Inhibition of adenosine deaminase by analogues of adenosine and inosine, incorporating a common heterocyclic base, 4(7)-amino-6(5)H-imidazo[4,5-d]pyridazin-7(4)one.
Four nucleoside analogues ( 1- 4) containing a common heterocyclic base, 4(7)-amino-6(5) H-imidazo[4,5- d]pyridazin-7(4)one, were screened against calf-intestine adenosine deaminase. Compounds 1 and 3 with K(i) values of 10-12 microM are more than four times as potent inhibitors of ADA compared with 2 and 4, with K(i) values of 51-52 microM. Also, 3 is not a substrate of ADA. Nucleosides 3 and 4 also exhibit moderate in vitro activity against breast cancer cell lines, while all four are only minimally or nontoxic to the normal cells.
Ujjinamatada
Ravi K
RK
Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
Phatak
Pornima
P
Burger
Angelika M
AM
Hosmane
Ramachandra S
RS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry*; D013329:Structure-Activity Relationship
C528505:4(7)-amino-6(5)H-imidazo(4,5-d)pyridazin-7(4)-one; D058892:Adenosine Deaminase Inhibitors; D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; D007288:Inosine; D000241:Adenosine