Metal-ion binding properties of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, Cidofovir). A nucleotide analogue with activity against DNA viruses

0489564 - ÚOCHB 2019 RIV NL eng J - Článek v odborném periodiku
Blindauer, C. A. - Sigel, A. - Operschall, B. P. - Holý, Antonín - Sigel, H.
Metal-ion binding properties of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, Cidofovir). A nucleotide analogue with activity against DNA viruses.
Inorganica chimica acta. Roč. 472, Mar 1 (2018), s. 283-294. ISSN 0020-1693. E-ISSN 1873-3255
Institucionální podpora: RVO:61388963
Klíčová slova: acyclic nucleoside phosphonates * antivirals * chelates * isomeric equilibria * metal ion complexes * nucleotide analogues
Obor OECD: Organic chemistry
Impakt faktor: 2.433, rok: 2018

The acyclic nucleoside phosphonate (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, Cidofovir) has been approved for clinical use in antiviral therapy. We determined the acidity constants of H-2(HPMPC)(+/-), as well as that of the nucleobase-free (hydroxy-2-(phosphonomethoxy)propane (H(HPMP)(-)) (I = 0.1 M, NaNO3, 25 degrees C). Given that in vivo nucleotides and their analogues participate in reactions typically as metal ion (M2+) complexes, the stability constants of the M(H,HPMPC)(+), M(HPMPC), and M(HPMP) complexes with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ were measured. Comparisons between results for HPMP2- and previous data for PME2- (CH3CH2-O-CH2PO32-, phosphonomethoxyethane) revealed the hydroxyl-group effect. The hydroxyl group stabilizes only complexes with the heavier alkaline earth metal ions (Ca2+, Sr2+, Ba2+). For all other complexes, the enhanced stability can solely be explained by the formation of 5-membered chelates involving the ether oxygen, these occur in equilibrium with simple 'open' phosphonate-M2+ species. The stability of the M(HPMPC) complexes is also higher than expected for a phosphonate-only coordination, indicating that chelates are formed, but comparison with the HPMP2- data shows that the cytosine base does not affect complex stability. Similar observations were made previously with related cytosine derivatives. The stability data for the monoprotonated M(H,HPMPC)(+) complexes suggest that these carry H+ predominantly on the phosphonate group, and M2+ on the nucleobase.
Trvalý link: http://hdl.handle.net/11104/0283965