title: A systematic SAR study of C10 modified paclitaxel analogues using a combinatorial approach.
abstract: A library with 63 paclitaxel analogues modified at the C10 position of paclitaxel has been prepared using parallel solution phase synthesis. Most of the C10 analogues were slightly less active than paclitaxel in the tubulin assembly assay and had reduced potency in the B16 melanoma and MCF-7 cell line cytotoxicity assays. These modifications at C10, however, did not lead to the total loss of activity, indicating that the C10 moiety of paclitaxel may not be directly involved in the drug-microtubule interactions, but could influence its binding affinity to P-glycoprotein. Approximately 50% of the analogues demonstrated better activity against the drug resistant cell line MCF7-ADR. However, the increase in activity was 10-fold at most. This result demonstrates that the cytotoxicity against this drug resistant cancer cell line is sensitive to structural changes at the C10 position of paclitaxel. It was also found that the presence of a nitrogen atom in the C10 substituent might play a role in the interaction of analogues with microtubules.
authors.affiliation: Department of Medicinal Chemistry, and the Drug Discovery Program, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Liu
authors.forename: Syed M
authors.initials: SM
authors.lastname: Ali
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Boge
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.forename: Samuel
authors.initials: S
authors.lastname: Victory
authors.forename: Jan
authors.initials: J
authors.lastname: Zygmunt
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Marquez
authors.forename: Richard H
authors.initials: RH
authors.lastname: Himes
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002855:Chromatography, Thin Layer; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D006840:Hydrocarbons, Alicyclic / Q000737:chemistry; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D013058:Mass Spectrometry; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000633:toxicity; D012996:Solutions; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D005227:Fatty Acids; D006840:Hydrocarbons, Alicyclic; D006841:Hydrocarbons, Aromatic; D012996:Solutions; D017239:Paclitaxel