The high affinity for polynuclear platinum compounds (PPCs), including the Phase II clinical trial compound, BBR3464, for glycosoaminoglycans (GAGs) has identified a new mechanism of cellular accumulation for this class of antitumor agents, one not shared by the mononuclear cisplatin and oxaliplatin. [1] Cell-surface and extracellular matrix glycoaminoglycans (GAGs) are complex oligosaccharides that regulate several aspects of cancer biology, including tumor progression, invasion and metastasis. Tumors aberrantly express various glycans, where proliferation and motility of tumor cells is potentiated by their ability to bind growth-factors, such as FGF and VEGF, and to directly activate tyrosine kinase receptors.[2] We here demonstrate that the strong binding of PPCs to oligosaccharides provides a new approach to glycan-based targeting through protection against enzymatic cleavage by heparanase.[3] The end result of inhibition of heparanase cleavage and growth factor binding to GAGs is a reduction in tumor invasion and angiogenesis. Metalloglycomics - the study of defined coordination compounds with oligosaccharides - has rich and multiple applications in the area of structure and function of this third major class of biomolecules after DNA/RNA and proteins. The inherent ability to alter oxidation state, coordination number and geometry, and substitution lability of ligands allows study of a wide variety of structural types to enhance shielding and enzyme inhibition. In this context, the polynuclear platinum structure represents a potentially rich chemotype and has promise as a dual-function chemotherapeutic allying its DNA-binding ability to that of anti-metastasis. References [1] H. Silva, F. Frézard, E.J. Peterson, P. Kabolizadeh, J.J. Ryan, N.P. Farrell, Mol. Pharm. 2012, 9, 1795-1802. [2] M.M. Fuster, and J.D. Esko, Nature Rev. Cancer 2005, 5, 526-542. [3] J.B. Mangrum, B.J. Engelmann, E.J.Peterson, J.J. Ryan, S.J. Berners-Price, N.P. Farrell. Chem. Commun. 2014, 50, 4056 – 4058.

Metalloglycomics approach to antimetastatic platinum

249th National Meeting (2015)

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