2018 |
Noureini, S K; Kheirabadi, M; Masoumi, F; Khosrogerdi, F; Zarei, Y; Suarez-Rozas, C; Salas-Norambuena, J; Cassels, B K Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine Artículo de revista International Journal of Molecular Sciences, 19 (4), 2018, ISSN: 1422-0067. Resumen | Enlaces | BibTeX | Etiquetas: apoptosis, assay binding boldine, cells, derivative, domain, inhibition, n-benzylsecoboldine, site, stress, telomerase @article{RN387, title = {Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine}, author = { S.K. Noureini and M. Kheirabadi and F. Masoumi and F. Khosrogerdi and Y. Zarei and C. Suarez-Rozas and J. Salas-Norambuena and B.K. Cassels}, url = {/brokenurl#<Go to ISI>://WOS:000434978700318}, doi = {10.3390/ijms19041239}, issn = {1422-0067}, year = {2018}, date = {2018-01-01}, journal = {International Journal of Molecular Sciences}, volume = {19}, number = {4}, abstract = {Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC50 value of about 0.17 +/- 0.1 mu M for BSB, roughly 400 times stronger than boldine, while the LD50 in the cytotoxicity assays were 12.5 and 21.88 mu M, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC50 for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations.}, keywords = {apoptosis, assay binding boldine, cells, derivative, domain, inhibition, n-benzylsecoboldine, site, stress, telomerase}, pubstate = {published}, tppubtype = {article} } Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC50 value of about 0.17 +/- 0.1 mu M for BSB, roughly 400 times stronger than boldine, while the LD50 in the cytotoxicity assays were 12.5 and 21.88 mu M, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC50 for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations. |
2018 |
Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine Artículo de revista International Journal of Molecular Sciences, 19 (4), 2018, ISSN: 1422-0067. |