The Synthesis and Bioassay of Novel Pyrroles

新型吡咯类化合物的合成及生物测定

• 批准号: 8271103
• 负责人: JOHN T. GUPTON
• 金额: $ 34.86万
• 依托单位: UNIVERSITY OF RICHMOND
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271103
• 关键词: Acids; Adverse effects; Amides; Area; Attention; Biological; Biological Assay; Biological Factors; Blood Vessels; Breast Cancer Cell; Cancer cell line; Carbon; Cell Death; Cell Survival; Cells; Chemotherapy-Oncologic Procedure; Clinical; Colorectal Cancer; Coupled; Data; Development; Disease; Drug resistance; Evaluation; Exhibits; Funding; Goals; Grant; HIV; HIV Integrase Inhibitors; In Vitro; Indoles; Inhibitory Concentration 50; Lead; Malignant neoplasm of prostate; Marines; Melanoma Cell; Methodology; Modeling; Molecular Models; Multi-Drug Resistance; Mus; Pharmaceutical Preparations; Positioning Attribute; Process; Property; Protein Kinase Inhibitors; Proteins; Pyrroles; Reaction; Research; Salts; Sodium Chloride; Source; Specific qualifier value; Staurosporine; Structure-Activity Relationship; Subcategory; System; Topoisomerase; Treatment-Related Cancer; United States National Institutes of Health; Work; Xenograft procedure; analog; antitumor agent; cancer cell; chemotherapeutic agent; cytotoxic; cytotoxicity; drug candidate; drug discovery; experience; in vitro activity; in vivo; interest; marine natural product; meetings; molecular modeling; novel; promoter; protein kinase inhibitor; tubulin polymerization inhibitor

DESCRIPTION (provided by applicant): This proposal represents a continuation of work initiated under NIH AREA grant CA 67236-04. Natural products of marine origin continue to be a rich source of biologically interesting compounds and pyrrole containing marine natural products in particular have demonstrated activity as anti-tumor agents, multidrug resistant reversal agents, vascular disrupting agents and inhibitors of HIV integrase. These pyrrole containing natural products are usually characterized by highly oxygenated phenyl or heterocyclic groups attached at carbons 3 and 4 of the pyrrole ring system along with carbonyl containing functionality located at carbons 2 and/or 5. The synthetic methodology that we have established and are developing allows for rapid construction of highly substituted and highly functionalized pyrroles. This methodology also allows for great structural diversity for structure activity relationship (SAR) studies, which could lead to chemotherapeutic agents with increased potency and decreased toxic side effects. Work proposed for the new funding cycle will involve applying our synthetic methodology along with some new and complimentary methodology to the synthesis of the marine natural products lycogallic acid, lycogarubin B, lycogarubin C, lynamycin E and related compounds, such as new analogs of JG-03-14. JG-03-14 is an interesting synthetic pyrrole, which has emerged from our research efforts, and has demonstrated in vitro activity (IC50 of 35 nM) against breast cancer cell lines and in vivo activit against a mouse prostate cancer xenograft. JG-03-14 has also been shown to be active against drug resistant breast cancer cell lines, an inhibitor of tubulin polymerization, a vascular disrupting agent and a promoter of autophagic cell death. Our current and evolving synthetic methodologies will allow us to extend our targets to these important bioactive, natural products and new JG-03-14 analogs. All of the target molecules, their precursors and their analogs will be subject to biological evaluation by a team of highly experienced collaborators and such studies will be coupled with molecular modeling by an additional collaborator. Since our project encompasses synthesis, bioassay and molecular modeling driven SAR, we believe that a novel and viable clinical candidate for cancer chemotherapy may well emerge from such studies. PUBLIC HEALTH RELEVANCE: The development of new and novel chemotherapeutic agents for a particular disease state continues to depend to a significant degree on the discovery of a "lead compound", which can be further developed into a viable drug candidate. Naturally occurring compounds continue to be a major source of "drug leads" and our current proposal seeks to utilize our pyrrole forming reactions to synthesize biologically interesting natural products such as lycogallic acid, lycogarubins B and C, lynamycin E and related compounds. In addition to these natural product targets, we will continue to develop new derivatives of our synthetic pyrrole, JG-03-14, which continues to exhibit promising biological properties. The majority of these natural products, their analogs and precursors along with JG-03-14 analogs will be biologically evaluated and computationally modeled by a team of highly experienced collaborators.

描述（由申请人提供）：本提案是NIH AREA资助CA 67236-04下启动的工作的延续。海洋来源的天然产物仍然是生物学上令人感兴趣的化合物的丰富来源，特别是含有吡咯的海洋天然产物已被证明具有作为抗肿瘤剂、多药耐药逆转剂、血管破坏剂和HIV整合酶抑制剂的活性。这些含吡咯的天然产物的特征通常是在吡咯环系统的碳3和4处连接高度氧化的苯基或杂环基团，以及沿着位于碳2和/或5处的含羰基官能团。我们已经建立并正在开发的合成方法允许快速构建高度取代和高度官能化的吡咯。该方法还允许用于结构活性关系（SAR）研究的大的结构多样性，这可能导致具有增加的效力和降低的毒副作用的化学治疗剂。为新的供资周期提出的工作将涉及应用我们的合成方法沿着一些新的补充方法，合成海洋天然产品石蒜酸、石蒜红素B、石蒜红素C、林霉素E和相关化合物，如JG-03-14的新类似物。JG-03-14是一种有趣的合成吡咯，它已经从我们的研究工作中出现，并已证明对乳腺癌细胞系的体外活性（IC 50为35 nM）和对小鼠前列腺癌异种移植物的体内活性。JG-03-14还被证明对耐药乳腺癌细胞系、微管蛋白聚合的抑制剂、血管破坏剂和自噬细胞死亡的促进剂具有活性。我们目前和不断发展的合成方法将使我们能够将目标扩展到这些重要的生物活性天然产物和新的JG-03-14类似物。所有的目标分子，它们的前体和它们的类似物将由一个经验丰富的合作者团队进行生物学评价，这些研究将与另一个合作者的分子建模相结合。由于我们的项目包括合成，生物测定和分子模拟驱动的SAR，我们相信，一个新的和可行的癌症化疗的临床候选人很可能出现从这样的研究。 公共卫生相关性：用于特定疾病状态的新的和新颖的化学治疗剂的开发继续在很大程度上依赖于“先导化合物”的发现，其可以进一步开发成可行的候选药物。天然存在的化合物仍然是“药物先导物”的主要来源，并且我们目前的提议寻求利用我们的吡咯形成反应来合成生物学上感兴趣的天然产物，例如石蒜酸、石蒜红素B和C、林霉素E和相关化合物。除了这些天然产物目标，我们将继续开发我们的合成吡咯JG-03-14的新衍生物，它继续表现出有前途的生物学特性。这些天然产物中的大多数，它们的类似物和前体沿着JG-03-14类似物将由一组经验丰富的合作者进行生物学评价和计算建模。

项目成果

The application of vinylogous iminium salt derivatives to efficient formal syntheses of the marine akaloids lamellarin G trimethyl ether and ningalin B.

• DOI: 10.1016/j.tet.2009.03.085
• 发表时间: 2009-05-30
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Gupton JT;Giglio BC;Eaton JE;Rieck EA;Smith KL;Keough MJ;Barelli PJ;Firich LT;Hempel JE;Smith TM;Kanters RP
• 通讯作者: Kanters RP

Further studies on vinamidinium salt amine exchange reactions, borohydride reductions and subsequent transformations.

• DOI: 10.1016/j.tet.2010.08.075
• 发表时间: 2010-10-30
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Gupton JT;Telang N;Jia X;Giglio BC;Eaton JE;Barelli PJ;Hovaizi M;Hall KE;Welden RS;Keough MJ;Worrall EF;Finzel KL;Kluball EJ;Kanters RP;Smith TM;Smith SQ;Nunes SR;Wright MT;Birnstihl JM
• 通讯作者: Birnstihl JM

Effects of a pyrrole-based, microtubule-depolymerizing compound on RAW 264.7 macrophages.

• DOI: 10.1016/j.cbi.2016.01.009
• 发表时间: 2016-02-25
• 期刊: Chemico-biological interactions
• 影响因子: 5.1
• 作者: Ciemniecki JA;Lewis CP;Gupton JT;Fischer-Stenger K
• 通讯作者: Fischer-Stenger K

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

• DOI: 10.1021/ml200217u
• 发表时间: 2012-01-12
• 期刊: ACS MEDICINAL CHEMISTRY LETTERS
• 影响因子: 4.2
• 作者: Da, Chenxiao;Telang, Nakul;Barelli, Peter;Jia, Xin;Gupton, John T.;Mooberry, Susan L.;Kellogg, Glen E.
• 通讯作者: Kellogg, Glen E.

The application of formyl group activation of bromopyrrole esters to formal syntheses of lycogarubin C, permethyl storniamide A and lamellarin G trimethyl ether.

溴吡咯酯的甲酰基活化在番茄红素C、全甲基斯托尼酰胺A和板层素G三甲醚的形式合成中的应用。

• DOI: 10.1016/j.tet.2014.11.035
• 发表时间: 2014
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Gupton,JohnT;Telang,Nakul;Patteson,Jon;Lescalleet,Kristin;Yeudall,Scott;Sobieski,John;Harrison,Andrew;Curry,Will
• 通讯作者: Curry,Will