Synthesis and evaluation of unsymmetrically substituted polyamine analogues as modulators of human spermidine/spermine-N1-acetyltransferase (SSAT) and as potential antitumor agents.
Spermidine/spermine-N1-acetyltransferase (SSAT), the rate-limiting step in polyamine catabolism, is critical for the interconversion and modulation of cellular polyamines. Inhibitor-initiated induction of this enzyme also appears to correlate with the sensitivity of tumor cells to a class of novel polyamine analogues, the bis(ethyl)polyamines. Thus, terminally alkylated polyamines which modulate the cellular level of SSAT could be of great value for understanding the role of this enzyme both in analogue-mediated cytotoxicity and in overall cellular polyamine metabolism. Such analogues could also become important therapeutic agents by disrupting cellular polyamine metabolism. The structure-activity relationships defining the interaction of polyamine analogues with SSAT have not been fully elucidated, and, in particular, unsymmetrically alkylated polyamines have not been synthesized and evaluated as modulators of SSAT. To this end, we now report the synthesis and preliminary biological evaluation of N1-ethyl-N11-propargyl-4,8-diazaundecane and N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane via a synthetic pathway which represents an efficient route to a variety of unsymmetrically substituted polyamine analogues. The title compounds act as effective inhibitors of isolated human SSAT and produce a differential superinduction of SSAT in situ which appears to be associated with a cell specific cytotoxic response in two human lung cancer cell lines. In so doing, these analogues exhibit promising antitumor activity against cultured human lung cancer cells.
Saab
N H
NH
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202.
West
E E
EE
Bieszk
N C
NC
Preuss
C V
CV
Mank
A R
AR
Casero
R A
RA
Woster
P M
PM
D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D016923:Cell Death / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D015394:Molecular Structure; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase; C083628:N(1)-ethyl-N(11)-propargyl-4,8-diazaundecane-1,11-diamine; C083629:N(1)-ethyl-N-(11)-((cyclopropyl)methyl)-4,8-diazaundecane-1,11-diamine