Synthesis of bis-spermine dimers that are potent polyamine transport inhibitors.
A series of novel spermine dimer analogues was synthesized and assessed for their ability to inhibit spermidine transport into MDA-MB-231 breast carcinoma cells. Two spermine molecules were tethered via their N(1) primary amines with naphthalenedisulfonic acid, adamantanedicarboxylic acid and a series of aliphatic dicarboxylic acids. The linked spermine analogues were potent polyamine transport inhibitors and inhibited cell growth cytostatically in combination with a polyamine synthesis inhibitor. Variation in the linker length did not alter polyamine transport inhibition. The amount of charge on the molecule may influence the molecular interaction with the transporter since the most potent spermidine transport inhibitors contained 5-6 positive charges.
Graminski
Gerard F
GF
Oridigm Corporation, 4010 Stone Way North, Suite 220, Seattle, WA 98103, USA. jgraminski@oridigm.com
Carlson
C Lance
CL
Ziemer
Josh R
JR
Cai
Feng
F
Vermeulen
Nicolaas M J
NM
Vanderwerf
Scott M
SM
Burns
Mark R
MR
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry; D019281:Dimerization; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D013095:Spermidine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D011073:Polyamines; D013096:Spermine; D013095:Spermidine