Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products

描述（由申请人提供）：拟议研究的目标是开发新的化学方法，以合成生物活性类黄酮和氧杂蒽酮衍生的天然产物，从而产生新型抗癌和抗感染药物。将开发的化学方法包括用于合成异戊二烯基类黄酮和相关Diels-Alder天然产物的新型[4 + 2]缩合环加成，使用手性硼络合物的2 '-羟基查耳酮和二烯的对映选择性[4+2]环加成，3-阿洛氧基黄酮的金属催化不对称重排，异呋喃与5-羟基色酮的乙烯基加成以合成四氢蒽酮，以及间醌甲基化物（m-QM）中间体的光环加成反应，以构建双环[3.2.2]环体系。Porco教授及其同事将这些新方法应用于生物活性天然产物目标的化学合成，包括kuwanons G和H，sangennol F，sangennon C，sorocenol B，secalonic acids A和D，microsphaerin B和acremoxanthone A。目前正在进行合作，以评估生物测定中的化合物，包括其作为人胃泌素释放肽受体（GRP-R）拮抗剂、E3泛素连接酶gp 78抑制剂以及针对疟疾寄生虫恶性疟原虫地理分离株的功效。本项目的主要目标是：完成GRP-R拮抗剂kuwanons G和H的全合成，以及sorocenol B、sanggenol F、sanggenon A和C的不对称合成。开展了四羟基蒽酮blennolides A和B的不对称合成，完成了二聚体天然产物secalonic acid A和D以及microsphaerin B的全合成。实现了抗感染药物acremodinin A和acremoxanthone A的合成。拟议的项目将为Porco教授及其合作者提供新的研究方向，涉及在有机反应中使用纳米粒子，不对称催化和新颖的环加成策略，这些都是目前资助计划所不可能的。 公共卫生相关性：拟议的研究计划的目标是开发新的方法来合成复杂的，类黄酮和吨酮衍生的天然产物，并研究其生物学特性的合作努力。复杂天然产物的计划合成与公共健康的相关性需要鉴定新的、具有生物活性的抗肿瘤和抗感染剂。具体地，这样的试剂将可用作新的药理学疗法和作为针对人类癌症和疟疾的细胞毒性剂。

DESCRIPTION (provided by applicant): The goal of the proposed research is develop new chemical methodologies to enable the synthesis of bioactive flavonoid and xanthone-derived natural products that could lead to novel, anti-cancer and anti-infective agents. Chemical methodologies that will be developed include novel [4+2] dehydrogenative cycloadditions for the synthesis of prenylflavonoid and related Diels-Alder natural products, enantioselective [4+2] cycloadditions of 2'-hydroxychalcones and dienes using chiral boron complexes, metal-catalyzed, asymmetric rearrangement of 3-alloxyflavones, vinylogous addition of siloxyfurans to 5-hydroxychromones to synthesize tetrahydroxanthones, and photocycloaddition of m-quinone methide (m-QM) intermediates to construct bicyclo[3.2.2] ring systems. Professor Porco and colleagues will apply these new methodologies to the chemical synthesis of bioactive natural product targets including kuwanons G and H, sangennol F, sangennon C, sorocenol B, secalonic acids A and D, microsphaerin B, and acremoxanthone A. Collaborations are in place to evaluate compounds in biological assays, including their efficacy as human gastrin-releasing peptide receptor (GRP-R) antagonists, as inhibitors of the E3 ubiquitin ligase gp78, and against geographic isolates of the malarial parasite P. falciparum. The aims of the proposed project are to: Achieve total syntheses of the GRP-R antagonists kuwanons G and H and the asymmetric syntheses of sorocenol B, sanggenol F, and sanggenons A and C. Develop asymmetric syntheses of the tetrahydroxanthones blennolides A and B and accomplish total syntheses of the dimeric natural products secalonic acids A and D and microsphaerin B. Achieve syntheses of the anti-infective agents acremodinin A and acremoxanthone A. The proposed project will enable new research directions for Professor Porco and his collaborators involving the use of nanoparticles in organic reactions, asymmetric catalysis, and novel cycloaddition strategies that are not possible with current grant programs. PUBLIC HEALTH RELEVANCE: The goal of the proposed research program is to develop new methodologies for the syntheses of complex, flavonoid and xanthone-derived natural products and to study their biological properties in collaborative efforts. The relevance to public health of the planned syntheses of complex natural products entails identification of novel, biologically active antitumor and anti-infective agents. Specifically, such agents will be useful as novel pharmacological therapies and as cytotoxic agents against both human cancers and malaria.