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

A lanthanide catalyzed modification of Weinreb’s amidation was employed to prepare a series of sterically encumbered Aryl Isoxazolyl aMides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.), and the structure activity relationship for anticancer activity surveyed. The mean GI 50 against the NCI60 cell line panel for the length of the oligopyrrole moiety ( n = the number of pyrroles) was observed as 1 > 0 ≫ 2 > 3 for the bis-dimethylaminopropyl series 23–26) and 1 > 2 ≫ 0 for the mono-dimethylaminopropyl series (27–29); and for the anthracenyl C(10) position was Ph ≈ Cl ≫ H > Br ( 28, 30–32). Based upon preliminary experiments, a structural argument is advanced suggesting that the preliminary experiments toward understanding the Mechanism of action are more consistent with G4 stabilization than B-DNA intercalation. 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.