Precursor-directed generation of amidine containing ammosamide analogs: Ammosamides E-P

Ende Pan, Nathaniel W. Oswald, Aaron G. Legako, Janie M. Life, Bruce A. Posner, John B. MacMillan

Research output: Contribution to journalArticle

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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 IC50 values (0.4 to 0.8 μM).

Original languageEnglish (US)
Pages (from-to)482-488
Number of pages7
JournalChemical Science
Volume4
Issue number1
DOIs
StatePublished - 2013

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Amidines
Amines
Cells
NAD(P)H Dehydrogenase (Quinone)
Alkaloids
Fermentation
Ions

ASJC Scopus subject areas

  • Chemistry(all)

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Precursor-directed generation of amidine containing ammosamide analogs : Ammosamides E-P. / Pan, Ende; Oswald, Nathaniel W.; Legako, Aaron G.; Life, Janie M.; Posner, Bruce A.; MacMillan, John B.

In: Chemical Science, Vol. 4, No. 1, 2013, p. 482-488.

Research output: Contribution to journalArticle

Pan, Ende ; Oswald, Nathaniel W. ; Legako, Aaron G. ; Life, Janie M. ; Posner, Bruce A. ; MacMillan, John B. / Precursor-directed generation of amidine containing ammosamide analogs : Ammosamides E-P. In: Chemical Science. 2013 ; Vol. 4, No. 1. pp. 482-488.
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