The homo-aza-steroidal ester of [p-[bis(2-chloroethyl)amino]phenoxy] acetic acid, 3 beta-hydroxy 13 alpha - amino - 13,17 - seco - 5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenoxyacetate, gave a 100% increase in lifespan over controls in the treatment of L1210 leukemia by IP administration on a days 1 and 4 treatment schedule. This ester gave a maximum activity of 383% increased lifespan over controls in the treatment of P388 leukemia by IP administration on a daily treatment schedule. Activity in advanced L1210 (41% increased lifespan) and P388 leukemias (173% increased lifespan) was maintained, indicating that this compound is the most promising of a number of congeners tested to date.
Three new modified steroidal alkylating agents, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenylacetate, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis-(2-chloroethyl)aminophenylbutyrate, and 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenylacetate are active in treatment of L1210 and P388 leukemias. A stereoisomer of the first compound, 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13, 17-lactam-p-bis(2-chloroethyl)aminophenylacetate, was tested in L1210 leukemia. This stereoisomer, in which the alkylating agent is linked to the modified steroid in the axial position, is active only as much higher doses in L1210 leukemia. The results of testing these compounds and previous results from similar compounds allow certain conclusions to be drawn regarding structure-activity relationships. The presence of the lactam moiety is the major structural feature that confers activity in the murine leukemias. The steric arrangement of the alkylating moiety at position 3 and the hydrogen atom at position 5 influence toxicity and antileukemic activity.
The N, N‐bis(2‐chloroethyl)aminobenzoate isomers and the 4‐methyl‐3‐N, N‐bis(2‐chloro‐ethyl)aminobenzoate of 3β‐hydroxy‐13α‐amino‐13,17‐seco‐5α‐androstan‐17‐oic‐13,17‐lactam, 3α‐hydroxy‐13α‐amino‐13,17‐seco‐5α‐androstan‐17‐oic‐13,17‐lactam, 3α‐hydroxy‐13α‐amino‐13,17‐seco‐5‐androsten‐17‐oic‐13,17‐lactam and 17β‐hydroxy‐3‐aza‐A‐homo‐4α‐androsten‐4‐one, have been prepared and their biological activity evaluated against P388 leukemia in vivo and Ehrlich Ascites tumor (EAT), P388 and L1210 leukemias and Baby Hamster cells (BHK) in vitro. The esters in which the alkylating congener is linked to the lactam alcohol in the axial position are inactive in vivo in P388 leukemia, while compounds 1, 4, 6, 13, 14 and the alkylating congeners 17, 18 and 20 are active. The effect of the homo‐azasteroidal of N, N‐bis(2‐chloroethyl)aminobenzoic acid isomers and of 4‐methyl‐3‐N, N‐bis(2‐chloroethyl)aminobenzoic acid on the incorporation of the radioactive precursor into the DNA of L1210, P388 leukemias, Ehrlich ascites tumor and, baby Hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursor was obtained with the ortho derivatives, yielding <70% inhibition of thymidine incorporation in all tumor lines tested.
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