title: Precursor-Directed Generation of Amidine Containing Ammosamide Analogs: Ammosamides E-P.
abstract: Ammosamides E-F (1-2), are amidine analogs of the ammosamide family of alkaloids isolated from a marine-derived Streptomyces variabilis. Further studies with S. variabilis revealed a variety of aryl and alkyl amines added into the fermentation media could be efficiently incorporated into the ammosamide framework to generate a library of precursor-directed amidine analogs, ammosamides G-P (9 - 18). We demonstrate that the amines are introduced via non-enzymatic addition to the iminium ion of ammosamide C. Biological evaluation of the amidine analogs against quinone reductase 2 (QR2) showed low nM potency for a number of analogs. When tested for in vivo activity against a panel of non-small cell lung cancer (NSCLC) cell-lines there was a clear increase in potency by incorporation of lipophilic alkylamines, with the most potent compounds having sub μM IC(50) values (0.4 to 0.8 μM).
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, USA.
authors.forename: Ende
authors.initials: E
authors.lastname: Pan
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Oswald
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Legako
authors.forename: Janie M
authors.initials: JM
authors.lastname: Life
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.forename: John B
authors.initials: JB
authors.lastname: Macmillan