SAR study of tyrosine–chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines

Abstract

Amino acids were transformed and coupled to chlorambucil, a well-known chemotherapeutic agent, in an attempt to create new anticancer drugs with selectivity for breast cancer cells. Among the amino acids available, tyrosine was selected to act as an estrogenic ligand. It is hypothesized that tyrosine, which shows some structural similitude with estradiol, could possibly mimic the natural hormone and, subsequently, bind to the estrogen receptor. In this exploratory study, several tyrosine-drug conjugates have been designed. Thus, ortho-, meta- and para-tyrosine-chlorambucil analogs were synthesized in order to generate new anticancer drugs with structural diversity, more specifically in regards to the phenol group location. These new analogs were produced in good yield following efficient synthetic methodology. All the tyrosine-chlorambucil hybrids were more effective than the parent drug, chlorambucil. In vitro biological evaluation on estrogen receptor positive and estrogen receptor negative (ER(+) and ER(-)) breast cancer cell lines revealed an enhanced cytotoxic activity for compounds with the phenol function located at position meta. Molecular docking calculations were performed for the pure L-ortho, L-meta- and L-para-tyrosine phenolic regioisomers. The synthesis of all tyrosine-chlorambucil hybrid regioisomers and their biological activity are reported herein. Possible orientations within the targeted protein [estrogen receptor alpha (ERα)] are discussed in relation to the biological activity.

Therapeutic Potential of Nitrogen Mustard Based Hybrid Molecules

“…Molecular modeling study indicated that the phenol group of tyrosine also interact with the estrogen receptor binding site in the same manner as the A-ring phenol of estradiol. Therefore, the tyrosine was modified to mimic the structure of estradiol (Muthyala et al, 2003; Descoteaux et al, 2012b). Tyrosinamide, combined tyrosine with hydroxyaniline, was proved to be structurally similar to estradiol.…”

Multimarker Screening of Oxidative Stress in Aging

“…All compounds with tyrosine showed higher cytotoxicity than pure chlorambucil. Compared to the other regioisomers, the m -tyrosine-chlorambucil compound showed greater cytotoxicity and it was also slightly more specific for hormone-dependent cancer cells, probably due to closer similarity to estradiol [53]. …”

Current research on anti-breast cancer synthetic compounds

“…4). 108 Novel plumbagin hydrazonates were prepared, structurally characterized and evaluated for anti-proliferative activity against the BC cell lines. Compounds 121 and 122 were especially promising against triple negative MDA-MB-231 (IC 50 values 1.9 and 2.1 mM, respectively) and MDA-MB-468 BC cell lines via inhibiting NF-B expression (Fig.…”