eprintid: 18689 rev_number: 16 userid: 1418 dir: disk0/00/01/86/89 datestamp: 2013-05-14 14:21:11 lastmod: 2019-02-02 15:58:46 status_changed: 2013-05-14 14:21:11 type: article metadata_visibility: show item_issues_count: 0 eprint_status: archive creators_name: Hamel, E creators_name: Day, BW creators_name: Miller, JH creators_name: Jung, MK creators_name: Northcote, PT creators_name: Ghosh, AK creators_name: Curran, DP creators_name: Cushman, M creators_name: Nicolaou, KC creators_name: Paterson, I creators_name: Sorensen, EJ creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: curran@pitt.edu creators_email: creators_email: creators_email: creators_email: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: CURRAN creators_id: creators_id: creators_id: creators_id: title: Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly ispublished: pub divisions: sch_as_chemistry full_text_status: public abstract: Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in the laulimalide site, which is distinct from the taxoid site. In a tubulin assembly system containing microtubule-associated proteins and GTP, however, peloruside A was significantly less active than laulimalide, inducing assembly in a manner that was most similar to sarcodictyins A and B. Because peloruside A thus far seems to be the only compound that mimics the action of laulimalide, we examined combinations of microtubule-stabilizing agents for synergistic effects on tubulin assembly. We found that peloruside A and laulimalide showed no synergism but that both compounds could act synergistically with a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, the steroid derivative 17β-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien- 3-ol, and cyclostreptin]. None of the taxoid site compounds showed any synergism with each other. From an initial study with peloruside A and cyclostreptin, we conclude that the synergism phenomenon derives, at least in part, from an apparent lowering of the tubulin critical concentration with drug combinations compared with single drugs. The apparent binding of peloruside A in the laulimalide site led us to attempt construction of a pharmacophore model based on superposition of an energy-minimized structure of peloruside A on the crystal structure of laulimalide. Although the different sizes of the macrocycles limited our ability to superimpose the two molecules, atom correspondences that were observed were consistent with the difficulty so far experienced in creation of fully active analogs of laulimalide. date: 2006-11-24 date_type: published publication: Molecular Pharmacology volume: 70 number: 5 pagerange: 1555 - 1564 refereed: TRUE issn: 0026-895X id_number: 10.1124/mol.106.027847 pmid: 16887932 mesh_headings: Bicyclo Compounds, Heterocyclic--chemistry mesh_headings: Bicyclo Compounds, Heterocyclic--pharmacology mesh_headings: Drug Synergism mesh_headings: Glutamic Acid--metabolism mesh_headings: Guanosine Triphosphate--metabolism mesh_headings: Humans mesh_headings: Lactones--chemistry mesh_headings: Lactones--pharmacology mesh_headings: Macrolides mesh_headings: Microtubule-Associated Proteins--metabolism mesh_headings: Models, Molecular mesh_headings: Paclitaxel--pharmacology mesh_headings: Taxoids--chemistry mesh_headings: Taxoids--pharmacology mesh_headings: Temperature mesh_headings: Tubulin--metabolism mesh_headings: Tumor Cells, Cultured chemical_names: Bicyclo Compounds, Heterocyclic chemical_names: Lactones chemical_names: Macrolides chemical_names: Microtubule-Associated Proteins chemical_names: Taxoids chemical_names: Tubulin chemical_names: laulimalide chemical_names: peloruside A chemical_names: Paclitaxel chemical_names: Glutamic Acid chemical_names: Guanosine Triphosphate citation: Hamel, E and Day, BW and Miller, JH and Jung, MK and Northcote, PT and Ghosh, AK and Curran, DP and Cushman, M and Nicolaou, KC and Paterson, I and Sorensen, EJ (2006) Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly. Molecular Pharmacology, 70 (5). 1555 - 1564. ISSN 0026-895X document_url: http://d-scholarship-dev.library.pitt.edu/18689/1/licence.txt