Quinoline alkaloids as intercalative topoisomerase inhibitors Export

@article{citeulike:4501059, abstract = {Abstract\ \ Quinoline alkaloids are abundant in the Rutaceae, and many have exhibited cytotoxic activity. Because structurally related antitumor alkaloids such as camptothecin and fagaronine are known to function as intercalative topoisomerase poisons, it is hypothesized that cytotoxic Stauranthus alkaloids may also serve as intercalative topoisomerase inhibitors. To test this hypothesis theoretically, ten Stauranthus quinoline alkaloids were examined for potential intercalation into DNA using a molecular docking approach. Four of the alkaloids (stauranthine, skimmianine, 3′,6′-dihydroxy-3′,6′-dihydrostauranthine, and trans-3′,4′-dihydroxy-3′,4′-dihydrostauranthine) were able to intercalatively dock consistently into DNA. In order to probe the intermolecular interactions that may be responsible for intercalation of these quinoline alkaloids, density functional calculations have been carried out using both the B3LYP and M06 functionals. M06 calculations indicated favorable π–π interactions between either skimmianine or stauranthine and the guanine–cytosine base pair. Furthermore, the lowest-energy face-to-face orientation of stauranthine with guanine is consistent with favorable dipole–dipole orientations, favorable electrostatic interactions, and favorable frontier molecular orbital interactions. Likewise, the lowest-energy face-to-face orientation of stauranthine with the guanine–cytosine base pair reveals favorable electrostatic interactions as well as frontier molecular orbital interactions. Thus, not only can quinoline alkaloids dock intercalatively into DNA, but the docked orientations are also electronically favorable. Figure\ Lowest-energy face-to-face π–π interaction between stauranthine and guanine}, author = {Byler, Kendall and Wang, Chen and Setzer, William}, citeulike-article-id = {4501059}, citeulike-linkout-0 = {http://dx.doi.org/10.1007/s00894-009-0501-6}, citeulike-linkout-1 = {http://www.springerlink.com/content/67526684111q1520}, day = {1}, doi = {10.1007/s00894-009-0501-6}, journal = {Journal of Molecular Modeling}, keywords = {ab-initio, inhibitors, modeling, topoisomerase}, month = {December}, number = {12}, pages = {1417--1426}, posted-at = {2009-10-30 23:20:34}, priority = {2}, title = {Quinoline alkaloids as intercalative topoisomerase inhibitors}, url = {http://dx.doi.org/10.1007/s00894-009-0501-6}, volume = {15}, year = {2009} }

TY - JOUR ID - citeulike:4501059 L3 - citeulike-article-id:4501059 N2 - Abstract  Quinoline alkaloids are abundant in the Rutaceae, and many have exhibited cytotoxic activity. Because structurally related antitumor alkaloids such as camptothecin and fagaronine are known to function as intercalative topoisomerase poisons, it is hypothesized that cytotoxic Stauranthus alkaloids may also serve as intercalative topoisomerase inhibitors. To test this hypothesis theoretically, ten Stauranthus quinoline alkaloids were examined for potential intercalation into DNA using a molecular docking approach. Four of the alkaloids (stauranthine, skimmianine, 3′,6′-dihydroxy-3′,6′-dihydrostauranthine, and trans-3′,4′-dihydroxy-3′,4′-dihydrostauranthine) were able to intercalatively dock consistently into DNA. In order to probe the intermolecular interactions that may be responsible for intercalation of these quinoline alkaloids, density functional calculations have been carried out using both the B3LYP and M06 functionals. M06 calculations indicated favorable π–π interactions between either skimmianine or stauranthine and the guanine–cytosine base pair. Furthermore, the lowest-energy face-to-face orientation of stauranthine with guanine is consistent with favorable dipole–dipole orientations, favorable electrostatic interactions, and favorable frontier molecular orbital interactions. Likewise, the lowest-energy face-to-face orientation of stauranthine with the guanine–cytosine base pair reveals favorable electrostatic interactions as well as frontier molecular orbital interactions. Thus, not only can quinoline alkaloids dock intercalatively into DNA, but the docked orientations are also electronically favorable. Figure Lowest-energy face-to-face π–π interaction between stauranthine and guanine IS - 12 JF - Journal of Molecular Modeling EP - 1426 TI - Quinoline alkaloids as intercalative topoisomerase inhibitors VL - 15 SP - 1417 KW - ab-initio KW - inhibitors KW - modeling KW - topoisomerase AU - Byler, Kendall AU - Wang, Chen AU - Setzer, William PY - 2009/12/01/ UR - http://dx.doi.org/10.1007/s00894-009-0501-6 ER -