Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer Export

@article{citeulike:5229554, abstract = {Irinotecan (CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I). However, overexpression of ABCG2 (BCRP/MXR/ABCP) reportedly confers cancer cells resistance to SN-38, the active form of CPT-11. To circumvent the ABCG2-associated drug resistance, the structure-activity-relationship (SAR) of 14 new camptothecin (CPT) analogues has been studied with respect to the substrate specificity of ABCG2. While the lactone E ring is a prerequisite for anticancer activity, modifications of the A or B rings do not significantly affect Topo I inhibition. Based on the substrate specificity of ABCG2, it is strongly suggested that CPT analogues with a hydroxyl group at position 10 or 11 of the A ring are recognized by ABCG2 and are thereby effectively extruded from cancer cells. To develop a platform for the molecular modeling to circumvent anticancer drug resistance, we have carried out quantum chemical calculations and neural network SAR analysis. Electrostatic potential iso-surfaces generated by ab initio MO calculations using restricted Hartree-Fock method have revealed that negative potential localized at positions 10 or 11 in the A ring is important for recognition by ABCG2.}, author = {Nakagawa, H. and Saito, H. and Ikegami, Y. and Aidahyugaji, S. and Sawada, S. and Ishikawa, T.}, citeulike-article-id = {5229554}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.canlet.2005.05.052}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0304383505009286}, day = {08}, doi = {10.1016/j.canlet.2005.05.052}, issn = {03043835}, journal = {Cancer Letters}, keywords = {camptothecin, cancer, inhibitors, irinotecan}, month = {March}, number = {1}, pages = {81--89}, posted-at = {2009-07-22 16:19:08}, priority = {2}, title = {Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer}, url = {http://dx.doi.org/10.1016/j.canlet.2005.05.052}, volume = {234}, year = {2006} }

TY - JOUR ID - citeulike:5229554 L3 - citeulike-article-id:5229554 N2 - Irinotecan (CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I). However, overexpression of ABCG2 (BCRP/MXR/ABCP) reportedly confers cancer cells resistance to SN-38, the active form of CPT-11. To circumvent the ABCG2-associated drug resistance, the structure-activity-relationship (SAR) of 14 new camptothecin (CPT) analogues has been studied with respect to the substrate specificity of ABCG2. While the lactone E ring is a prerequisite for anticancer activity, modifications of the A or B rings do not significantly affect Topo I inhibition. Based on the substrate specificity of ABCG2, it is strongly suggested that CPT analogues with a hydroxyl group at position 10 or 11 of the A ring are recognized by ABCG2 and are thereby effectively extruded from cancer cells. To develop a platform for the molecular modeling to circumvent anticancer drug resistance, we have carried out quantum chemical calculations and neural network SAR analysis. Electrostatic potential iso-surfaces generated by ab initio MO calculations using restricted Hartree-Fock method have revealed that negative potential localized at positions 10 or 11 in the A ring is important for recognition by ABCG2. IS - 1 JF - Cancer Letters SN - 03043835 EP - 89 TI - Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer VL - 234 SP - 81 KW - camptothecin KW - cancer KW - inhibitors KW - irinotecan AU - Nakagawa, H AU - Saito, H AU - Ikegami, Y AU - Aidahyugaji, S AU - Sawada, S AU - Ishikawa, T PY - 2006/03/08/ UR - http://dx.doi.org/10.1016/j.canlet.2005.05.052 ER -