Synthesis, In Vivo Antileukemic Evaluation and Comparative Study of Novel 5α-7-Keto Steroidal Esters of Chlorambucil and its Active Metabolite

Abstract

Recent structure-antileukemic activity studies showed that the steroidal part of complex molecules containing DNA alkylators does not play only the role of the “biological carrier”. New such compounds designed to possess an allylic 7-ketone showed enhanced antileukemic potency compared with derivatives with a simple steroidal skeleton. In order to investigate whether the enhancement of the antileukemic potency is attributed to the introduction of the 7-ketone or to the Δg⁵-7-keto conjugated steroidal system we decided to reduce the Δ⁵ double bond. The 5α-7-keto-steroidal skeletons synthesized were tethered to chlorambucil and phenyl acetic acid's nitrogen mustard and studied against leukemia P338 in vivo. The reduction of the double bond had a negative impact on the antileukemic potency since the comparative study of the novel derivatives showed that a series of very potent Δ⁵-7-keto-steroidal esters were converted by this modification to compounds with marginally accepted activity.