Design, synthesis and enzymatic activity of highly selective human mitochondrial thymidine kinase inhibitors.
Highly selective arabinofuranosyl nucleosides, which inhibit the mitochondrial thymidine kinase (TK-2) without affecting the closely related herpes simplex virus type 1 thymidine kinase (HSV-1 TK), varicella-zoster virus thymidine kinase (VZV-TK), cytosolic thymidine kinase (TK-1) or the multifunctional Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK), have been obtained. SAR studies indicate a close relation between the length of the substituent at the 2' position of the arabinofuranosyl moiety and the inhibitory activity.
Manfredini
S
S
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy. mv9@dns.unfie.it
Baraldi
P G
PG
Durini
E
E
Porcu
L
L
Angusti
A
A
Vertuani
S
S
Solaroli
N
N
De Clercq
E
E
Karlsson
A
A
Balzarini
J
J
D001087:Arabinonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000201:enzymology*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000037:antagonists & inhibitors
D001087:Arabinonucleosides; D004791:Enzyme Inhibitors; D014764:Viral Proteins; C105339:thymidine kinase 2; D013937:Thymidine Kinase