Innovative on-DNA synthesis of sulfides and sulfoximines: enriching the DEL synthesis toolbox 

Functional groups containing sulfur are essential in drug design, with 249 FDA-approved pharmaceuticals featuring sulfur-bearing moieties. Sulfides, constituting 8.8% of these compounds, are prominent, with examples like Festamoxin, Cimetidine, Thiethylperazine, and Pergolide highlighting their significance. Recent attention has shifted towards sulfoximines, appreciated for their favorable physicochemical properties and metabolic stability. Noteworthy kinase inhibitors such as AZD 67389 and Roniciclib feature sulfoximine groups, indicating the potential of such functionalities in drug development. 

Despite the increasing interest, sulfoximines remain underutilized due to outdated synthetic methods and limited resources. DNA-encoded library technology (DELT) offers promise in overcoming these challenges, providing a cost-effective alternative to High Throughput Screening (HTS). However, DELT’s exploration of chemical space is constrained by the available chemical transformations and sulfoximines are not available in routine DELs. 

To address this limitation, researchers such as our DEL platform team are actively developing novel on-DNA synthesis methods to expand DELT’s capabilities. In this study, we focused on the on-DNA synthesis of sulfides and sulfoximines, and developed a robust approach, demonstrating wide applicability and easy implementation in routine DEL synthesis. Despite the potential for DNA damage, our methodology ensures broad functional group tolerance and minimizes undesired reactivities. This advancement holds promise for accessing previously unexplored chemical space within DNA-encoded libraries, offering new avenues for drug discovery. 

Zhaomei Sun, Ying Zhong, Yahui Chen, Lingqian Xiao, Jiangying Wang, Fanming Zeng, Kexin Yang, Nicolas Duchemin, and Yun Jin Hu.

Organic Letters  2024 26 (19), 4082-4087

DOI: 10.1021/acs.orglett.4c01138