Theoretical study and application of 2-phenyl-1,3,4-thiadiazole derivatives with optical and inhibitory activity against SHP1

As one member of PTPs, Src homology-2 domain-containing protein tyrosine phosphatase 1 (SHP1) is mainly restricted to hematopoietic and epithelial cells and widely accepted as a convergent node for oncogenic cell-signaling cascades. Developing efficient methods for rapidly tracing and inhibiting the SHP1 activity in complex biological systems is of considerable significance for advancing the integration of diagnosis and treatment of related disease. On this goal, we designed and synthesized five 2-phenyl-1,3,4-thiadiazole derivatives (PT2, PT5, PT8, PT9 and PT10) here basing on the reported SHP1 inhibitors (PT1, PT3, PT4, PT6 and PT7) with planarity structure. The photophysical properties and inhibitory activities of these 2-phenyl-1,3,4-thiadiazole derivatives (PT1 ‒ PT10) for SHP1 were thoroughly studied from theoretical aspect and experimental application. The representative compound PT10 exhibited the larger quantum yield than the other molecules because of smaller geometric relaxation and reorganization energy of the excited state, which was consistent with the results from the fluorescence experiments in organic solvent. In addition, PT10 showed selectively fluorescence response for SHP1 activity and low-cytotoxicity on Hela cells. Lastly, it indicated the potential application in two-photon cell fluorescence imaging in the future according to the calculated excellent two-photon absorption properties. In this contribution, we offered the fluorescent and activated molecule PT10 against SHP1 firstly, which achieved the integration of visualization and inhibitory activity of SHP1 preliminarily in enzyme molecular level.