SAR study of tyrosine–chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines
| Autor: | Sophie Parent, Eric Asselin, Kevin Brasseur, Gervais Bérubé, Caroline Descôteaux, Valérie Leblanc |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Cell Survival Clinical Biochemistry Estrogen receptor Antineoplastic Agents Breast Neoplasms Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship Cell Line Tumor medicine Humans Computer Simulation Tyrosine chemistry.chemical_classification Binding Sites Chlorambucil Chemistry Organic Chemistry Estrogen Receptor alpha Hydrogen Bonding Stereoisomerism Biological activity Ligand (biochemistry) In vitro Amino acid Female Estrogen receptor alpha medicine.drug |
| Zdroj: | Amino Acids. 43:923-935 |
| ISSN: | 1438-2199 0939-4451 |
| DOI: | 10.1007/s00726-011-1152-3 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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