3-Deazaneplanocin: a new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60.
3-Deazaneplanocin, a new carbocyclic analog of adenosine, was synthesized as an inhibitor of S-adenosylhomocysteine hydrolase. The Ki of 3-deazaneplanocin for a purified hamster liver preparation of S-adenosylhomocysteine hydrolase was 5 X 10(-11) M, making this inhibitor 250-fold more potent than the previously known most potent inhibitor of this enzyme, 3-deazaaristeromycin. Inhibition was competitive with the substrate adenosine. Human promyelocytic leukemia (HL-60) cells treated with 10(-5) M 3-deazaneplanocin showed a pronounced elevation in S-adenosylhomocysteine which was 4-fold greater than that produced by an equimolar concentration of 3-deazaaristeromycim. This effect preceded a moderate reduction in cell growth and viability following continuous exposure for 6 days. Cellular differentiation as monitored by the reduction of nitroblue tetrazolium was not markedly affected except after 4 days exposure to 10(-5) M 3-deazaneplanocin where 60% of the viable cells were positive. These results indicate that 3-deazaneplanocin may have therapeutic potential as an anticancer or antiviral drug.
Glazer
R I
RI
Hartman
K D
KD
Knode
M C
MC
Richard
M M
MM
Chiang
P K
PK
Tseng
C K
CK
Marquez
V E
VE
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology
C048460:3-deazaneplanocin; C034583:3-deazaaristeromycin; C031096:neplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine