Synthesis and biological evaluation of clitocine analogues as adenosine kinase inhibitors.
Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.
Lee
C H
CH
Neurological and Urological Diseases Research, Global Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. lance.lee@abott.com
Daanen
J F
JF
Jiang
M
M
Yu
H
H
Kohlhaas
K L
KL
Alexander
K
K
Jarvis
M F
MF
Kowaluk
E L
EL
Bhagwat
S S
SS
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001671:Biochemistry / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D011741:Pyrimidine Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
C448386:5'-deoxy-5'-amino-clitocine; D004791:Enzyme Inhibitors; D011741:Pyrimidine Nucleosides; C055433:clitocine; D000248:Adenosine Kinase