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Design and synthesis of 8-hydroxyquinoline-based radioprotective agents.

Ariyasu S1, Sawa A2, Morita A3, Hanaya K2, Hoshi M2, Takahashi I4, Wang B5, Aoki S6.

Bioorg Med Chem. 2014 ;22(15):3891-905.

1Center for Technologies Against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.and

2Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.and

3Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.and

4Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, Japan.and

5Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.and

6Center for Technologies Against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan. Electronic address: [email protected]

 

Abstract 

In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death of normal cells is caused, at least in part, by apoptosis, which undergoes via activation of p53 and increase in the p53 protein, a zinc-containing transcriptional factor, in response to cellular damage. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. We report herein on the radioprotective activity of 8-hydroxyquinoline (8HQ) derivatives that were initially designed so as to interact with the Zn(2+) in p53. Indeed, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against {Gamma}-ray radiation (10 Gy), accompanied by a low cytotoxicity. However, mechanistic studies revealed that the interaction of these drugs with p53 is weak and the mechanism for inhibiting apoptosis appears to be different from that of previously reported radioprotectors such as bispicen, which inhibits apoptosis via the denaturation of p53 as well as by blocking both transcription-dependent and -independent apoptotic pathways.

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