Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia selective cytotoxins.
A series of novel tricyclic triazine-di- N-oxides (TTOs) related to tirapazamine have been designed and prepared. A wide range of structural arrangements with cycloalkyl, oxygen-, and nitrogen-containing saturated rings fused to the triazine core, coupled with various side chains linked to either hemisphere, resulted in TTO analogues that displayed hypoxia-selective cytotoxicity in vitro. Optimal rates of hypoxic metabolism and tissue diffusion coefficients were achieved with fused cycloalkyl rings in combination with both the 3-aminoalkyl or 3-alkyl substituents linked to weakly basic soluble amines. The selection was further refined using pharmacokinetic/pharmacodynamic model predictions of the in vivo hypoxic potency (AUC req) and selectivity (HCD) with 12 TTO analogues predicted to be active in vivo, subject to the achievement of adequate plasma pharmacokinetics.
Hay
Michael P
MP
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. m.hay@auckland.ac.nz
Hicks
Kevin O
KO
Pchalek
Karin
K
Lee
Ho H
HH
Blaser
Adrian
A
Pruijn
Frederik B
FB
Anderson
Robert F
RF
Shinde
Sujata S
SS
Wilson
William R
WR
Denny
William A
WA
D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002627:Chemistry, Physical; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004583:Electrons; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010087:Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*
D003603:Cytotoxins; D006575:Heterocyclic Compounds, 3-Ring; D010087:Oxides; D014227:Triazines