Presentation Design, synthesis and radioprotecting activity of metal-chelator and hydroxyquinoline-based derivatives.

Aoki, Shin  ,  Morita, Akinori  ,  Shinya Ariyasu  ,  Sawa, Akiko  ,  Asanuma, Tetsuo  ,  Onoda, Takayoshi  ,  Nishi, Yurie  ,  Wang, Bing  ,  Kamiya, Kenji  ,  Yoshio Hosoi  ,  Tanaka , Tomohiro  ,  Hisamatsu , Yosuke

In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. 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. The mechanisms responsible for p53-induced apoptosis are classified into a transcription-dependent pathway and a transcription-independent pathway. In this paper, we report on the radioprotective activity of Zn2+ chelators such as TPEN (Tetrakis(2-pyridylmethyl)ethylenediamine) and bispicen (N,N’-Bis(2-pyridylmethyl)-1,2-ethanediamine) , and 8-hydroxyquinoline (8HQ) derivatives that were designed so as to interact with the Zn2+ in p53. It was revealed that bispicen induces a conformational change in p53, resulting in inhibition of its complexation with DNA and the inhibition of both the p53-mediated transcription-dependent and independent pathways (Oncotarget, 4, 2439-2450, 2013).As for the 8HQ derivatives, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against g-ray radiation (10 Gy), accompanied by a low cytotoxicity. 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 (Bioorg. Med. Chem. 22, 3891-3905, 2014; Biochem. Biophys. Res. Commun. 450, 1498-1504, 2014). Key words: 8-Hydroxyquinoline, Radioprotector, Mechanistic study
日本放射線影響学会第58回大会(学会出席・発表)参加日程: 平成27年5月25日〜29日

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