Title of article :
Synthesis and evaluation of a polyamine phosphinate and phosphonamidate as transition-state analogue inhibitors of spermidine/spermine-N1-acetyltransferase Original Research Article
Author/Authors :
Ronghui Wu، نويسنده , , Nada H. Saab، نويسنده , , Huatao Huang، نويسنده , , Laurie Wiest، نويسنده , , Anthony E. Pegg، نويسنده , , Robert A. Casero Jr، نويسنده , , Patrick M. Woster، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 1996
Pages :
12
From page :
825
To page :
836
Abstract :
Polyamine analogues such as bis(ethyl)norspermine and NI-ethyl-NII-[(cyclopropyl)methyl]-4,8-diazaundecane (CPENSpm) act as inhibitors of the enzyme spermidine/spermine-N′-acetyltransferase (SSAT) in vitro and possess impressive antitumor activity against a number of cell lines. However, the propensity of these compounds to superinduce SSAT in intact cells limits their usefulness in studies aimed at elucidating the role of SSAT in cellular metabolism. The recently synthesized alkylpolyamine analogue NI-ethyl-NII-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm, 3) is also an effective inhibitor of SSAT and has potent antitumor activity, but does not appear to superinduce SSAT. These findings suggest that it is possible to synthesize polyamine analogues that can be used for selective inhibition of the enzyme in cellular metabolic studies. Along these lines, the phosphate-based transition state analogues 4 and 5 were synthesized and evaluated as inhibitors of isolated SSAT. Phosphonamidate 4 was rapidly hydrolyzed under the assay conditions, and thus did not inhibit the enzyme. However, the phosphinate analogue 5 was an effective inhibitor of purified human SSAT, with a Ki value of 250 μM. The inhibitory activity of 5 was also compared with that of CHENSpm (IC50 = 13 μM), as well as a series of bis-substituted alkylpolyamine analogues. The unsymmetrically substituted polyamine analogue CHENSpm (3) and the phosphinate transition state analogue 5 represent the first functional, nonsuperinducing inhibitors of human SSAT.
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
1996
Journal title :
Bioorganic and Medicinal Chemistry
Record number :
1300774
Link To Document :
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