Design and synthesis of phosphonoacetic acid (PPA) ester and amide bioisosters of ribofuranosylnucleoside diphosphates as potential ribonucleotide reductase inhibitors and evaluation of their enzyme inhibitory, cytostatic and antiviral activity.
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'-phosphonoacetic acid, amide and ester analogues of adenosine, uridine and cytidine with the aim to verify both substrate specificity and contribution 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 RNR showing a degree of inhibition that ranged from 350 microM for the UDP analogue 5'-deoxy-5'-N-(phosphon-acetyl)uridine sodium salt (amide) to 600 microM for the CDP analogue 5'-O-[(diethyl-phosphon)acetyl]cytidine (ester). None of the tested compounds displayed noteworthy cytostatic activity at 100-500 microM 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 microM) against HSV-2 and a modest inhibitory activity (EC50: 110 microM) against HIV-1, respectively.
Manfredini
Stefano
S
Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy. s.manfredini@unife.it
Solaroli
Nicola
N
Angusti
Angela
A
Nalin
Federico
F
Durini
Elisa
E
Vertuani
Silvia
S
Pricl
Sabrina
S
Ferrone
Marco
M
Spadari
Silvio
S
Focher
Federico
F
Verri
Annalisa
A
De Clercq
Erik
E
Balzarini
Jan
J
D000577:Amides / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004952:Esters; D009705:Nucleosides; D012264:Ribonucleotide Reductases; D010746:Phosphonoacetic Acid