Synthesis and testing of new antileukemic Schiff bases of N-hydroxy-N'-aminoguanidine against CCRF-CEM/0 human leukemia cells in vitro and synergism studies with cytarabine (Ara-C).
A series of eight new N-hydroxy-N'-aminoguanidine (HAG) Schiff bases [ArCH = NNHC(= NH)NHOH.tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-1-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-1-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 +/- 0.1 microM) and the 4-methoxy-2-hydroxyphenyl derivative (LK02) to be the least potent (IC50, 121 +/- 16 microM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 +/- 7.1 microM) and was about 32 times more potent than LK10 (IC50, 97.6 +/- 0.9 microM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods.(ABSTRACT TRUNCATED AT 250 WORDS)
Koneru
P B
PB
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles 90033.
Lien
E J
EJ
Avramis
V I
VI
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology*; D010084:Oxidation-Reduction; D012545:Schiff Bases / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006146:Guanidines; D007546:Isoquinolines; D012545:Schiff Bases; D003561:Cytarabine; C062817:N-hydroxy-N'-aminoguanidine; C081047:LK 11