Annamalai Murali, Hristeva Stanimira, Bielska Martyna, Ortega Raquel, Kumar Kamal
Max-Planck-Institut für molekulare Physiologie, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil Figge-Str. 76a, 44227 Dortmund, Germany.
Molecules. 2017 May 18;22(5):827. doi: 10.3390/molecules22050827.
Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high ³ character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in ³ features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.
尽管天然产物在成功的药物发现史上做出了巨大贡献，但仍存在重大局限性，这使得制药行业在药物发现研究中回避天然产物。天然产物的极度稀缺以及结构复杂性使其实际的合成获取和进一步修饰极具挑战性。尽管制药行业采用了其他替代技术，特别是组合化学，以快速获得大量具有简单框架的小分子，这些小分子往往缺乏三维复杂性，但在发现先导分子方面几乎没有取得任何成功。为了获得具有天然产物结构特征的化学类型，例如高立体特征，基于天然产物核心骨架合成化合物库是一种很有前景的策略。在此，我们报告了一种受天然产物启发的合成方法，用于药物发现研究，合成了六种不同的化学类型及其衍生物。这些双环杂环和碳环骨架非常新颖，富含立体特征，具有理想的物理化学性质以展现类药特性。进一步利用骨架上的官能团生成相应的化合物库。还展示了其中两个化合物库的合成示例，每个库约有350种化合物。整个化合物库正在欧洲先导工厂联盟内进行各种生物筛选。
