Comparative study of sister chromatid exchange induction and antitumor effects by homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]butyric acid.

The present work was undertaken in order to test the hypothesis that the Sister Chromatid Exchange (SCE) assay in vitro can be used for the prediction of in vivo tumor response to newly synthesized potential chemotherapeutics. The effect of three homo-aza-steroidal esters containing the -CONH- in the steroidal nucleus, 1, 2, and 3 on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The three substances induced statistically significant enhancement of SCEs and of cell division delays. Compounds 1 and 3 were identified, on a molar basis, as more effective inducers of SCEs and of cell division delays compared with compound 2. Compounds 1 and 3 had upon both experimental tumors better therapeutic effects compared with compound 2 at equitoxic doses. Therefore, the order of the antitumor effectiveness of the three compounds coincided with the order of the cytogenetic effects they induced.

Conjugated system of homo-aza-steroidal esters in cancer chemotherapy.

The homo-aza-steroidal esters of conjugated carboxylic derivatives of nitrogen mustards are reviewed. Particularly we discuss the antitumor activity of cinnamic acid and benzoic acid mustard isomers, esters of homo-aza-steroids in which the mustard acid is linked to the C-3 or C17 position, while the lactam nucleus is in the D or A ring of the steroid respectively. The current literature indicates that the potential is due to the synergistic activity of both the steroidal lactam and the mustard of the acids. Steroidal lactams, namely 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam, the isomer 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic- 13,17-lactam, 3 beta-hydroxy-13 alpha-amino 13,17-seco-5-androsten-17-oic-13,17-lactam and the 17 beta-hydroxy-3-aza-A-homo- 4 alpha-androsten-4-one, have been used as biological platforms of the cinnamic acid, of the benzoic acid mustard isomers and the 4-methyl-benzoic acid mustard. The twelve esters of cinnamic acid mustard isomers were tested against P388, L1210 leukemias Ehrlich ascites tumor (EAT) and melanoma B16 in vivo. The effect of homo-aza-steroidal esters of N,N-bis(2-chloroethyl) amino cinnamic acid isomers on the incorporation of the radioactive precursors into DNA, RNA and proteins of L1210, P388 leukemias, Ehrlich ascites tumor (EAT) and Baby Hamster Kidney (BHK) cells, was investigated. The effect of the homo-aza-steroidal esters of N,N-bis(2-chloroethyl) aminobenzoic acid isomers on the incorporation of radioactive precursors into DNA, RNA and proteins was studied in L1210, P388 leukemias, Ehrlich ascites tumor and Baby hamster kidney cells.

Antitumor activity of homo-aza-steroidal esters of p-N, N-bis(2-chloroethyl)aminophenoxyacetic acid.

The homo-aza-steroidal esters of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline are reviewed. In particular, we discuss the antitumor activity of the esters of homo-aza steroids in which the p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid is linked to the C-3 or C-17 position, while the lactam nucleus is linked to the D or A ring of the modified steroid respectively. The current literature indicates clearly that the potential of these esters is due to the synergistic activity of both the lactam and the p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid.

Hybrid anticancer compounds. Steroidal lactam esters of carboxylic derivatives of N,N-bis (2-chloroethyl) aniline (review).

For the rational design of more specific alkylating agents, we suggested new biological platforms able to deliver the alkylating moieties to specific target site and on the other hand we hoped to lead in compounds with synergistic activity. As biological platforms have been used steroidal lactams of A and D- ring and as alkylating agents carboxylic derivatives of N,N-bis (2-Chloroethyl) aniline which combine to the steroid by an easily cleaved ester bond. These homo-aza-steroidal esters gave satisfactory results in early and advanced P388, L1210 leukemias and solid tumors. Whereas unmodified steroidal esters have generally been reported to be inactive in treatment of L1210 leukemia. The steric arrangement of the alkylating moiety greatly effects toxicity and activity of the drugs, while the steric arrangement of the hydrogen atom at position 5 influences these parameters. Isosterism of alkylating agent is the factor for biological action. The amide group of the lactam molecule may be essential for activity.

Structure-function activity of azasterols and nitrogen-containing steroids.

Thirty-nine nitrogen-containing steroids were tested against two gram-negative, five gram-positive, and two yeast organisms. Many of these steroids have been previously reported to inhibit various metabolic processes involving sterol metabolism. While low minimal inhibitory concentration (MIC) values were recorded for sterol producing yeast, growth of bacteria which contain no sterols was also inhibited. Structure-function studies provided no relationship between biological activity and hypocholesteremic effects of these azasteroids. A hypothesis put forward is that amino and azasteroids are effectors of membrane which, in the case of mitochondria, lead to changes in adenosine triphosphate levels and/or dehydrogenase activity. Their effects on sterol metabolism, therefore, may be of secondary consideration.