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

Abstract

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs)¥ (22-33) is 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.

Preparation of chiral isoxazole carbinols via catalytic asymmetric Corey-Bakshi-Shibata reduction.

“…5 The existence of a safe route for drug metabolism is an important design feature for potential investigational new drugs containing the isoxazole. Our own interest in the biological activity of several classes of isoxazoles [6][7][8] required access into isoxazole carbinols in chiral form for metabolic fate experiments.…”

AIMing towards improved antitumor efficacy

“…Techniques using fluorescent compounds in the visualization of tumors during surgery, referred to as tumor paint, are actively being developed. 2–4 We have recently reported on the synthesis, bioactivity and structure-activity relationship (SAR) of fluorescent anthracenyl isoxazole amides (AIMs, 1 ), 5 as well as their dimeric analogues ( 2 ) 6 depicted in Chart 1. The AIMs have shown promising activity in the National Cancer Institute’s 60-cell line screening protocol (NCI 60) and could be exploited for tumor imaging.…”

“…11 The acyl chlorides were then condensed with the bis-dimethylamino propyl pyrrole amine 6,11,12 under modified Schotten-Baumann conditions (Scheme 1 and Supplementary Data). Purification was accomplished via preparative TLC on silica gel eluting with 10% ammonium hydroxide in methanol.…”

“…Our working hypothesis is that AIMs exert their antitumor activity by binding a specific cellular target, 6,9 that is, G-quadruplex (G4) DNA. 19,20 The topology of the AIM by sc-xrd is similar to that observed in our computational docking study of the AIMs with human telomeric G4; Figure 1.B illustrates AIM 3a docked with coordinates from PDB accession 1KF1, 21 whereas Figure 1.C shows the low energy interaction calculated for the solution conformation of the G4, PDB accession number 2JSM, 22–24 docked with 3c.…”

The rearrangement of 3-nitropyridinium salts to 3-nitropyrroles

“…[25][26][27][28][29] The extraordinary biological and synthetic significance of compounds of the pyrrole series is a powerful stimulus to motivation the development of new approaches to the synthesis of these compounds. [30][31][32][33][34] In this paper we present novel results of our investigations of the nitropyridinium salt rearrangement to 2-acyl-4-nitropyrroles.…”