Title:Synthesis, Preferentially Hypoxic Apoptosis and Anti-Angiogenic Activity of 3- Amino-1,2,4-Benzotriazine-1,4-Dioxide Bearing Alkyl Linkers with a 3-Amino-1,2,4- Benzotriazine-1-Oxide Moiety
Volume: 14
Issue: 10
Author(s): Chun-I Lee, Chien-Ming Huang, Wen-Hsin Huang and An-Rong Lee
Affiliation:
Keywords:
Anti-angiogensis, apoptosis, 3-amino-1, 2, 4-benzotriazine-1, 4-dioxide (tirapazamine), bioreductive agent, hypoxic cytotoxin.
Abstract: 3-(Aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives were synthesized by the structural modification of
3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) that incorporated homologue-alkyl linkers, without or with an extended 3-
amino-1,2,4-benzotriazine-1-oxide moiety at the 3-position of the TPZ. According to sequential evaluation of preferentially normoxic
and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds exhibited hypoxic cytotoxicity
greater than or comparable to that of TPZ. Among them, compounds 9a and 9b more powerfully inhibited the proliferation of MCF-7,
NCI-H460 and HCT-116 in hypoxia than did TPZ. The representative of 3-(aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended
derivatives, 9a exhibited greater hypoxic cytotoxicity than TPZ, mediated by cell cycle arrest. The induction of DNA damage, the
activation of caspase 3/7 and cleaved poly(ADP-ribose) polymerase-related apoptosis, which were detected in HCT-116 cells in both
normoxia and hypoxia. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts that were exposed to the selected 7b, 8g,
9a and 9b exhibited 80-90% inhibition of tube formation at 20 µM, whereas TPZ exhibited approximately 50% inhibition of
tube formation at 20 µM. At 2 µM, 9a and 9b significantly reduced the areas, lengths, paths and joints of tube formation by 70-80% and
45-50%, respectively. These results reveal that most of synthesized TPZ derivatives in this study exhibited more potent anti-angiogenesis
than TPZ.
