Adenosine kinase inhibitors. 4. 6,8-Disubstituted purine nucleoside derivatives. Synthesis, conformation, and enzyme inhibition.
6,8-Disubstituted purine nucleosides were synthesized and evaluated as adenosine kinase inhibitors (AKIs). A method was developed to selectively substitute arylamines for halogens at C6 and C8 which utilizes alkali salts of arylamino anions. Regioselectivity was found to be counterion dependent. Potassium and sodium salts add selectively to C6 of 6-chloro-8-iodo-9-(2,3,5-tris-O-tert-butyldimethylsilyl-beta-d-ribofuranosyl)purine (7a) while lithium salts add to C6 and C8 positions. Differential 6,8-bisarylamin-N,N'-diylpurine nucleosides such as 8-anilin-N-yl-6-indolin-N-yl-9-(beta-d-ribofuranosyl)purine (10b) can be prepared by employing stepwise reactions of potassium and then lithium salts of different arylamino anions followed by fluoride ion-induced desilylation. Other C8-substituted compounds were prepared by way of either C8 lithiation chemistry or palladium cross-coupling reactions. Several of these compounds were potent AKIs (e.g. 10b, AK IC(50) = 0.019 microM) and are more potent than the previous best purine-based AKI 5'-deoxy-5'-aminoadenosine (AK IC(50) = 0.170 microM). AK inhibitory potency was greatest for those compounds with (1)H NMR evidence of a predominant anti glycosyl bond conformation, whereas most analogues adopt a syn conformation because of steric repulsions between the C8 substituent and the ribose group. The inhibitors are proposed to bind in the anti conformation with the hydrophobic C6 and C8 substituents contributing to AK affinity in a manner similar to the C4 and C5 aryl substituents of the potent diaryltubercidin nucleoside inhibitor series.
Bookser
Brett C
BC
Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. bookser@ mbasis.com
Matelich
Michael C
MC
Ollis
Kristin
K
Ugarkar
Bheemarao G
BG
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
C500853:8-anilin-N-yl-6-indolin-N-yl-9-ribofuranosylpurine; D007211:Indoles; D011684:Purine Nucleosides; D000248:Adenosine Kinase