Design, synthesis and biological evaluation of novel lamellarin derivatives targeting cancer cells mitochondria
| Project/Area Number |
16K14986
|
|---|
| Research Category |
Grant-in-Aid for Challenging Exploratory Research
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Aquatic life science
|
|---|
| Research Institution | Nagasaki University |
|---|
Principal Investigator |
ISHIBASHI Fumito 長崎大学, 水産・環境科学総合研究科(水産), 教授 (10192486)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
平坂 勝也 長崎大学, 海洋未来イノベーション機構, 准教授 (70432747)
|
|---|
| Research Collaborator |
YASUDA Keisuke
SUZUKI Tatsuya
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
|---|
| Keywords | ラメラリン / ピロールアルカロイド / ミトコンドリア / トポイソメラーゼ / 抗がん活性化合物 / トリフェニルホスホニウムカチオン / ミトコンドリア標的薬 / 海産アルカロイド / トポイソメラーゼ阻害 / 抗がん活性 / 海洋天然物 / 脂溶性TPPカチオン / トポイソメラーゼ阻害活性 / 生理活性 / 癌 / 有機化学 |
|---|
| Outline of Final Research Achievements |
The marine alkaloids lamellarins displays high anticancer activity by inhibiting both nuclear and mitochondrial topoisomerase I, however, they are equally toxic to normal cell lines. TPP cation is known to accumulate in mitochondria in preference to mitochondria of tumor cells compared with nontumor cells. We aimed to create novel mitochondria-targeting agents by incorporating TPP cation in the structure of lamellarin. We established a novel synthetic route to 1-dearyl lamellarin, which is applicable for synthesis of lamellarin itself. By this method the lamellarin alcohol was synthesized and the TPP cation moiety is tethered to the C-1 position of lamellarin through a valerate linker. The ester-linked compound is designed to be hydrolyzed under physiological condition and liberate active lamellarin alcohol after passing through mitochondrial inner membrane. The TPP-lamellarin thus synthesized showed 3-fold higher cytotocicity against HeLa cells than the parental lamellarin alcohol.
|
| Academic Significance and Societal Importance of the Research Achievements |
抗がん活性化合物にTPPカチオンを結合させることによるがん細胞選択性の増大効果は既に複数例報告されているが，本研究により導入効果の実証例がさらに増えた。がん細胞に集積するリガンドを利用する原理は，広く他の抗がん活性物質への応用にも期待できる。ラメラリンの合成法は多く知られているが，パラジウムなどの高価なレアメタル触媒を用いた反応を基盤としたものが殆どである。本研究の結果，Paal-Knorr反応を利用した簡便で効率的なラメラリンの新規合成方法が確立された。
|
Report
(4 results)
Research Products
(6 results)
-
-
-
[Journal Article] Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant2017
Author(s)
Tsutomu Fukuda, Teppei Umeki, Keiji Tokushima, Gao Xiang, Yuki Yoshida, Fumito Ishibashi, Yusuke Oku, Naoyuki Nishiya, Yoshimasa Uehara, Masatomo Iwao
-
Journal Title
Bioorganic & Medicinal Chemistry
Volume: 25
Issue: 24
Pages: 6563-6580
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
