Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp3-hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity. To date, several approaches have been implemented for mapping and navigating into the chemical space of NPs to explore the different aspects of chemical space. The approaches providing novel opportunities to synthesize NP-inspired compound libraries involve NP-based fragments and ring distortion strategies. These methodologies allow access to areas of chemical space that are less explored, and consequently help to overcome the limitations in the use of NPs in drug discovery, such as lack of accessibility and synthetic intractability. In this review, we describe how NPs have recently been used as a platform for the development of diverse compounds with high structural and stereochemical complexity. In addition, we show developed strategies aiming to reengineer NPs toward the expansion of NP-based chemical space by fragment-based approaches and chemical degradation to yield novel compounds to enable drug discovery.

天然产物（Natural Products, NPs）是优质的生物活性分子来源，其携带诸多具有生物偏向性的结构特征，可支撑合成化合物的创新性设计。天然产物的结构特征为sp3杂化碳原子与氧原子占比高，且包含螺环、桥环与联环系，同时含有大量手性中心，整体结构多样性显著。迄今为止，学界已开发出多种用于绘制与遍历天然产物化学空间的方法，以全方位探究化学空间的不同维度。其中，基于天然产物片段的方法与环畸变策略，为合成受天然产物启发的化合物库提供了全新机遇。此类方法能够进入此前较少被探索的化学空间区域，进而助力克服天然产物在药物研发应用中的局限，如可获取性不足、合成难度高等问题。本综述将阐述近年来天然产物作为平台，用于开发兼具高结构复杂度与立体化学复杂性的多样化化合物的相关研究进展。此外，本文还将介绍已开发的相关策略：通过基于片段的方法与化学降解手段对天然产物进行重构，以拓展基于天然产物的化学空间，从而获得可用于药物研发的新型化合物。