Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

Abstract

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects.

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…6,7 Although FBDD has proven to be a successful method of drug discovery that achieves great chemical diversity, it remains a challenge to create the same degree of structural diversity in fragment libraries. [8][9][10][11][12] Structural diversity is highly desired because molecular shape is among the most important factors dictating biological effects of molecules. 8,9,13,14 Also, increased 3D shape can lead to greater aqueous solubility due to greater solvation and poorer solid-state crystal lattice packing, as well as improved ADMET properties (absorption, distribution, metabolism, excretion, and toxicity).…”

“…8,9 The lack of structural diversity in fragment libraries is in large part due to the challenge of producing small, organic molecules with inherent 3D shape. 8 Efforts to create 3D organic fragments have included diversity-oriented synthesis, 8,11,14 combinatorial libraries, 9 incorporation of cubanes, 16 and incorporation of chiral carbon atoms, 10 all of which pose signicant synthetic challenges. Herein, this issue is addressed by introducing the rst metallofragment (mF) library composed entirely of small, inorganic complexes with inherent 3D topologies.…”

Application of Fragment-Based Drug Discovery to Versatile Targets

“…This library contains approximately 20,000 compounds with selected chemical properties and molecular weight of 150-350 Da (Bollag et al, 2012). The availability of diverse compound libraries makes FBDD possible to be applied to various targets (Kidd et al, 2018).…”

AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite

“…Diversity-oriented synthesis is a major concept in drug discovery [ 6 , 7 , 8 ], and it is currently in a paradigm shift towards biological performance diversity instead of plain chemical diversity [ 9 ]. Based on the above, it may be a reasonable strategy to target biological diversity by utilizing RONS-mediated oxidation as a driving principle for an antioxidant-inspired biorelevant expansion of chemical space.…”