A Proposal for the Synthesis of the Lomaiviticin Aglycon

描述（由申请人提供）：在过去的几十年里，天然存在的物质及其半或完全合成的类似物在维持人类健康方面起着非常重要的作用。因此，继续研究这些物质的快速和有效的化学合成方法是一个优先事项。本提案的目的是发明合成1,4-二羰基络合物的方法，并利用这些方法制备具有生物活性的天然产物。图1所示的lomaivicticins A(1)和B(2)就是这些靶点的例子。这对二聚体重氮苯并芴苷显示出有效的dna损伤活性和有希望的细胞毒性活性。特别是洛美维汀A对多种癌细胞的IC50值在0.01 ~ 98 ng/mL之间，并表现出不同于已知的dna损伤药物阿霉素和丝裂霉素C的细胞毒性，这表明它具有前所未有的作用机制。鉴于这些数据，必须解决这些药剂的制备问题。此外，本提案中的想法可能对其他1,4-二羰基络合物天然产物的合成具有广泛的意义，可能有助于寻找新的药物和/或制备具有已证实活性的化合物。拟议的项目与公共卫生的相关性是双重的：它可以1)为洛马维汀的合成提供蓝图，这是一对抗肿瘤抗生素，生物活性尚不完全确定，但非常有希望；2)为在许多生物活性化合物中发现的某些敏感和复杂的分子亚结构的构建提供了一种通用方法。

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.