Synthesis and Study of Complex Antiproliferative and Antimalarial Natural Products

复杂的抗增殖和抗疟天然产物的合成与研究

基本信息

  • 批准号:
    8885326
  • 负责人:
  • 金额:
    $ 30.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-08 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This proposal describes the synthesis and studies of the ocimyquines and gukulenins, natural products that exhibit potent antimalarial and antiproliferative effects, respectively. Ocimyquines are nanomolar inhibitors of malaria parasites that are equally potent against drug-sensitive and -resistant strains, and have demonstrated high therapeutic indices in cell culture. In addition, they display prophylactic and curative activty in mouse models, without measurable toxicity. The gukulenins are low nanomolar inhibitors of several cancer cell lines and are very promising candidates for the treatment of colorectal cancer, the second-leading cause of cancer-related deaths in the United States. Both families of natural products possess molecular architectures that are unique. The ocimyquines contain a tetrasubstituted aminocyclopropane embedded within a pentacyclic carbon skeleton whereas the gukulenins are dimeric a-tropolone natural products containing six carbocyclic rings. Although these two families of compounds are unique among anti-infectives and anti-proliferative compounds, and show potent and potentially clinically-useful activities, no syntheses or synthetic studies have been reported. In addition, little is known about their structure-function relationships, and the mechanisms underlying their efficacy and selectivity remain unknown. The objectives of this proposal are to complete concise and convergent syntheses of the ocimyquines and gukulenins and evaluate their efficacy as radical cure anti-malarials and anti-proliferative agents. We have made significant progress toward the syntheses of both families of metabolites, having developed chemistry to access many of the key substructures of the targets. Our synthetic efforts have led to the development of new methods for the synthesis of tetrasubstituted aminocyclopropanes by a ring expansion-ring contraction strategy and 3,5,6-trisubsituted-a-tropolone rings by a novel reductive cleavage reaction. The collaborative nature of the proposal provides the infrastructure required to evaluate the antimalarial prophylactic and therapeutic activity of the ocimyquines and their synthetic derivatives and to elucidate their biological target. In addition, we will conduct structure-functin studies of the gukulenins, test the hypothesis that the natural products engage in reversible covalent bond formation with their target, and identify candidate binding proteins. These experiments will lead to the identification of new antimalarial and anticancer agents with improved potencies and activities, provide insights into the biological mechanisms underlying these activities, and lay the foundation for their preclinical evaluation as new treatments for malaria and colorectal cancer.
 描述(由申请人提供):本提案描述了分别表现出强效抗疟和抗增殖作用的天然产物ocimyquines和gukulenins的合成和研究。罗咪喹是疟疾寄生虫的纳摩尔抑制剂,其对药物敏感株和耐药株同样有效,并且在细胞培养物中已证明具有高治疗指数。此外,它们在小鼠模型中显示出预防和治疗活性,没有可测量的毒性。gukulenins是几种癌细胞系的低纳摩尔抑制剂,并且是治疗结直肠癌的非常有希望的候选物,结直肠癌是美国癌症相关死亡的第二大原因。这两类天然产物都具有独特的分子结构。ocimyquines含有嵌入在五环碳骨架内的四取代的氨基环丙烷,而gukulenins是含有六个碳环的二聚α-环庚三烯酚酮天然产物。虽然这两个家族的化合物在抗感染和抗增殖化合物中是独特的,并且显示出有效的和潜在的临床有用的活性,但尚未报道合成或合成研究。此外,对它们的结构-功能关系知之甚少,其功效和选择性的机制仍然未知。本提案的目的是完成罗咪喹类和古枯菌素类的简明和收敛的合成,并评价它们作为根治性抗疟疾和抗增殖剂的功效。我们在合成这两个代谢物家族方面取得了重大进展,开发了化学方法来获得目标的许多关键子结构。我们的合成工作已经导致了新的方法的发展,用于合成四取代的氨基环丙烷的扩环-缩环策略和3,5,6-三取代的-a-环酚酮环的一种新的还原裂解反应。该提案的协作性质提供了评价ocimyquines及其合成衍生物的抗疟疾预防和治疗活性以及阐明其生物靶点所需的基础设施。此外,我们将进行gukulenins的结构-功能研究,测试的假设,天然产物从事可逆共价键形成与其目标,并确定候选结合蛋白。这些实验将导致新的抗疟和抗癌药物的鉴定,提高效力和活动,提供这些活动的生物学机制的见解,并奠定了基础,为他们的临床前评价作为疟疾和结直肠癌的新疗法。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Seth B. Herzon其他文献

Macrocyclic colibactins
大环大肠杆菌素
  • DOI:
    10.1038/s41557-020-00551-8
  • 发表时间:
    2020-09-21
  • 期刊:
  • 影响因子:
    20.200
  • 作者:
    Seth B. Herzon
  • 通讯作者:
    Seth B. Herzon
Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer
大肠杆菌素对前列腺癌具有雄激素依赖性和非依赖性影响
  • DOI:
    10.1016/j.euo.2024.10.015
  • 发表时间:
    2025-06-01
  • 期刊:
  • 影响因子:
    9.300
  • 作者:
    Raag Agrawal;Sarah Al-Hiyari;Rupert Hugh-White;Robert Hromas;Yash Patel;Elizabeth A. Williamson;Mohammed F.E. Mootor;Alfredo Gonzalez;Jianmin Fu;Roni Haas;Madison Jordan;Brian L. Wickes;Ghouse Mohammed;Mao Tian;Molly J. Doris;Christian Jobin;Kevin M. Wernke;Yu Pan;Takafumi N. Yamaguchi;Seth B. Herzon;Michael A. Liss
  • 通讯作者:
    Michael A. Liss
Genome-scale CRISPR/Cas9 screening reveals the role of emPSMD4/em in colibactin-mediated cell cycle arrest
基因组规模的 CRISPR/Cas9 筛选揭示了 emPSMD4/em 在大肠菌素介导的细胞周期停滞中的作用
  • DOI:
    10.1128/msphere.00692-24
  • 发表时间:
    2025-02-21
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Michael W. Dougherty;Ryan M. Hoffmann;Maria C. Hernandez;Yougant Airan;Raad Z. Gharaibeh;Seth B. Herzon;Ye Yang;Christian Jobin
  • 通讯作者:
    Christian Jobin
Structural study on human microbiome-derived polyketide synthases that assemble genotoxic colibactin
  • DOI:
    10.1016/j.str.2025.04.017
  • 发表时间:
    2025-07-03
  • 期刊:
  • 影响因子:
    4.300
  • 作者:
    Minjae Kim;Jinwoo Kim;Gyu Sung Lee;Paul Dominic B. Olinares;Yougant Airan;Jasmine L. Chow;Jongseok Park;Yujin Jeong;Jiho Park;Brian T. Chait;Seth B. Herzon;Chung Sub Kim;Jin Young Kang
  • 通讯作者:
    Jin Young Kang
1073 GENOME-SCALE CRISPR/CAS9 SCREENING REVEALS THE ROLE OF PSMD4 IN COLIBACTIN-MEDIATED CELL CYCLE ARREST
  • DOI:
    10.1016/s0016-5085(24)01066-7
  • 发表时间:
    2024-05-18
  • 期刊:
  • 影响因子:
  • 作者:
    Michael W. Dougherty;Ryan M. Hoffmann;Yougant Airan;Raad Z. Gharaibeh;Seth B. Herzon;Ye Yang;Christian Jobin
  • 通讯作者:
    Christian Jobin

Seth B. Herzon的其他文献

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{{ truncateString('Seth B. Herzon', 18)}}的其他基金

Synthetic and translational studies of antitumor and antimicrobial natural products
抗肿瘤和抗菌天然产物的合成和转化研究
  • 批准号:
    9922967
  • 财政年份:
    2019
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and translational studies of antitumor and antimicrobial natural products
抗肿瘤和抗菌天然产物的合成和转化研究
  • 批准号:
    10392862
  • 财政年份:
    2019
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and translational studies of antitumor and antimicrobial natural products
抗肿瘤和抗菌天然产物的合成和转化研究
  • 批准号:
    10601007
  • 财政年份:
    2019
  • 资助金额:
    $ 30.74万
  • 项目类别:
Structural and functional studies of colibactin
大肠杆菌素的结构和功能研究
  • 批准号:
    10467675
  • 财政年份:
    2017
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and Chemical Biological Studies of the Diazofluorene Antitumor Antibiot
重氮芴抗肿瘤抗生素的合成及化学生物学研究
  • 批准号:
    8305516
  • 财政年份:
    2011
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and Chemical Biological Studies of the Diazofluorene Antitumor Antibiot
重氮芴抗肿瘤抗生素的合成及化学生物学研究
  • 批准号:
    8042127
  • 财政年份:
    2011
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and Chemical Biological Studies of the Diazofluorene Antitumor Antibiot
重氮芴抗肿瘤抗生素的合成及化学生物学研究
  • 批准号:
    8459029
  • 财政年份:
    2011
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and Chemical Biological Studies of the Diazofluorene Antitumor Antibiot
重氮芴抗肿瘤抗生素的合成及化学生物学研究
  • 批准号:
    8840964
  • 财政年份:
    2011
  • 资助金额:
    $ 30.74万
  • 项目类别:
Synthetic and Chemical Biological Studies of the Diazofluorene Antitumor Antibiot
重氮芴抗肿瘤抗生素的合成及化学生物学研究
  • 批准号:
    8655165
  • 财政年份:
    2011
  • 资助金额:
    $ 30.74万
  • 项目类别:
A Method for the Alkylation of Alcohols and Amines
醇和胺的烷基化方法
  • 批准号:
    7157188
  • 财政年份:
    2006
  • 资助金额:
    $ 30.74万
  • 项目类别:

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