Synthesis of androstene oxime-nitrogen mustard bioconjugates as potent antineoplastic agents

- Nitrogen mustard conjugates of various steroidal oximes were synthesized.
- The compounds were evaluated on human cancer cell lines for in vitro cytotoxicity.
- The DNA alkylation activity was investigated by in vitro NBP assay.
- The most potent conjugate 8 inhibited the IGROV1 cell line with GI50 = 0.937 µM.
- The D-ring derived nitrogen mustard conjugates emerged as the most potent compounds.

In the present study, synthesis and antineoplastic activity of phenylacetic acid and benzoic acid nitrogen mustard conjugates of various steroidal oximes are reported for the first time. The conjugation was achieved through a more stable oxime-ester linkage and the resulting newly synthesized conjugates were evaluated in vitro on various human cancer cell lines for cytotoxicity. The extent of their alkylating activity was investigated by the in vitro colorimetric 4-(p-nitrobenzyl)pyridine (NBP) assay. The 17E-steroidal oxime-benzoic acid mustard ester 3β-acetoxy-17E-[p-(N,N-bis(2-chloroethyl)amino)]benzoyloxyimino-androst-5-ene (8) emerged as the most potent conjugate having significant cytotoxicity on most of the NCI 60-cell lines. Outstanding growth inhibition was observed on the IGROV1 ovarian cancer cell line with GI50 = 0.937 µM. In general, the D-ring derived androstene oxime-nitrogen mustard conjugates were found to possess better antineoplastic activity over a variety of cancer cells in comparison to those derived from other rings of the steroid skeleton.

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