Modeling the preferred shapes of polyamine transporter ligands and dihydromotuporamine-C mimics: shovel versus hoe.
Preferred conformers generated from motuporamine and anthracene-polyamine derivatives provided insight into the shapes associated with polyamine transporter (PAT) recognition and potentially dihydromotuporamine C (4a) bioactivity. Molecular modeling revealed that N(1)-(anthracen-9-ylmethyl)-3,3-triamine (6a), N(1)-(anthracen-9-ylmethyl)-4,4-triamine (6b), N(1)-(anthracen-9-ylmethyl)-N(1)-ethyl-3,3-triamine (7a), N(1)-(anthracen-9-ylmethyl)-N(1)-ethyl-4,4-triamine (7b), and 4a all preferred a hoe motif. This hoe shape was defined by the all-anti polyamine shaft extending above the relatively flat, appended ring system. The hoe geometry was also inferred by the (1)H NMR spectrum of the free amine of 7a (CDCl(3)), which showed a strong shielding effect of the anthracene ring on the chemical shifts associated with the appended polyamine chain. This shielding effect was found to be independent over a broad concentration range of 7a, which also supported an intramolecular phenomenon. The degree of substitution at the N(1)-position seems to be an important determinant of both the molecular shape preferences and biological activity of anthracenylmethyl-polyamine conjugates.
Breitbeil
Fred
F
Groupe Cycle Cellulaire, CNRS UMR 6061, IFR 97, Facult de Medecine, Universit Rennes 1, 2 Av. du Pr Leon Bernard, CS 34317, F-35043 Rennes Cedex, France.
Kaur
Navneet
N
Delcros
Jean-Guy
JG
Martin
Bénédicte
B
Abboud
Khalil A
KA
Phanstiel
Otto
O
D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011437:Propylamines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D011073:Polyamines; D011437:Propylamines; C510298:dihydromotuporamine C