Design of novel tyrosine-nitrogen mustard hybrid molecules active against uterine, ovarian and breast cancer cell lines

l-para-Tyrosine was linked to ortho-hydroxyaniline, meta-hydroxyaniline and para-hydroxyaniline giving three distinct tyrosinamide molecules. The new extended amino acid derivatives were constructed to imitate, in part, the estradiol (E2, the natural female sex hormone) nucleus. The resulting tyrosinamides were then linked to chlorambucil either directly, or via a 5 and 10 carbon atoms spacer chain. This was done in an attempt to target cancerous cells expressing the estrogen receptor alpha (ERα) and to obtain a more specific chemotherapeutic agent. The tyrosinamide–chlorambucil molecules were designed and synthesized in good yields, according to two different approaches. The novel compounds were evaluated for their anticancer efficacy in hormone-dependent and hormone-independent (ER+; MCF-7 and ER−; MDA-MB-231) breast cancer cell lines. Interestingly, the meta-hydroxyphenyl-tyrosinamide-chlorambucil derivatives were more active than the ortho- and para- analogs. The molecules bearing a 5 carbon atoms spacer were selected for additional biological study using a panel of female cancerous cells; breast (ZR-75-1, MDA-MB-436, MDA-MB-468), ovarian (OVCAR-3, A2780) and uterine (Ishikawa, HEC-1A). It was discovered that for breast cancer cells, the new compounds were up to 4.2 times more active than chlorambucil itself.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The synthesis of tyrosine-nitrogen mustard hybrid molecules is reported. ► Made from N-Boc-l-tyrosine by a convergent synthesis with excellent overall yield. ► Tested for their cytotoxicity on a panel of female cancer cells by the MTT assay. ► The meta-hydroxyphenyl hybrids were more active than the ortho- and para- analogs. ► On breast cancer cells, the hybrids were up to 4.2 times more active than chlorambucil.