Purine derivatives as competitive inhibitors of human erythrocyte membrane phosphatidylinositol 4-kinase

Abstract

The possibility of deriving a potent, cell-penetrating inhibitor of human erythrocyte PI 4-kinase, competitive with respect to ATP, has been investigated in a series of purine derivatives and analogues. The purine nucleus is not essential for binding to the ATP site but offers the advantage of synthetic accessibility to its derivatives. The optimum substitution pattern in purine was found to be an electron-releasing substituent in the 6-position (e.g. amino, as in adenine, 1) and a compact, lipophilic group in either the 8-position or, preferably, the 9-position, suggesting the importance of the N-1 lone pair and hydrophobic contributions of the 8- and 9-substituents to binding. The most potent inhibitor synthesized was 9-cyclohexyladenine (54), which has an apparent Ki value of 3.7 microM.

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

“…In early 90's, several purine and 7-deazapurine derivatives from both natural and synthetic sources (e.g., 9-cyclohexyladenine or echiguanine A) were identified as inhibitors of PI4K from human erythrocytes [115][116][117][118][119] which was subsequently identified as PI4K IIα [120]. An ATP analog was also found to inhibit PI4K class II enzyme from sheep brain with potency comparable to that of adenosine [121].…”

Structure−Activity Relationships of New 1H-Imidazo[4,5-c]quinolin-4-amine Derivatives as Allosteric Enhancers of the A3 Adenosine Receptor

“…The next step involved ring-closure, which was carried out on three different ways. Compounds 8 − 11 were prepared by ring closure of the appropriate carboxylic acids and 3,4-diaminoquinoline ( 6 ) in polyphosphoric acid . Compounds 12 and 13 were prepared by ring-closure of 2-furoyl chloride and hexanoyl chloride, respectively, with 3,4-diaminoquinoline ( 6 ) .…”

“…Compounds 8-11 were prepared by ring closure of the appropriate carboxylic acids and 3,4-diaminoquinoline (6) in polyphosphoric acid. 21 Compounds 12 and 13 were prepared by ring-closure of 2-furoyl chloride and hexanoyl chloride, respectively, with 3,4-diaminoquinoline (6). 22 Compound 7 was prepared by ring-closure of 3,4-diaminoquinoline (6) with formic acid in trimethylorthoformate.…”

A Switchable Intramolecular Hydrogen Bond in Polysubstituted 5-Nitrosopyrimidines

“…43 Our switchable 5-nitrosopyrimidines might thus mimic two different purine derivatives depending on the orientation of the nitroso group. For example, form A of compound 6e (Figure 6) resembles 2amino-9-phenyladenine, which can act as a phosphatidylinositol-kinase inhibitor, 44 whereas form B of the same compound resembles 2-amino-6-phenylaminopurine, which can act as a cytokinin-receptor activator. 45 Theoretically, one compound may hence target two different metabolic pathways.…”