STRUCTURAL/SYNTHETIC STUDIES OF BIOACTIVE MARINE AGENTS

海洋生物活性剂的结构/综合研究

• 批准号: 6019071
• 负责人: DANIEL ROMO
• 金额: $ 10.63万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6019071
• 关键词: Porifera; Tunicata; X ray crystallography; animal extract; antimitotics; antineoplastics; cell differentiation; chemical structure function; cyclization; drug design /synthesis /production; immunomodulators; lactams; molecular rearrangement; nuclear magnetic resonance spectroscopy; saltwater environment; stereochemistry; tubulin

DESCRIPTION: The objectives of this proposal include the structure determination and total synthesis of novel marine natural products displaying potent biological activity. Targets are said to include bistramide A, a tunicate isolate inducing cellular differentiation, pateamine A, a marine sponge isolate exhibiting immunomodulating properties, and curacin A, a marine bacterial antimitotic agent which inhibits tubulin polymerization. It is reported that bistramide A promises to be a useful new tool for the study of mechanisms involved in cellular differentiation, a capacity lost by some cancerous cells and that methods for the preparation of crystalline derivatives of bistramide A suitable for x-ray analysis are proposed as a means to determine its relative and absolute stereochemistry. The principal investigator notes that a convergent, stereoflexible route is proposed for the enantioselective, total synthesis of bistramide A and that key features of the synthesis include an Ireland-Claisen rearrangement and a samarium diiodide mediated, sequential acyl substitution/redox process. It is indicated that the synthesis of structural derivatives and a bistramide A affinity matrix will allow preliminary investigations into the mode of action of these agents. The principal investigator states that as a first step towards understanding how pateamine A exerts its immunomodulating effects, an initial objective in collaboration with Professor M. Munro (University of Canterbury. New Zealand) is determination of its relative and absolute stereochemistry by using a combination of semi-synthesis, natural product degradation, molecular modeling, and NMR spectroscopy and that structural verification is to be accomplished by executing a convergent, enantioselective synthesis of pateamine. It is indicated that the convergent nature of the synthesis will allow access to significant quantities of pateamine A and structural derivatives for further evaluation as potential immunosuppressive agents by Dr. G. Faircloth (PharmaMar, USA) and for investigations into their mechanism of action. It is noted that a convergent, enantioselective synthesis of four diastereomers of curacin A will enable spectroscopic comparison to an authentic sample for stereochemical determination of this antimitotic agent. The principal investigator states that a key step in the synthetic approach includes a novel Stille-type coupling of a cyclopropyl stannane to a cysteine derived- thiazoline triflate to prepare the structurally unique cyclopropyl-thiazoline portion of curacin A and structural variants in this region of the molecule. These derivatives are to be evaluated for their ability to inhibit tubulin polymerization by Dr. E. Hamel (National Cancer Institute-NIH). It is suggested that these investigations may lead to a novel class of antineoplastic agents that exert their effects via the colchicine binding site of tubulin in contrast to other known inhibitors of tubulin polymerization which exert their effects at the vinblastine binding site.

描述：该提案的目标包括结构 新型海洋天然产物的测定与全合成 显示出有效的生物活性。据说目标包括 bistramide A，一种诱导细胞分化的被囊动物分离物， pateamine A，一种具有免疫调节作用的海洋海绵分离物 特性，以及 curacin A，一种海洋细菌抗有丝分裂剂， 抑制微管蛋白聚合。 据报道，bistramide A有望成为一种有用的新工具 研究细胞分化、能力丧失的机制 由一些癌细胞和制备方法 适用于 X 射线分析的 bistramide A 结晶衍生物有 提议作为确定其相对和绝对的手段 立体化学。首席研究员指出，一个趋同的、 提出了立体柔性路线用于对映选择性、总 bistramide A 的合成，该合成的主要特征包括 爱尔兰-克莱森重排和二碘化钐介导， 顺序酰基取代/氧化还原过程。据表明， 结构衍生物和 bistramide A 亲和基质的合成 将允许对这些行动方式进行初步调查 代理。 首席研究员表示，作为迈向的第一步 了解 pateamine A 如何发挥其免疫调节作用， 与 M. Munro 教授（大学 坎特伯雷。新西兰）是确定其相对和 通过使用半合成的组合进行绝对立体化学， 天然产物降解、分子建模和核磁共振波谱 结构验证是通过执行来完成的 巴巴胺的收敛、对映选择性合成。表明的是 合成的收敛性质将允许获得重要的 大量的巴巴胺A和结构衍生物用于进一步 G. Faircloth 博士评估其作为潜在的免疫抑制剂 （PharmaMar，美国）并研究其作用机制。 值得注意的是，四种物质的会聚、对映选择性合成 curacin A 的非对映异构体将能够与 用于立体化学测定这种抗有丝分裂的真实样品 代理人。首席研究员表示，该研究的关键一步是 合成方法包括一种新颖的 Stille 型耦合 环丙基锡烷转化为半胱氨酸衍生的三氟甲磺酸噻唑啉 制备 Curacin 结构独特的环丙基噻唑啉部分 A 和该分子区域的结构变体。这些 将评估衍生物抑制微管蛋白的能力 由 E. Hamel 博士（美国国家癌症研究所 - NIH）进行聚合。这是 表明这些研究可能会导致一类新的 通过秋水仙碱发挥作用的抗肿瘤药 微管蛋白的结合位点与其他已知的微管蛋白抑制剂相比 聚合作用在长春花碱结合位点发挥作用。

项目成果

Total synthesis of the spirocyclic imine marine toxin (-)-gymnodimine and an unnatural C4-epimer.

• DOI: 10.1021/ja207385y
• 发表时间: 2011-12-14
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Kong, Ke;Moussa, Ziad;Lee, Changsuk;Romo, Daniel
• 通讯作者: Romo, Daniel

Functional mimicry revealed by the crystal structure of an eIF4A:RNA complex bound to the interfacial inhibitor, desmethyl pateamine A.

• DOI: 10.1016/j.chembiol.2020.12.006
• 发表时间: 2021-06-17
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Naineni SK;Liang J;Hull K;Cencic R;Zhu M;Northcote P;Teesdale-Spittle P;Romo D;Nagar B;Pelletier J
• 通讯作者: Pelletier J

A beta-lactone route to chiral gamma-substituted alpha-amino acids: application to the concise synthesis of (S)-alpha-azidobutyro lactone and a natural amino acid.

• DOI: 10.1021/ol017120b
• 发表时间: 2002-01
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: R. L. Tennyson;Guillermo S. Cortez;Hector J. Galicia;Charles R. Kreiman;C. Thompson;D. Romo

Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents.

• DOI: 10.1016/j.bmc.2013.11.046
• 发表时间: 2014-01-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Low WK;Li J;Zhu M;Kommaraju SS;Shah-Mittal J;Hull K;Liu JO;Romo D
• 通讯作者: Romo D

Synthesis, characterization, and utility of thermoresponsive natural/unnatural product macroligands for affinity chromatography.

用于亲和色谱的热响应性天然/非天然产物大配体的合成、表征和效用。

• DOI: 10.1021/ol062045w
• 发表时间: 2006
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Zhou,Min;Sivaramakrishnan,Ananthapadmanab;Ponnamperuma,Krishan;Low,Woon-Kai;Li,Chunmei;Liu,JunO;Bergbreiter,DavidE;Romo,Daniel
• 通讯作者: Romo,Daniel