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- DYRK1A (1)
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- Semitendinosus tendon autograft (1)
- TVT (1)
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In a 40-year-old caucasian patient with stress incontinence was a TVT operation performed with an autologous semitendinosus tendon transplant. The operation was done with spinal anesthesia. The tendon of the right musculus semitendinosus was stripped from the popliteal fossa and used instead of a synthetic tape as midurethral sling, as it is done in a classical retropubic TVT procedure. The operation was performed successfully. On the first day after the operation the transurethral catheter was removed, continence was reached, and no urinary retention was seen. Mobility and power of the affected leg did not change.
The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure-activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.