Development of viable synthetic route to the furaquinocins and its application to creating new antitumor agents

呋喃喹啉的可行合成路线的开发及其在新型抗肿瘤药物中的应用

• 批准号: 09554045
• 负责人: SUZUKI Keisuke
• 金额: $ 6.53万
• 依托单位: Tokyo Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09554045/
• 关键词: furaquinocin; antitumor compound; chemical synthesis; 抗生物質; 全合成; 転位反応; 立体選択的反応

An efficient and flexible synthetic route to the furaquinocins, a new class of antibiotics which show cytotoxic activity against HeLa S3 and B16 melanoma cells but no antimicrobial activity, was developed. These compounds pose new synthetic challenges due to their unique hybrid structure composed of the polyketide-derived naphthoquinone and the isoprenoid side chain, including (1) stereocontrol of three contiguous stereogenic centers at C-2, C-3 (quaternary), and C-10, (2) selective construction of the densely functionalized naphthoquinone, and (3) establishment of the sterically congested aromatic-isoprenoid hybrid structure.Stereocontrolled construction of two of the three contiguous stereogenic centers, including a quaternary chiral center, was effected by the 1,2-rearrangement of optically active epoxy alcohol armed with the cobalt-complexed alkyne as the migrating group. The alkyne in the resulting homopropargyl alcohol, after decoordination of the cobalt, effectively worked as the C2 unit for constructing the naphthofuran skeleton by an electrocyclic benzannulation. The third chiral center was constructed by stereoselective methylenation of the aldehyde, adjacent to the quaternary chiral center, by a sulfur ylide. Through the resulting epoxide as the common intermediate, total syntheses of furaquinocin D, furaquinocin A, furaquinocin B, and furaquinocin H were achieved in a convergent manner.Biological activity test revealed that some of the synthetic intermediates exhibit potent cyctocidal activities comparable to natural furaquinocins, which provides a valuable information for designing new synthetic antitumor agents.

开发了一种高效、灵活的合成呋喃喹诺酮类抗生素的方法，这类抗生素对HeLa S3和B16黑色素瘤细胞具有细胞毒活性，但没有抗菌活性。这些化合物由于其独特的由聚酮衍生的萘醌和类异戊二烯侧链组成的杂化结构而提出了新的合成挑战，包括(1)C-2、C-3(四元)和C-10三个连续立体中心的立体控制，(2)选择性地构建了稠密官能化的萘醌，以及(3)建立了空间致密的芳香族-异戊二烯杂化结构。生成的高丙叉醇中的炔，在钴被解离后，有效地作为C2单元，通过电环苯环化来构建萘并呋喃骨架。第三个手性中心是通过乙醛的立体选择性亚甲基化而构建的，该亚甲基化位于第四个手性中心附近，由一个硫叶立德组成。通过合成的环氧化物作为常见的中间体，以聚合的方式实现了呋喃西林D、呋喃西林A、呋喃西林B和呋喃西林H的全合成。生物活性测试表明，一些合成的中间体具有与天然呋喃西林相当的杀细胞活性，这为设计新的合成抗癌药物提供了有价值的信息。

项目成果

T. Saito, T. Matsumoto, K, Suzuki: "Implication and Improvement of Stereoselective Methylenetion of a Chiral Aldehyde Related to Total Synthesis of Furaquinocins"Tetrahedron Lett.. 38. 3755-3758 (1997)

T. Saito、T. Matsumoto、K、Suzuki：“与呋喃喹啉全合成相关的手性醛的立体选择性亚甲基化的含义和改进”Tetrahedron Lett.. 38. 3755-3758 (1997)

T. Nakagawa, K. Suzuki: "Novel Migrating Group in 1,2-Anionotropic Reactions : Cobalt-Complexation Facilitates 1,2-Shift of Alkynyl Groups"J. Am. Chem. Soc.. 118. 8949-8950 (1996)

T. Nakakawa，K. Suzuki：“1,2-阴离子异性反应中的新型迁移基团：钴络合促进炔基基团的 1,2-转变”J。

T. Saito, T. Matsumoto, K, Suzuki: "Total Synthesis of the Fraquinocins"J. Am. Chem. Soc.. 120. 11633-11644 (1998)

T. Saito、T. Matsumoto、K、Suzuki：“Fraquinocins 的全合成”J。