Design, synthesis and biological activities of antiangiogenic hypoxic cytotoxin, triazine-N-oxide derivatives.
For cancer therapy, hypoxia represents an important tumor specific target. Therefore we designed and synthesized antiangiogenic hypoxic cytotoxins as 'hypoxia modifiers'. They can be activated bioreductively in hypoxic cells to kill the oxygen-deficient tumor cells selectively and prevent their re-growth. The aromatic heterocycle di-N-oxides, tirapazamine (TPZ), TX-1102, and TX-402 inhibited growth of EMT6/KU cells, SAS/neo cells, and SAS/Trp248 cells (mutant p53 gene transformant) under hypoxic condition. They also induced apoptosis selectively at a dose of 10 microM each under hypoxic condition for 5 h. Their hypoxic cytotoxicities and apoptosis inducing activities were p53-independent because the activities in SAS/neo cells were almost similar to that in SAS/Trp248 cells. In angiogenesis inhibition assay using chick embryo chorioallantoic membrane (CAM), TPZ, TX-1102, TX-402 and TX-1033 showed 40, 25, 60 and 60% inhibition of angiogenesis each at a dose of 10 microg/CAM. On the other hand, the nitrosopyrimidine, TX-1041 had neither antiangiogenic activity nor cytotoxicity. Therefore the di-N-oxide group is thought to be required for the biological activities. TX-1102 was a potent antiangiogenic hypoxic cytotoxin inducing apoptosis p53-independently.
Nagasawa
Hideko
H
Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Minamijosanjima-cho 2-1, Tokushima 770-8506, Japan.
Yamashita
Mao
M
Mikamo
Naoko
N
Shimamura
Mariko
M
Oka
Shigenori
S
Uto
Yoshihiro
Y
Hori
Hitoshi
H
D000332:Aerobiosis; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002642:Chick Embryo; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D003603:Cytotoxins; D014227:Triazines; D016159:Tumor Suppressor Protein p53