Diamine and triamine analogs and derivatives as inhibitors of deoxyhypusine synthase: synthesis and biological activity.
Deoxyhypusine synthase catalyzes the initial step in the posttranslational formation of the amino acid hypusine [N epsilon-(4-amino-2-hydroxybutyl)lysine] in eukaryotic initiation factor 5A (eIF-5A). eIF-5A and its hypusine modification are believed to be essential for cell growth. A number of compounds related to diamines and triamines were synthesized and tested as inhibitors of this enzyme. The findings indicate that the long chain triamines 2a and 2b and their guanyl derivatives 3a, 3b, 4a, and 4b exert inhibition by binding to enzyme through only a portion of their structures at any one time. The inhibition exhibited by N-ethyl-1,7-diaminoheptane 20 and its guanyl derivative 21 supports this notion and is evidence for participation of the secondary amino group in binding to enzyme. There is preliminary evidence that amidino and isothiuronium groups may also serve as basic centers for binding to enzyme. Few of the compounds tested here were comparable in inhibitory potency to 1-guanidino-7-aminoheptane (GC7) the most effective known inhibitor of deoxhypusine synthase, and none proved nearly as efficient as GC7 in inhibiting the enzyme in Chinese hamster ovary cells. Hence, unlike the antiproliferative effect of GC7, for which there is evidence of cause by interference with deoxhypusine synthase catalysis (Park, M. H.; Wolff, E. C.; Lee, Y. B.; Folk, J. E. J. Biol. Chem. 269, 1994, 27827-27832), the effective growth arrest exerted by several of the newly synthesized compounds cannot be attributed to inhibition of hypusine synthesis.
Lee
Y B
YB
Laboratory of Cellular Development and Oncology, National Institute of Dental Research, Bethesda, Maryland 20892-4330, USA.
Park
M H
MH
Folk
J E
JE
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D051381:Rats; D013095:Spermidine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology; D000097574:Eukaryotic Translation Initiation Factor 5A
D003959:Diamines; D008239:Lysine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010448:Peptide Initiation Factors; D011073:Polyamines; D016601:RNA-Binding Proteins; D013095:Spermidine; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C063507:deoxyhypusine synthase