[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

The advent of modern C–H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C–H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C–H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Organic synthesis provides opportunities to transform drug discovery

For over 35 years, biological scientists have come to rely on the research protocols and methodologies in the critically acclaimed Methods in Molecular Biology series. The series was the first to introduce the step-by-step protocols approach that has become the standard in all biomedical protocol publishing. Each protocol is provided in readilyreproducible step-bystep fashion, opening with an introductory overview, a list of the materials and reagents needed to complete the experiment, and followed by a detailed procedure that is supported with a helpful notes section offering tips and tricks of the trade as well as troubleshooting advice. These hallmark features were introduced by series editor Dr. John Walker and constitute the key ingredient in each and every volume of the Methods in Molecular Biology series. Tested and trusted, comprehensive and reliable, all protocols from the series are indexed in PubMed.

Methods Molecular Biology

The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.

Expanding the medicinal chemistry synthetic toolbox

Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small-molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel 'pseudo-natural product' classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we identify design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small-molecule discovery.

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Principle and design of pseudo-natural products.

As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201604193

Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

https://pubs.rsc.org/en/content/articlepdf/2015/cc/c5cc03002a

A Systematic Approach to Diverse, Lead-Like Scaffolds from α,α-Disubstituted Amino Acids.

Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.

/pdf/a-unified-lead-oriented-synthesis-of-over-fifty-molecular-dndw1u6jdj.pdf

A unified lead-oriented synthesis of over fifty molecular scaffolds

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top-down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3-rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.

Daniel J. Foley

Papers

Principle and design of pseudo-natural products.

Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

A Systematic Approach to Diverse, Lead-Like Scaffolds from α,α-Disubstituted Amino Acids.

A unified lead-oriented synthesis of over fifty molecular scaffolds

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.