Nichole A Pianovich1, Mathew Dean2, Adam Lassak2, Krzysztof Reiss2, Branko S Jursic3. 1. Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA. 2. Neurological Cancer Research, Stanley S. Scott Cancer Center, Department of Medicine, LSU Health Sciences Center, New Orleans, LA 70119 USA. 3. Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA; STEPHARM, LLC., PO Box 24220, New Orleans, LA 70184, USA. Electronic address: bjursic1@uno.edu.
Abstract
Diazinane and aryl moieties with vinylamine linkers were synthesized to investigate the importance of their structural variations as potential anti-glioblastoma agents. Structural variations incorporated on to the diazinane moiety included oxa and thio derivatives, each with a variety of nitrogen-bound substituents. The size and shape of the aromatic moiety was varied, with the final variation introducing two carbonyl groups, yielding a substituted anthraquinone. Readily available diazinanes and aryl amines were used asan advantageous foundation. Several parameters were calculated whilst engineering these compounds, including: ClogP, molecular polarizability, polar surface area, minimal molecular projected area, and pKa. In addition, a simple and efficient procedure was developed to synthesize these compounds. It was demonstrated that a vinylamine with 1,3-diazinane-2,4,6-trione and 1-anthraquinone moiety is the most promising drug candidate causing almost 70% of LN229 tumor cell death at 1µg/ml. In addition, its molecular polarizability, polar surface area and minimal molecular projected area indicate a possible potential of this molecule for crossing BBB.
Diazinane and aryl moieties with n class="Chemical">vinylamine linkers were synthesized to investigate the importance of their structural variations as potential anti-glioblastoma agents. Structural variations incorporated on to the diazinane moiety included oxa and thio derivatives, each with a variety of nitrogen-bound substituents. The size and shape of the aromatic moiety was varied, with the final variation introducing two carbonyl groups, yielding a substituted anthraquinone. Readily available diazinanes and aryl amines were used asan advantageous foundation. Several parameters were calculated whilst engineering these compounds, including: ClogP, molecular polarizability, polar surface area, minimal molecular projected area, and pKa. In addition, a simple and efficient procedure was developed to synthesize these compounds. It was demonstrated that a vinylamine with 1,3-diazinane-2,4,6-trione and 1-anthraquinone moiety is the most promising drug candidate causing almost 70% of LN229tumor cell death at 1µg/ml. In addition, its molecular polarizability, polar surface area and minimal molecular projected area indicate a possible potential of this molecule for crossing BBB.
Authors: Olivier L Chinot; Wolfgang Wick; Warren Mason; Roger Henriksson; Frank Saran; Ryo Nishikawa; Antoine F Carpentier; Khe Hoang-Xuan; Petr Kavan; Dana Cernea; Alba A Brandes; Magalie Hilton; Lauren Abrey; Timothy Cloughesy Journal: N Engl J Med Date: 2014-02-20 Impact factor: 91.245
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