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.
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References
Armitage JO (1993) LeukeranR (Chlorambucil). In: Borroughs Wellcome Co (ed) Current Clinical Guide, 2nd edn. Oncology Products Wellcome Oncology NMC Publ. Inc, New York, p 37
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242
Bertin C, Weston LA, Huang T, Jander G, Owens T, Meinwald J, Schroeder FC (2007) Grass roots chemistry: meta-Tyrosine, an herbicidal nonprotein amino acid. Proc Natl Acad Sci 104(43):16964
Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47(4):936–942
Chrzanowski K, Bielawska A, Palka J (2003) Proline analogue of melphalan as a prodrug susceptible to the action of prolidase in breast cancer MDA-MB 231 cells. Farmaco 58(11):1113–1119
Contino-Pépin C, Parat A, Périno S, Lenoir C, Vidal M, Galons H, Karlik S, Pucci B (2009) Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application. Bioorganic Med Chem Lett 19(3):878–881
Demyttenaere-Kovatcheva A, Cronin MTD, Benfenati E, Roncaglioni A, LoPiparo E (2005) Identification of the structural requirements of the receptor-binding affinity of diphenolic azoles to estrogen receptors α and β by three-dimensional quantitative structure-activity relationship and structure-activity relationship analysis. J Med Chem 48(24):7628–7636
Descoteaux C, Leblanc V, Brasseur K, Gupta A, Asselin E, Berube G (2010) Synthesis of d- and l-tyrosine–chlorambucil analogs active against breast cancer cell lines. Bioorganic Med Chem Lett 20(24):7388–7392. doi:10.1016/j.bmcl.2010.10.039
Durand G, Prosak RA, Han Y, Ortial S, Rockenbauer A, Pucci B, Villamena FA (2009) Spin trapping and cytoprotective properties of fluorinated amphiphilic carrier conjugates of cyclic versus linear nitrones. Chem Res Toxicol 22(9):1570–1581
Gabano E, Cassino C, Bonetti S, Prandi C, Colangelo D, Ghiglia A, Osella D (2005) Synthesis and characterisation of estrogenic carriers for cytotoxic Pt(II) fragments: biological activity of the resulting complexes. Org Biomol Chem 3(19):3531–3539. doi:10.1039/b507716h
Gengrinnovitch S, Izakovich E (2005) Conjugates of amino acids with drugs or with imaging agents for cancer therapy and diagnosis Israel Patent, WO 2005072061
Gupta A, Saha P, Descoteaux C, Leblanc V, Asselin E, Berube G (2010) Design, synthesis and biological evaluation of estradiol–chlorambucil hybrids as anticancer agents. Bioorganic Med Chem Lett 20(5):1614–1618. doi:10.1016/j.bmcl.2010.01.053
Gust R, Beck W, Jaouen G, Schönenberger H (2009) Optimization of cisplatin for the treatment of hormone dependent tumoral diseases: Part 1: use of steroidal ligands. Coord Chem Rev 253(21–22):2742–2759. doi:10.1016/j.ccr.2009.02.025
Joy S, Nair PS, Hariharan R, Pillai MR (2006) Detailed comparison of the protein-ligand docking efficiencies of GOLD, a commercial package and ArgusLab, a licensable freeware. In Silico Biol 6(6):601–605
Karl J, Gust R, Spruss T, Schneider MR, Schoenenberger H, Engel J, Wrobel KH, Lux F, Haeberlin ST (1988) Ring-substituted [1, 2-bis (4-hydroxyphenyl) ethylenediamine] dichloroplatinum (II) complexes: compounds with a selective effect on the hormone-dependent mammary carcinoma. J Med Chem 31(1):72–83
Magrath IT (1994) Targeted approaches to cancer therapy. Int J Cancer 56(2):163–166
Muthyala RS, Carlson KE, Katzenellenbogen JA (2003) Exploration of the bicyclo[3.3.1]nonane system as a template for the development of new ligands for the estrogen receptor. Bioorganic Med Chem Lett 13(24):4485–4488
Ortial S, Durand G, Poeggeler B, Polidori A, Pappolla MA, Böker J, Hardeland R, Pucci B (2006) Fluorinated amphiphilic amino acid derivatives as antioxidant carriers: a new class of protective agents. J Med Chem 49(9):2812–2820
Otto AM, Faderl M, Schönenberger H (1991) Dissociation of estrogenic and cytotoxic properties of an estrogen receptor-binding platinum complex in human breast cancer cell lines. Cancer Res 51(12):3217
Palmer AJ, Wallace HM (2010) The polyamine transport system as a target for anticancer drug development. Amino acids 38(2):415–422
Perrin D, Armarego W (1988) Purification of laboratory chemicals. Pergamon Press edn, Oxford
Sachdeva MS (1998) Drug targeting systems for cancer chemotherapy. Expert Opin Investig Drugs 7(11):1849–1864. doi:10.1517/13543784.7.11.1849
Shanle EK, Xu W (2010) Selectively targeting estrogen receptors for cancer treatment. Adv Drug Deliv Rev 62(13):1265–1276. doi:10.1016/j.addr.2010.08.001
Still W, Kahn M, Mitra A (1978) Rapid chromatographic techniques for preparative separation with moderate resolution. J Org Chem 43(14):2923
Tanenbaum DM, Wang Y, Williams SP, Sigler PB (1998) Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc Natl Acad Sci USA 95(11):5998–6003
Thompson MA (2004) Molecular docking using ArgusLab, an efficient shape-based search algorithm and the AScore scoring function. In: ACS meeting, Philadelphia
Thompson MA ArgusLab 4.0. Seattle
Van Themsche C, Parent S, Leblanc V, Descoteaux C, Simard AM, Berube G, Asselin E (2009) VP-128, a novel oestradiol-platinum(II) hybrid with selective anti-tumour activity towards hormone-dependent breast cancer cells in vivo. Endocr Relat Cancer 16(4):1185–1195. doi:10.1677/ERC-09-0113
Acknowledgments
The authors wish to thank the Fonds de Recherche sur la Nature et les Technologies du Québec (FQRNT) for essential financial support. The NSERC student fellowship for Caroline Descôteaux is gratefully acknowledged.
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Descôteaux, C., Brasseur, K., Leblanc, V. et al. SAR study of tyrosine–chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines. Amino Acids 43, 923–935 (2012). https://doi.org/10.1007/s00726-011-1152-3
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DOI: https://doi.org/10.1007/s00726-011-1152-3