A Proposal for the Synthesis of the Lomaiviticin Aglycon

合成 Lomaiviticin 苷元的提案

• 批准号: 7544847
• 负责人: Carlos Ariel Guerrero
• 金额: $ 4.48万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544847
• 关键词: 1,3-Butadiene; Address; Adriamycin PFS; Biological; Biological Factors; Cancer cell line; Complex; DNA Damage; DNA Sequence Rearrangement; Data; Disulfides; Exhibits; Facility Construction Funding Category; Glycosides; Health; Human; Inhibitory Concentration 50; Methodology; Methods; Mitomycin; Modification; Molecular; Numbers; Pharmaceutical Preparations; Preparation; Public Health; Range; Research; adduct; analog; antineoplastic antibiotics; chemical synthesis; cytotoxic; cytotoxicity; lomaiviticin A; method development; novel

DESCRIPTION (provided by applicant): For the past several decades naturally occurring substances and their semi- or fully synthetic analogues have comprised a very important part in maintaining human health. Continuing research into methodology for the rapid and efficient chemical synthesis of these substances is therefore a priority. The aims of this proposal are to invent methods for the synthesis of complex 1,4-dicarbonyl compounds and to use these methods to prepare biologically active natural products. Such targets are exemplified by lomaiviticins A (1) and B (2) shown in Figure 1. This pair of dimeric diazobenzofluorene glycosides demonstrated potent DNA-damaging activity and promising cytotoxic activity. Lomaiviticin A in particular showed IC50 values ranging from 0.01 to 98 ng/mL against a number of cancer cell lines and exhibited a cytotoxicity profile that differed from the known DNA-damaging drugs adriamycin and mitomycin C suggesting an unprecedented mechanism of action. In view of such data, the preparation of these agents must be addressed. In addition, the ideas in this proposal may have broad implications for the synthesis of other complex 1,4-dicarbonyl natural products, possibly facilitating the search for novel medicinal agents and/or the preparation of compounds with proven activity. PUBLIC HEALTH RELEVANCE The relevance of the proposed project to public health is two-fold: it may 1) provide a blueprint for the synthesis of the lomaiviticins, a pair of antitumor antibiotics with incompletely determined but very promising biological activity; and 2) provide a general method for the construction of certain sensitive and complex molecular substructures that are found in many biologically active compounds.

描述（由申请人提供）：在过去的几十年中，自然存在的物质及其半合成类似物在维持人类健康方面非常重要。因此，对这些物质快速有效化学合成的方法论的持续研究是一个优先事项。该提案的目的是发明合成复杂1,4-二碳偶氮词的合成方法，并使用这些方法来制备生物活性的天然产物。图1中所示的洛氏素毒素A（1）和B（2）例证了此类靶标。这对二聚体二氧化氮二氮乙烯糖苷表现出有效的DNA破坏活性和有希望的细胞毒性活性。特别是洛氏素素A的IC50值范围为0.01至98 ng/ml，针对多种癌细胞系，并且表现出与已知的DNA损害药物Adrimycin和Mitymycin C不同的细胞毒性谱，表明表明一种前所未有的作用机制。鉴于此类数据，必须解决这些代理的准备。此外，该提案中的思想可能对其他复杂的1,4-二碳酮天然产物的综合有广泛的影响，这可能促进了寻找新型药用剂和/或制备具有可靠活性的化合物。公共卫生相关性与公共卫生的相关性是两个方面：5月1日）为合成Lomaivitics的合成提供了蓝图，Lomaivitic蛋白是一对抗肿瘤抗生素，具有不完全确定但非常有前途的生物学活性； 2）提供了一种在许多生物活性化合物中发现的某些灵敏和复杂的分子下结构的一般方法。