Discovery and Characterization of R/S-N-3-Cyanophenyl-N′-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines

Abstract

A new series of N-aryl-N′-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N′-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors.

Novel HDAC inhibitor MAKV-8 and imatinib synergistically kill chronic myeloid leukemia cells via inhibition of BCR-ABL/MYC-signaling: effect on imatinib resistance and stem cells

“…Docking studies were carried out as previously reported [54] using the Protein Data Bank (PDB) codes 4BKX, 4LY1, 4A69, 2VQM, 5EDU, 3C10, and 3EW8 corresponding to HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, and HDAC8, respectively. MAKV-6, MAKV-7, MAKV-8, MAKV-10, and MAKV-12, and SAHA were drawn using ChemDraw Professional software version 15.0 (PerkinElmer Informatics).…”

The Fungal Metabolite Eurochevalierine, a Sequiterpene Alkaloid, Displays Anti-Cancer Properties through Selective Sirtuin 1/2 Inhibition

“…The natural SIRT inhibitor nicotinamide was also included as a reference compound for in vitro SIRT3 inhibition [ 34 ]. Besides suramin, additional references SIRT1/2, SIRT1, and SIRT2 inhibitors, namely, sirtinol, EX-527, and AGK2, respectively, performed in a similar range or less efficiently [ 15 ].…”

“…Docking studies were performed as previously described [ 15 ] with a docking grid size of 25 Å × 25 Å × 25 Å, which encompassed the entire inhibitor binding pocket of SIRT1 and 2 structures. To prepare the SIRT coordinates for docking simulation, ligands and all water molecules were removed except static water molecules in the binding site that could play important roles in the actual inhibition.…”

“…3 Suramin and sirtinol, EX-527, and AGK2 were used as in vitro reference inhibitors of SIRT1/2, SIRT1, and SIRT2, respectively. Data from [ 15 ] obtained in the same experimental conditions. 4 70% and 5 59% are the remaining enzymatic activity at 100 µM compared to the control set to 100%.…”

“…For instance, the SIRT1/2 inhibitor sirtinol triggers growth arrest in human breast and lung cancer cells [ 14 ]. Similarly, the benzopyran-based compound 18 inhibits SIRT1/2 activities and acts as a cytostatic agent in glioblastoma cells [ 15 ], whereas the dual SIRT1/2 inhibitor tenovin-1 induces apoptosis in sarcoma cells [ 16 ]. Other specific sirtuin inhibitors (SIRTi) have been reported to trigger cancer cell death, including the SIRT1 inhibitors NCO-01 and -04, and the SIRT2 inhibitors AEM1 and AEM2, which induce cell death in T-cell leukemia/lymphoma [ 17 ] and in non-small cell lung cancer [ 18 ], respectively.…”