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The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Duocarmicinas/farmacología , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas/síntesis química , Duocarmicinas/química , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Pulling up our socks! In this Editorial, ChemMedChem Editor-in-Chief Natalia Ortúzar discusses how editors, reviewers and authors might all pull together to address the issue of reproducibility of data reported in the literature.
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Química Farmacéutica , Publicaciones Periódicas como Asunto/normas , Proyectos de Investigación/normasRESUMEN
Fabulous at five! When ChemistryOpen was launched in 2011, it was the first society-owned general chemistry journal to publish open-access articles exclusively. Five years down the line, it has featured excellent work in all fields of chemistry, leading to an impressive first full impact factor of 3.25. In this Editorial, read about how ChemistryOpen has grown over the past five years and made its mark as a high-quality open-access journal with impact.
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Happy birthday! Issue 01/2016 marks the 10th anniversary of ChemMedChem. With a complete set of 10 volumes, the Editorial Team takes a look back at how the journal, and indeed the field of medicinal chemistry, have evolved and changed over the past decade.