed slight differential toxicity toward EMT6 cells at 3 mM concentration and radiosensitizing activity comparable to misonidazole at 1 mM concentration.
Saari
W S
WS
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Schwering
J E
JE
Lyle
P A
PA
Engelhardt
E L
EL
Sartorelli
A C
AC
Rockwell
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010100:Oxygen / Q000008:administration & dosage*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D009578:Nitrobenzenes; D010100:Oxygen; D013449:Sulfonamides; C071276:N-(2-aminoethyl)-N-methyl-3-nitro-4-(1-methyl-1-nitroethyl)benzenesulfonamide; D000096926:Benzenesulfonamides