Abstract
Organometallic derivatization of nucleosides is a highly promising strategy for the improvement of the therapeutic profile of nucleosides. Herein, a methodology for the synthesis of metalated adenosine with a deprotected ribose moiety is described. Platinum(II) N-heterocyclic carbene complexes based on adenosine were synthesized, namely N-heterocyclic carbenes bearing a protected and unprotected ribose ring. Reaction of the 8-bromo-2′,3′,5′-tri-O-acetyladenosine with Pt(PPh3)4 by C8−Br oxidative addition yielded complex 1, with a PtII centre bonded to C-8 and an unprotonated N7. Complex 1 reacted at N7 with HBF4 or methyl iodide, yielding protic carbene 2 or methyl carbene 3, respectively. Deprotection of 1 to yield 4 was achieved with NH4OH. Deprotected compound 4 reacted at N7 with HCl solutions to yield protic NHC 5 or with methyl iodide yielding methyl carbene 6. Protic N-heterocyclic carbene 5 is not stable in DMSO solutions leading to the formation of compound 7, in which a bromide was replaced by chloride. The cis-influence of complexes 1–7 was examined by 31P{1H} and 195Pt NMR. Complexes 2, 3, 5, 6 and 7 induce a decrease of 1JPt,P of more than 300 Hz, as result of the higher cis-influence of the N-heterocyclic carbene when compared to the azolato ligand in 1 and 4.
Highlights
Organometallic functionalization is a very promising strategy to improve the biological activity of drugs, of which ferrocifen [1] and ferroquine are very good examples [2].the organometallic derivatization of nucleosides, often used in the clinic in treatment of several diseases, has the potential to improve their therapeutic profile and to promote additional modes of action due to the incorporation of the metal
We have recently reported the synthesis of platinum and palladium NHCs based on been developed, mostly derived adenosine itself through functionalization guanosine derivatives
We have synthesized a new set of Platinum(II) complexes based on adenosine Nheterocyclic carbenes by means of C-Br oxidative addition to Pt(0)PPh3
Summary
Organometallic functionalization is a very promising strategy to improve the biological activity of drugs, of which ferrocifen [1] and ferroquine are very good examples [2]. This multi-signaling molecule restores the intracellular energy levels and mediates tissue protection by adjusting the oxygen levels, acting as an anti-inflammatory agent, and stimulating angiogenesis [3] These functions are achieved by activating specific adenosine receptors (ARs), which represent pharmacological targets for the treatment of several human diseases, including neurological, inflammatory or ischaemic conditions. Hahn’s group describedthe a synthetic for Watson–Crick base pairs, and that the presence of the metal does not influence base-pairthe synthesis of guanosine and adenosine complexes with palladium [7] We examine the cis influence of these compounds by monitoring the effect of carbene formation on the coupling constant of the Pt–P bond
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