Inhibition of intrahepatic metastasis of hepatocellularcarcinoma by novel pyrrolidine derivatives

• Project/Area Number: 19591578
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: The University of Tokyo
• Principal Investigator: KARAKO Takashi The University of Tokyo, 医学部・附属病院, 助教 (00313213)
• Co-Investigator(Kenkyū-buntansha): MAKUUCHI Masatoshi 東京大学, 医学部・附属病院, 名誉教授 (60114641) ; NAKATA Munehiro 東海大学, 工学部, 教授 (00266371)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 肝臓外科学 / 肝細胞癌 / 肝内転移 / 化学療法 / ピロリジン誘導体 / 治療

Research Abstract

本研究では、癌細胞の浸潤や転移において重要な役割をもつマトリクス・メタロプロテイナーゼ(MMP)の活性を阻害することが可能な新規ピロリジン誘導体を合成し、その有効性を検討することを目的とした。研究代表者らと共に山東大学「中・日新薬スクリーニングセンター」を設立した研究協力者によって、本研究計画において多くの種類の新規ピロリジン誘導体が合成され、有効な化合物のスクリーニングが実施された。その結果、合成された新規ピロリジン誘導体の一種であるLY52が、他の細胞に毒性を示すことなく、乳癌細胞MDA-MB-231の増殖を有意に阻害することを見出した。また、当該化合物は、化合物設計時の想定どおり、ターゲットとするMMP-2の酵素活性を有意に阻害した。さらに、癌培養細胞株を用いたin vitro解析により、当該化合物が癌細胞の浸潤を有意に阻害することが明らかとなった。また、癌を移植したモデルマウスを用いたin vivo実験では、当該化合物の経口投与により肺に形成される腫瘍結節数が有意に減少した。以上のことから、新規ピロリジン誘導体LY52は、癌細胞の増殖のほか、間質組織への浸潤及び他の臓器への転移を阻害することができ、抗癌効果をもつ化合物として有効であることが示唆された。
一方、本研究計画では、抗癌効果をもつことが明らかとなった化合物の構造に基づいて、その結果を化合物設計にフィードバックさせて更なる新規化合物の設計及び化合物ライブラリの拡大を図ってきた。現在、MMPのように癌の進行に重要なタンパク質分解酵素をターゲットとして設計した新規化合物群を有するライブラリが構築された。従って、本研究計画による成果は、今後のタンパク質分解酵素をターゲットとした創薬研究に対して大きく貢献することができたと考えている。

Research Products

• [Journal Article] Galloyl cyclic-imide derivativeCH1104I inhibits tumor invasionthrough suppressing matrixmetalloproteinase activity (2008)
  • Author(s): Chen MH, Cui SX, Cheng YN, Sun LR, LiQB, Xu WF, Ward SG, Tang W, Qu XJ
  • Journal Title: Anticancer Drugs 19 Pages: 957-965
  • Peer Reviewed
• [Journal Article] Synthesis of new sulfonylpyrrolidine derivatives as matrixmetalloproteinase inhibitors (2008)
  • Author(s): Cheng XC, Wang Q, Fang H, Tang W, Xu WF
  • Journal Title: BioorgMed Chem 16 Pages: 7932-7938
  • Peer Reviewed
• [Journal Article] Design, synthesis and evaluationof novel sulfonyl pyrrolidinederivatives as matrixmetalloproteinase inhibitors (2008)
  • Author(s): Cheng XC, Wang Q, Fang H, Tang W, Xu WF
  • Journal Title: BioorgMed Chem 16 Pages: 5398-5404
  • Peer Reviewed
• [Journal Article] Strategies to overcome orcircumvent p-glycoprotein mediatedmultidrug resistance (2008)
  • Author(s): Yuan H, Li X, Wu J, Li J, Qu X, Xu W, Tang W
  • Journal Title: Curr Med Chem 15 Pages: 470-476
  • Peer Reviewed
• [Journal Article] Galloyl cyclic-imide derivative CH1104I inhibits tumor invas ion through suppressing matrix metalloproteinase activity. (2008)
  • Author(s): Chen MH, Cui SX, Cheng YN, Sun LR et al.
  • Journal Title: Anticancer Drugs 19 Pages: 957-965
  • Peer Reviewed
• [Journal Article] Positive KL-6 mucin expression combined with decreased membr anous β-catenin expression indicates worse prognosis in colo rectal carcinoma. (2008)
  • Author(s): Zhang W, Tang W, Inagaki Y, Qiu M et al.
  • Journal Title: Ohcol Rep 20 Pages: 1013-1019
  • Peer Reviewed
• [Journal Article] Synthesis of new sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors. (2008)
  • Author(s): Cheng XC, Wang Q, Fang H, T ang W, Xu WF
  • Journal Title: Bioorg Med Chem 16 Pages: 7932-7938
  • Peer Reviewed
• [Journal Article] Design, synthesis and evaluation of novel sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors. (2008)
  • Author(s): Cheng XC, Wang Q, Fang H, T ang W, Xu WF
  • Journal Title: Bioorg Med Chem 16 Pages: 5398-5404
  • Peer Reviewed
• [Journal Article] Strategies to overcome or circumvent p-glycoprotein mediated multidrug resistance. (2008)
  • Author(s): Yuan H, Li X, Wu J, Li J, Qu X, Xu W, Tang W
  • Journal Title: Curr Med Chem 15 Pages: 470-476
  • Peer Reviewed
• [Journal Article] Design, synthesis and preliminary evaluation of novel pyrrolidine derivatives as matrix metalloProteinase inhibitors (2008)
  • Author(s): Cheng XC, Wang Q, Fang H, Tang W, Xu WF
  • Journal Title: Eur J Med Chem (掲載確定)
  • Peer Reviewed
• [Journal Article] Inhibition of human gastriccarcinoma cell growth by treatment ofN(3)-o-toluyl-fluorouracil as aprecursor of 5-fluorouracil (2007)
  • Author(s): Liu J, Li X, Cheng YN, Cui SX, Chen MH, Xu WF, Tian ZG, Makuuchi M, Tang W, QuXJ
  • Journal Title: Eur Jpharmacol574 2007 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Induction ofapoptosis in human hepatocellularcarcinoma cells by syntheticantineoplaston A10 (2007)
  • Author(s): Qu XJ, Cui SX, Tian Z, Li X, Chen MH, Xu WF, Inagaki Y, Deng YB, Makuuchi M, Nakata M, Tang W
  • Journal Title: Anticancer Res 27 Pages: 2427-2431
  • Peer Reviewed
• [Journal Article] KL-6mucin is a useful immunohistochemicalmarker for cholangiocarcinoma (2007)
  • Author(s): Tang W, Guo Q, Qu XJ, Inagaki Y, SeyamaY, Midorikawa Y, Gai R, Kokudo N, Sugawara Y, Nakata M, Makuuchi M
  • Journal Title: Oncol Rep 17 Pages: 737-741
  • Peer Reviewed
• [Journal Article] Recentadvances in P-gp-mediated MDRreversal mechanisms (2007)
  • Author(s): Li X, Qu XJ, Xu WF, Tang W
  • Journal Title: Methods Find ExpClin Pharmacol 29 Pages: 607-617
  • Peer Reviewed
• [Journal Article] Subcellular localizationof KL-6 mucin in colorectal carcinomacell lines : association withmetastatic potential and cellmorphology (2007)
  • Author(s): Guo Q, Tang W, Inagaki Y, Kokudo N, Sugawara Y, Karako H, Nakata M, Makuuchi M
  • Journal Title: Oncol Rep 17 Pages: 1057-1060
  • Peer Reviewed
• [Journal Article] KL-6 mucin is a useful immunohistochemical marker for cholangiocarcinoma (2007)
  • Author(s): Tang W, 他6名, Kokudo N, Sugawara Y, Nakata M, Makuuchi M
  • Journal Title: Oncol Rep 17 Pages: 737-741
  • Peer Reviewed
• [Journal Article] Inhibition of human gastric carcinoma cell growth by treatment of N(3)-o-toluyl-fluorouracil as a precursor of 5-fluorouracil (2007)
  • Author(s): Liu J, 他6名, Makuuchi M, Tang W, Qu XJ
  • Journal Title: Eur J Pharmacol 574 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Recent advances in P-glycoprotein-mediated multidrug resistance reversal mechanisms (2007)
  • Author(s): Li X, Li JP, Yuan HY, Gao X, Qu XJ, Xu WF, Tang W
  • Journal Title: Methods Find Exp Clin Pharmacol 29 Pages: 607-617
  • Peer Reviewed
• [Journal Article] Demographic and clinical characteristics of resectable hepatocellular carcinoma in China and Japan (2007)
  • Author(s): Yuan P, Tang W, 他12名, Makuuchi M
  • Journal Title: Hepato-Gastroenterol 54 Pages: 2343-2347
  • Peer Reviewed
• [Presentation] ANTINEOPLASTONA10 INHIBITS THE GROWTH OF HEPATOMACELLS THROUGH THE INDUCTION OFAPOPTOSIS (2008)
  • Author(s): Inagaki Y, Tang W, Qu XJ, Cui SX, LiX, Yuan YX, Tian ZG, Xu WF, Nakata M, Sugawara Y, Kokudo N
  • Organizer: 13th World Congress onAdvances in Oncology and 11thInternational Symposium on MolecularMedicine
  • Place of Presentation: Crete, Greece
  • Year and Date: 2008-10-10
• [Presentation] ANTINEOPLASTON A10 INHIBITS THE GROWTH OF HEPATOMA CELLS THROUGH THE INDUCTION OF APOPTOSIS. (2008)
  • Author(s): Inagaki Y, Tang W, Qu XJ, Cui SX et al.
  • Organizer: 13th World Congress on Advances in Oncology and 11th International Symposium on Molecular Medicine
  • Place of Presentation: ギリシャ、クレタ島
  • Year and Date: 2008-10-09
• [Presentation] Different expression profile of KL-6mucin in primary liver cancer tissues (2008)
  • Author(s): Tang W, Inagaki Y, Xu HL, Seyama Y, Nakata M, Sugawara Y, Kokudo N
  • Organizer: 第108回日本外科学会定期学術集会
  • Place of Presentation: 長崎, 日本
  • Year and Date: 2008-05-16
• [Presentation] Different expression profile of KL-6 mucin in primary liver cancer tissues. (2008)
  • Author(s): Tang W, Inagaki Y, Xu HL, Seynma Y et al
  • Organizer: 第108回日本外科学会定期学術集会
  • Place of Presentation: 日本、長崎
  • Year and Date: 2008-05-16
• [Presentation] Availability of KL-6 mucin as a tool for discriminating cholangiocarcinoma from hepatocellular carcinoma (2007)
  • Author(s): Inagaki Y, Xu HL, Kokudo N, Sugawara Y, Nakata M, Tang W
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会合同大会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2007-12-14
• [Presentation] Availability ofKL-6 mucin as a tool fordiscriminating cholangiocarcinomafrom hepatocellular carcinoma (2007)
  • Author(s): Inagaki Y, Xu HL, Kokudo N, SugawaraY, Nakata M, Tang W
  • Organizer: Congress of Biochemistry andMolecular Biology 2007 (第30回日本分子生物学会年会・第80回日本生化学会合同大会)
  • Place of Presentation: 横浜, 日本
  • Year and Date: 2007-12-13
• [Presentation] KL-6 mucin as a diagnostic marker for cholangiocarcinoma (2007)
  • Author(s): Inagaki Y, Xu HL, Tang W, Nakata M, Sugawara Y, Kokudo N
  • Organizer: China-Japan Joint Medical Workshop on Drug Discoveries and Therapeutics
  • Place of Presentation: 中国山東省済南
  • Year and Date: 2007-05-26
• [Presentation] KL-6 mucin as adiagnostic marker forcholangiocarcinoma. (2007)
  • Author(s): Inagaki Y, Xu HL, Tang W, Nakata M, Sugawara Y, Kokudo N
  • Organizer: China-JapanJoint Medical Workshop on Drug Discoveries and Therapeuticss
  • Place of Presentation: Jinan, China