Design and synthesis of phosphonoacetic acid (PPA) ester and amide bioisosters of ribofuranosylnucleoside diphosphates as potential ribonucleotide reductase inhibitors and evaluation of their enzyme inhibitor cytostatic and antiviral activity

• Published in: Antiviral chemistry & chemotherapy 2003-07, Vol.14 (4), p.183-194
• Main Authors: Manfredini, S, Solaroli, N, Angusti, A, Nalin, F, Durini, E, Vertuani, S, Pricl, S, Ferrol, M, Spadari, S, Focher, F, Verri, A, De Clercq, E, Balzarini, J
• Format: Article
• Language: English
• Subjects: Human immunodeficiency virus 1
• ISSN: 0956-3202

Continuing our investigations on inhibitors of ribonucleotide reductase (RNR), the crucial enzyme that catalyses the reduction of ribonucleotides to deoxyribonucleotides, we have now prepared and evaluated 5'-phos- phonoacetic acid, amide and ester analogues of adenosine, uridine and cytidine with the aim to verify both substrate specificity and contrib- ution to biological activity of diphosphate mimic moieties. A molecular modelling study has been conducted on the RNR R1 subunit, in order to verify the possible interaction of the proposed bioisosteric moieties. The study compounds were finally tested on the recombinant murine RNA showing a degree of inhibition that ranged from 350 mu M for the UDP analogue 5'-deoxy-5'-N-(phosphon-acetyl)uridine sodium salt (amide) to 600 mu M for the CDP analogue 5'-O-[(diethyl-phosphon)acetyl]cytidine (ester). None of the tested compounds displayed noteworthy cytostatic activity at 100-500 mu M concentrations whereas ADP analogue 5'-N-[(diethyl-phosphon) acetyl]adenosine (amide) and 5'-deoxy-5'-N-(phosphon-acetyl)adenosine sodium salt (amide) showed a moderate inhibitory activity (EC50: 48 mu M) against HSV-2 and a modest inhibitory activity (EC50: 110 mu M) against HIV-1, respectively.