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

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
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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



Anti-Cancer Agents in Medicinal Chemistry, 14(10): 1428-1446.

Author(s): Chun-I Lee, Chien-Ming Huang, Wen-Hsin Huang and An-Rong Lee.

Affiliation: Graduate Institute of Life Sciences, School and Institute of Pharmacy, National Defense Medical Center, No. 161, Section 6, Mingchuan E. Road, Taipei 11490, Taiwan.

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.




Keywords:

Anti-angiogensis, apoptosis, 3-amino-1, 2, 4-benzotriazine-1, 4-dioxide (tirapazamine), bioreductive agent, hypoxic cytotoxin.



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Article Details

Volume: 14
Issue Number: 10
First Page: 1428
Last Page: 1446
Page Count: 19
DOI: 10.2174/1871520614666141014130554
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