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Anticancer Agents Med Chem. 2014 Oct 14. [Epub ahead of print]

Synthesis, preferentially hypoxic apoptosis and anti-angiogenic activity of 1,2,4-benzotrazin-3-amine 1,4-dioxide bearing alkyl linkers with 1,2,4-benzotrazin-3-amine 1-oxide derivatives.

Author information

1
Graduate Institute of Life Sciences, School and Institute of Pharmacy, National Defense Medical Center, No. 161, Section 6, Mingchuan E. Road, Taipei 11490, Taiwan. Management Center, Department of Medical Research and Development, Show Chwan Health Care. wenhsin1495@gmail.com.

Abstract

3-(Aminoalkylamino)-1,2,4-benzotriazine 1,4-dioxide-extended derivatives were carried out by structural modifications of 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) that incorporated the homologue-alkyl linkers further with or without an extended 1,2,4-benzotrazin-3-amine 1-oxide moiety at 3-position of TPZ. After sequentially evaluated for preferentially normoxic and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds showed more potent hypoxic cytotoxicity than or comparable to that of TPZ. Among them, compound 9a and 9b were more potent inhibitory proliferation of MCF-7, NCI-H460 and HCT-116 in hypoxia than that of TPZ. The representative 9a showed the most potent hypoxic cytotoxicity in comparison to TPZ, mediated by cell cycle arrest, induction of DNA damage, activation of caspase 3/7 and the cleaved poly(ADP-ribose) polymerase-related apoptosis, which were conducted at HCT-116 cells in both normoxia and hypoxia, respectively. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts exposed to the selected 7b, 8g, 9a and 9b had 80-90% inhibition of tube formation at 20 μM, whereas TPZ inhibited about 50% tube formation at 20 μM. At 2 μM, 9a and 9b still had significant decrease in area, length, path and joint of tube formation of 70-80% and 45-50%, respectively. These results indicated that TPZ derivatives were more potent anti-angiogenesis.

PMID:
25312508

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