Novel steroid-linked conjugates of 17 beta-[N-[N'-(2-chloroethyl)-N'-nitroso]carbamoyl]amino acids and their antineoplastic activity against Noble Nb prostate carcinoma model in rats.
The novel steroid conjugates 17 beta-[N-[N'-(2-chloroethyl)-N'-nitroso] carbamoyl]-glycyl-19-nortestosterone (1) and 17 beta-[N-[N'-(2-chloroethyl)-N'-nitroso]carbamoyl]-L-alyanyl-19- nortestosterone (2) were synthesized and characterized with respect to affinity for steroid receptors and for androgenic efficacy. At an i.p. dosage of 50 mg/kg, conjugates 1 and 2 induced strong tumor inhibition of Nobel Nb prostate carcinoma in rats, but also a marked loss of body weight. In two further experiments, treatment with conjugate 2 at a dosage of 25 mg/kg demonstrated high antitumor activity without indication of toxicity. Conjugate 2 achieved the same tumor growth inhibition as a nearly twofold molar dose of cyclophosphamide. The results indicate reproducibly high antitumor activity of 2 in the Noble Nb model at a well tolerated dosage. A low dose equimolar mixture of unlinked N-(2-chloroethyl)-N-nitrosocarbamoyl (CNC)-alanine and 19-nortestosterone was significantly more toxic than conjugate 2, showing about the same adverse effect on the body weight as the conjugate at high dosage. CNC-L-alanine at equimolar dosage was highly toxic, causing early death of all animals.
Tang
W
W
Department of Chemistry, University of Kaiserslautern, Germany.
Schneider
M R
MR
Eisenbrand
G
G
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009277:Nandrolone / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000970:Antineoplastic Agents; D011944:Receptors, Androgen; D009277:Nandrolone