Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor

Abstract

The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

“…The use of thionyl chloride and DMF followed by treatment with sodium azide is also widely applied for the preparation of medicinally relevant compounds. This is exemplified in the recent development of inhibitors of the protein‐tyrosine phosphatase 4A3 (PTP4A3), such as compound 22 . Acid 20 was converted to the key acyl azide intermediate 21 successfully employing this protocol (Scheme ).…”

“…Wipf and collaborators reported the development of new small molecule inhibitors of the protein‐tyrosine phosphatase 4A3 (PTP4A3) . One of the synthetic routes involved a key Curtius rearrangement step.…”

“…Curtius rearrangement and concomitant cyclization required high temperatures which produced thienopyridone 67 . Finally, nitration followed by hydrogenation provided 22 (Scheme ) . Thienopyridone 22 is the most potent known inhibitor of PTP4A3 to date and was shown to be selective for the PTP4A family over 11 other phosphatases.…”

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

“…Thienopyridone also prevents the association of PRLs with CNNMs (39). Most recently, a more potent derivative of thienopyridone, Analog 13, has been developed, which showed IC50 values of 50, 52 and 18 nmol/L against PRL1, PRL2, and PRL3 respectively (40). Analog 3 is an easily accessible, low micromolar PRL inhibitor identified through virtual screening and structural activity relationship efforts and has proven useful for florescence microscopy and cellular based studies (Fig.…”

New Approaches to Difficult Drug Targets: The Phosphatase Story

“…Nevertheless, follow-up studies have exposed new analogs, which are at least 50-fold more potent and hold promise as further leads for PTP4A inhibitors. 81 Computational approaches have also been applied to the PTP4A family despite the lack of a large number of x-ray crystal structures. 82 One provocative report by Hoeger et al 54 used virtual screening approaches to identify novel small-molecule inhibitors of PTP4A3.…”