RESUMEN
Dimeric analogs of Anthracenyl Isoxazole Amides (AIMs) (the designation AIM is in honor of the memory of Professor Albert I. Meyers) were prepared and dimer 6 exhibited the highest efficacy to date for this class of anti-tumor compounds against the human glioma Central Nervous System cell line SNB-19.
Asunto(s)
Amidas/farmacología , Antineoplásicos/síntesis química , Neoplasias Encefálicas/tratamiento farmacológico , Química Farmacéutica/métodos , Glioma/tratamiento farmacológico , Amidas/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , ADN/química , Dimerización , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración de Iones de Hidrógeno , Modelos Químicos , Conformación MolecularRESUMEN
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.
Asunto(s)
Antracenos/síntesis química , Antracenos/farmacología , Antineoplásicos/síntesis química , Azoles/síntesis química , Azoles/farmacología , Netropsina/análogos & derivados , Antracenos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Azoles/química , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Netropsina/síntesis química , Netropsina/química , Netropsina/farmacología , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
A series of 9-(pyridin-2'-yl)-aminoacridines was prepared and analyzed for their ability to change the thermal denaturation temperature of genomic calf thymus DNA. Development of a QSAR equation indicated that electron withdrawing groups on the pyridine ring promoted the interaction with double stranded DNA.