A Proposal for the Synthesis of the Lomaiviticin Aglycon

描述（由申请人提供）：在过去的几十年中，天然存在的物质及其半合成或全合成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。这样的靶标由图1中所示的洛麦维他菌素A（1）和B（2）例示。这对二聚重氮苯并芴糖苷表现出有效的DNA损伤活性和有前途的细胞毒活性。洛麦替星A对许多癌细胞系的IC 50值范围为0.01至98 ng/mL，并显示出与已知DNA损伤药物阿霉素和丝裂霉素C不同的细胞毒性特征，表明其具有前所未有的作用机制。鉴于这些数据，必须解决这些制剂的制备问题。此外，该提案中的想法可能对其他复杂的1，4-二羰基天然产物的合成具有广泛的影响，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。公共卫生相关性拟议项目与公共卫生的相关性有两个方面：1）它可能为合成洛麦维他汀（lomaiviticins）提供蓝图，洛麦维他汀是一对具有不完全确定但非常有前途的生物活性的抗肿瘤抗生素; 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.