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

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)CRu6(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3) ((pyrene-R)C1) and (pyrene-R)CRu6(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(donq)(3) ((pyrene-R)C2), respectively. The inclusion of six monosubstituted pyrenyl-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)C1 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)C2 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]CF3SO3 (IC50 = 23 mu M) and [2]CF3SO3 (IC50 = 10 mu M), the most active compound [pyrene-R4C1]CF3SO3 being 2 orders of magnitude more cytotoxic (IC50 = 0.3 mu M) on these human ovarian cancer cell lines (A2780 and A2780cisR).