A Proposal for the Synthesis of the Lomaiviticin Aglycon

描述(申请人提供)：在过去的几十年里，自然产生的物质及其半合成或全合成类似物在维持人类健康方面构成了非常重要的部分。因此，继续研究快速有效地化学合成这些物质的方法是一个优先事项。本提案的目的是发明合成复杂的1，4-二羰基化合物的方法，并使用这些方法制备具有生物活性的天然产物。图1所示的洛麦维菌素A(1)和B(2)就是这种靶标的例证。这对二聚重氮苯并荧苷显示出强大的DNA损伤活性和良好的细胞毒活性。尤其是Lomaiviticin A对许多癌细胞的IC50值在0.01到98 ng/mL之间，并且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，这表明了一种前所未有的作用机制。鉴于这些数据，必须解决这些试剂的制备问题。此外，本提案中的想法可能对合成其他复杂的1，4-二羰基天然产物具有广泛的影响，可能有助于寻找新的药剂和/或制备具有已证实活性的化合物。与公众健康的相关性拟议的项目与公共健康的关系有两个方面：1)它可能为合成洛麦维菌素提供一个蓝图，这是一对生物活性尚未完全确定但非常有希望的抗肿瘤抗生素；2)为构建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提供了一种一般方法。

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.