A number of matrix metalloproteinases (MMPs) are important medicinal targets for conditions ranging from rheumatoid arthritis to cardiomyopathy, periodontal disease, liver cirrhosis, multiple sclerosis, and cancer invasion and metastasis, where they showed to have a dual role, inhibiting or promoting important processes involved in the pathology. MMPs contain a zinc (II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In an effort to devise new approaches to selective inhibitors, in this paper, we describe the synthesis and preliminary biological evaluation of amino acid derivatives as new zinc binding groups (ZBGs). The incorporation of selected metal-binding functions in more complex biphenyl sulfonamide moieties allowed the identification of one compound able to interact selectively with different MMP enzymatic isoforms. 1. Introduction Matrix metalloproteinases (MMPs) are 23-member zinc-dependent endopeptidases family involved in the extracellular matrix turnover [1]. Their aberrant regulation has been implicated in tumoral process, where they showed to have a dual role inhibiting or promoting cell growth and survival, angiogenesis and metastasis [2, 3] differentiation [4], and inflammation and immune surveillance [5]. Moreover, MMPs are overexpressed in a variety of tumor types, and their overexpression is associated with tumor aggressiveness and poor prognosis [6]. The specific alteration of the MMPs in malignant tissues and their participation in some of the major oncogenic mechanisms have both fuelled interest in the design and evaluation of MMP inhibitors (MMPIs) as anticancer agents [7, 8]. Generally, the MMPIs design involves peptide or peptidomimetic backbones containing a zinc-binding group (ZBG) able to interact with both the subpockets surrounding the active site ( and , , and ) and the zinc (II) ion present in the catalytic site, respectively [9, 10]. The greater part of MMPIs research has focused on developing the peptide or peptidomimetic containing a hydroxamic acid as chelating group. Although this design has produced potent inhibitors such as Batimastat [11, 12] and Marimastat [13] (Figure 1), none of these MMPIs has successfully completed clinical trials. Figure 1: Structures of Batimastat and Marimastat. The inability of hydroxamates to produce clinically viable compounds has been attributed to low oral availability, poor in vivo stability, and undesirable side effects associated with these compounds [14]. This has prompted the
References
[1]
M. D. Sternlicht and Z. Werb, “How matrix metalloproteinases regulate cell behavior,” Annual Review of Cell and Developmental Biology, vol. 17, pp. 463–516, 2001.
[2]
H. Nagase and J. F. Woessner Jr, “Matrix metalloproteinases,” The Journal of Biological Chemistry, vol. 274, no. 31, pp. 21491–21494, 1999.
[3]
C. Chang and Z. Werb, “The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis,” Trendsin Cell Biology, vol. 11, pp. S37–S43, 2001.
[4]
C. Streuli, “Extracellular matrix remodelling and cellular differentiation,” Current Opinion in Cell Biology, vol. 11, no. 5, pp. 634–640, 1999.
[5]
W. C. Parks, C. L. Wilson, and S. Y. López-Boado, “Matrix metalloproteinases as modulators of inflammation and innate immunity,” Nature Reviews Immunology, vol. 4, no. 8, pp. 617–629, 2004.
[6]
M. Egeblad and Z. Werb, “New functions for the matrix metalloproteinases in cancer progression,” Nature Reviews Cancer, vol. 2, no. 3, pp. 161–174, 2002.
[7]
S. Zucker, C. Jian, and W. T. Chen, “Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment,” Oncogene, vol. 19, no. 56, pp. 6642–6650, 2000.
[8]
C. M. Overall and C. López-Otín, “Strategies for MMP inhibition in cancer: innovations for the post-trial era,” Nature Reviews Cancer, vol. 2, pp. 657–672, 2002.
[9]
M. Hidalgo and S. G. Eckhardt, “Development of matrix mettaloproteinase inhibitors in cancer therapy,” Journalof the National Cancer Institute, vol. 93, no. 3, pp. 178–193, 2001.
[10]
J. F. Fisher and S. Mobashery, “Recent advances in MMP inhibitor design,” Cancer and Metastasis Reviews, vol. 25, no. 1, pp. 115–136, 2006.
[11]
B. Davies, P. D. Brown, N. East, M. J. Crimmin, and F. R. Balkwill, “A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts,” Cancer Research, vol. 53, pp. 2087–2091, 1993.
[12]
X. Wang, X. Fu, P. D. Brown, M. J. Crimmin, and R. M. Hoffman, “Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice,” Cancer Research, vol. 54, no. 17, pp. 4726–4728, 1994.
[13]
A. H. Drummond, P. Beckett, P. D. Brown et al., “Preclinical and clinical studies of MMP inhibitors in cancer,” Annals of the New York Academy of Sciences, vol. 878, pp. 228–235, 1999.
[14]
L. M. Coussens, B. Fingleton, and L. M. Matrisian, “Matrix metalloproteinase inhibitors and cancer: trials and tribulations,” Science, vol. 295, no. 5564, pp. 2387–2392, 2002.
[15]
E. Breuer, J. Frant, and R. Reich, “Recent non-hydroxamate matrix metalloproteinase inhibitors,” Expert Opinion on Therapeutic Patents, vol. 15, no. 3, pp. 253–269, 2005.
[16]
D. T. Puerta and S. M. Cohen, “A bioinorganic perspective on matrix metalloproteinase inhibition,” Current Topics in Medicinal Chemistry, vol. 4, no. 23, pp. 1551–1573, 2004.
[17]
Puerta, D. T. Mongan, J. Ba, L. Tran, J. McCammon, and S. M. Cohen, “Potent, selective pyrone-based inhibitors of stromelysin-1,” Journal of the American Chemical Society, vol. 127, pp. 14148–14149, 2005.
[18]
F. Grams, H. Brandstetter, S. DAlò et al., “Pyrimidine-2,4,6-Triones: a new effective and selective class of matrix metalloproteinase inhibitors,” Biological Chemistry, vol. 382, pp. 1277–1285, 2001.
[19]
M. T. Rubino, M. Agamennone, C. Campestre et al., “Cover picture: biphenyl sulfonylamino methyl bisphosphonic acids as inhibitors of matrix metalloproteinases and bone resorption,” Chemmedchem, vol. 6, no. 7, p. 1133, 2011.
[20]
J. W. Skiles, N. C. Gonnella, and A. Y. Jeng, “The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors,” Current Medicinal Chemistry, vol. 11, no. 22, pp. 2911–2977, 2004.
[21]
M. Whittaker, C. D. Floyd, P. Brown, and A. J. H. Gearing, “Design and therapeutic application of matrix metalloproteinase inhibitors,” ChemicalReviews, vol. 99, no. 9, pp. 2735–2776, 1999.
[22]
G. W. Kabalka, M. Varma, R. S. Varma, P. C. Srivastava, and F. F. Knapp Jr., “Tosylation of alcohols,” Journal of Organic Chemistry, vol. 51, no. 12, pp. 2386–2388, 1986.
[23]
P. Campiglia, I. Gomez-Monterrey, L. Longobardo, T. Lama, E. Novellino, and P. Grieco, “An efficient approach for monosulfide bridge formation in solid-phase peptide synthesis,” Tetrahedron Letters, vol. 45, no. 7, pp. 1453–1456, 2004.
[24]
C. K. Wada, J. H. Holms, M. L. Curtin et al., “Phenoxyphenyl sulfone N-formylhydroxylamines (Retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors,” Journal of Medicinal Chemistry, vol. 45, no. 1, pp. 219–232, 2002.
[25]
C. M. Overall and O. Kleifeld, “Towards third generation matrix metalloproteinase inhibitors for cancer therapy,” The British Journal of Cancer, vol. 94, no. 7, pp. 941–946, 2006.
[26]
B. G. Rao, “Recent developments in the design of specific matrix metalloproteinase inhibitors aided by structural and computational studies,” Current Pharmaceutical Design, vol. 11, no. 3, pp. 295–322, 2005.
[27]
F. E. Jacobsen, J. A. Lewis, and S. M. Cohen, “The design of inhibitors for medicinally relevant metalloproteins,” ChemMedChem, vol. 2, no. 2, pp. 152–171, 2007.
[28]
P. Cuniasse, L. Devel, A. Makaritis et al., “Future challenges facing the development of specific active-site-directed synthetic inhibitors of MMPs,” Biochimie, vol. 87, no. 3-4, pp. 393–402, 2005.
[29]
A. Agrawal, D. Romero-Perez, J. A. Jacobsen, F. J. Villarreal, and S. M. Cohen, “Zinc-binding groups modulate selective inhibition of MMPs,” ChemMedChem, vol. 3, no. 5, pp. 812–820, 2008.
[30]
J. ？qvist, C. Medina, and J. E. Samuelsson, “A new method for predicting binding affinity in computer-aided drug design,” Protein Engineering, vol. 7, no. 3, pp. 385–391, 1994.
[31]
T. Hansson and J. ？qvist, “Estimation of binding free energies for HIV proteinase inhibitors by molecular dynamics simulations,” Protein Engineering, vol. 8, no. 11, pp. 1137–1144, 1995.
[32]
C. M. Overall and O. Kleifeld, “Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy,” Nature Reviews Cancer, vol. 6, no. 3, pp. 227–239, 2006.
[33]
M. D. Martin and L. M. Matrisian, “The other side of MMPs: protective roles in tumor progression,” Cancer and Metastasis Reviews, vol. 26, pp. 717–724, 2007.
[34]
G. S. Butler and C. M. Overall, “Proteomic identification of multitasking proteins in unexpected locations complicates drug targeting,” Nature Reviews Drug Discovery, vol. 8, no. 12, pp. 935–948, 2009.
[35]
Maestro, Version 9. 3, MacroModel, Version 9. 9, Glide, Version 5. 8, Liaison, Version 5. 8, Strike, Version 2. 1, Schr？dinger LLC, New York, NY, USA, 2012.
[36]
T. A. Halgren, R. B. Murphy, R. A. Friesner et al., “Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening,” Journal of Medicinal Chemistry, vol. 47, no. 7, pp. 1750–1759, 2004.
[37]
R. A. Friesner, J. L. Banks, R. B. Murphy et al., “Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy,” Journal of Medicinal Chemistry, vol. 47, no. 7, pp. 1739–1749, 2004.
[38]
H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, et al., “The protein data bank,” Nucleic Acids Research, vol. 28, no. 1, pp. 235–242, 2000.
[39]
R. A. Friesner, R. B. Murphy, M. P. Repasky et al., “Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes,” Journal of Medicinal Chemistry, vol. 49, no. 21, pp. 6177–6196.
