Delivery of floxuridine derivatives to cancer cells by water-soluble organometallic cages.

Jeong Wu Yi, Nicolas P E Barry, Mona A Furrer, Olivier Zava, Paul J Dyson, Bruno Therrien, Byeang Hyean Kim

Department of Chemistry, Division of IBB, Pohang University of Science and Technology, Pohang 790-784, Korea.

Bioconjugate chemistry 2012 Mar 21

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The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (pPr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) or 5,8-dioxydo-1,4-naphthoquinonato (donq) bridges, in the presence of a pyrenyl-nucleoside derivatives (pyreneR), affords the triangular prismatic host-guest compounds [(pyrene-R)⊂Ru(6)(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R)⊂1](6+)) and [(pyrene-R)⊂Ru(6)(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(donq)(3)](6+) ([(pyrene-R)⊂2](6+)), respectively. The inclusion of six monosubstitutedpyrenyl-nucleosides (pyrene-R1 = 5'-(1-pyrenyl butanoate)-2'-deoxyuridine, pyrene-R2 = 5-fluoro-5'-(1-pyrenyl butanoate)-2'-deoxyuridine, pyrene-R3 = 5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-glycyl}-2'-deoxyuridine, pyrene-R4 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-glycyl}-2'-deoxyuridine, pyrene-R5 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl}-2'-deoxyvuridine, pyrene-R6 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl}-2'-deoxyuridine) has been accomplished. The carceplex nature of [(pyrene-R)⊂1](6+) with the pyrenyl moiety firmly encapsulated in the hydrophobic cavity of the cage with the nucleoside groups pointing outward was confirmed by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS), while the host-guest nature of [(pyrene-R)⊂2](6+) was studied in solution by NMR techniques. In contrast to the floxuridine compounds used in the clinic, the host-guest complexes are highly water-soluble. Consequently, the cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 and A2780cisR cancer cells. All the host-guest systems are more cytotoxic than the empty cages alone [1][CF(3)SO(3)](6) (IC(50) = 23 μM) and [2][CF(3)SO(3)](6) (IC(50) = 10 μM), the most active compound [pyrene-R4⊂1][CF(3)SO(3)](6)being 2 orders of magnitude more cytotoxic (IC(50) = 0.3 μM) on these human ovarian cancer cell lines (A2780 and A2780cisR).

Citation

Jeong Wu Yi, Nicolas P E Barry, Mona A Furrer, Olivier Zava, Paul J Dyson, Bruno Therrien, Byeang Hyean Kim. Delivery of floxuridine derivatives to cancer cells by water-soluble organometallic cages. Bioconjugate chemistry. 2012 Mar 21;23(3):461-71