Structure--anticancer and structure--genetic activity relationships of homo-aza-steroidal esters of N,N-bis(2-chloroethyl)aminocinnamic acid isomers.
Four steroidal lactams of the A- and D-rings were used for the esterification in the C-3 or C-17 positions, respectively, of their nuclei with the N,N-bis(2-chloroethyl)aminocinnamic acid isomers. The condensation reaction of the hydroxylic group of the steroidal lactams with each mustard was effected in dichloromethane in the presence of the catalyst p-dimethylaminopyridine and dicyclohexylcarbodiimide as dehydrating agent. The esters were obtained in pure form after column chromatography, and their structures were verified and confirmed by analytical methods (IR and UV spectra). The 12 esters were tested in vivo against P388, L1210 leukemias, Ehrlich ascites tumor, and melanoma B16. The esters 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17- oic-13,17-lactam-o,m,p-N,N-bis(2-chloroethyl)aminocinnamates, in which the alkylating agents are linked to the modified steroid in the axial position, are inactive in the above experimental animal tumor systems. The effect of the homo-aza-steroidal esters of N,N-bis(2-chloroethyl)aminocinnamic acid isomers on the incorporation of radioactive precursors into DNA, RNA, and proteins of L1210, P388 leukemias, Ehrlich ascites tumor, and baby hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursors was obtained with the ortho-derivatives, yielding > 40% inhibition of thymidine incorporation in all tumor lines tested. The effect of four esters in which the m- N,N-bis(2-chloroethyl)aminocinnamic acid is linked to the modified steroids on sister chromatid exchanges in human lymphocyte culture was investigated.
Catsoulacos
P
P
University of Patras, School of Health and Sciences, Department of Pharmacy, Greece.
Camoutsis
C
C
Papageorgiou
A
A
Margariti
E
E
Psaraki
K
K
Demopoulos
N
N
D000477:Alkylating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001378:Azasteroids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002934:Cinnamates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009153:Mutagens / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000378:metabolism
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D001378:Azasteroids; D002934:Cinnamates; D009153:Mutagens; D007930:Leucine; D013936:Thymidine; D014529:Uridine