Periodic Reporting for period 2 - SusDrug (Sustainable Approach to Drug Discovery)
Période du rapport: 2021-01-01 au 2022-06-30
Continuous and rapid generation of new small molecule libraries plays a crucial role in medicinal chemistry for the development of novel drugs. However, the synthesis of compounds with desired drug-like properties is becoming more and more challenging as such molecules have to possess certain complexity, which is not easy to achieve using established synthetic methods. This project directly addressed this issue by exploring the use of aromatic compounds (arenes) that are simple and readily available and can serve as precursors to complex and high-value intermediates for medicinal chemistry. By utilizing unique transformations that can rapidly convert arenes into complex molecules, a general reaction platform was established that can convert arenes into numerous compounds with varying degrees of functional and skeletal complexity and functionality. Given a large number of available arenes and permutations of possible reactions steps, such an approach can enable the sustainable preparation of new compound libraries with numerous opportunities. The overall objective of this project was the development of such diversifications and sustainable strategies, as well as their application to drug discovery. Accordingly, a general strategy was developed that led to the generation of highly functionalized cyclitols and aminocyclitols, which are an important class of bioactive compounds, ranging from anticancer to antiinfective agents. Moreover, several methodologies were devised that converted arenes into unique structural building motifs that opened up missing chemical space in drug design and discovery, providing unique opportunities for the design of the next generation of chemical libraries.
The main focus of this project was to develop a uniform dearomatization platform that can convert arenes into value-added compounds with favorable properties for drug discovery applications. Along these lines, three major directions were established: (1) Programmable dearomative functionalization; a sequence-specific installation of functionality into arenes to form of highly functionalized cyclitols and aminocyclitols. Focusing on olefin-based dearomative functionalizations, we were able to design many different and diverse functionalization options. In addition to developing these functionalization programs, we demonstrated the utility of this approach by preparation of valienamine from benzyl alcohol. (2) We designed a new generation of hybrid building blocks at the intersection of sp2/sp3 molecular space, utilizing dearomative cycloadditions. This strategy provided arenes fused to bicycles containing heteroatoms incorporated into their framework. (3) Using arenes as precursors, we designed and prepared several conformationally restricted surrogates for common heterocycles such as piperidines.
Compound library screening is one of the most effective and successful approaches used to identify potential biological targets during the drug development process. While very powerful, the development of new compound members is heavily impacted and limited by advances in synthetic organic chemistry. This comes as no surprise, as a steady increase in the number of diverse members requires a steady increase in the number of synthetic steps, or a continuous supply of different starting materials. While such strategies have proven to be effective for the preparation of small and uniquely diverse sets of compound collections, they fall short upon translation to larger-scale operations. Thus, one could argue that this type of chemical sustainability is one of the most important factors preventing diversification strategies from becoming an integral and necessary part of large-scale drug discovery processes. Our approach converts readily available aromatic compounds to a large set of functionalized compounds using chemistry that diverges significantly from existing methods. Using dearomatization strategy, we were able to showcase how a simple arene could be converted into numerous highly functionalized cyclohexanes, decorated with oxygen- and nitrogen-based functionality. Moreover, by using dearomatization, we were able to fill the missing gap in chemical space by delivering access to hybrid libraries containing fused aromatic (sp2) and sp3-rich motifs. Finally, we converted arenes into novel bioisosteres of common pharmacophores, providing more defined rigid motifs that could enable stronger bindings to biomolecular targets. Several bioisosteric replacements were accomplished, and these compounds are currently under evaluation.
All these efforts are aligned with the frontline of contemporary medicinal chemistry and drug discovery and provide unique solutions for accelerating drug design. Given the urgent need for the generation of novel and drug-like tailored compounds, this project provides specific guidelines and solutions for expanding the chemical space to uncharted, potentially more fertile regions for discovering new drugs.
All these efforts are aligned with the frontline of contemporary medicinal chemistry and drug discovery and provide unique solutions for accelerating drug design. Given the urgent need for the generation of novel and drug-like tailored compounds, this project provides specific guidelines and solutions for expanding the chemical space to uncharted, potentially more fertile regions for discovering new drugs.