Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

作者：Han Xiaochun; Li Chun; Mosher Michael D; Rider Kevin C; Zhou Peiwen; Crawford Ronald L; Fusco William; Paszczynski Andrzej; Natale Nicholas R^*

来源：Bioorganic & Medicinal Chemistry, 2009, 17(4): 1671-1680.

DOI：10.1016/j.bmc.2008.12.056

• Anthracene
• Anti-tumor
• G-quadruplex
• Isoxazole
• Pyrrole

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl(3) as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

• 出版日期2009-2-15