title: Novel microtubule-interacting phenoxy pyridine and phenyl sulfanyl pyridine analogues for cancer therapy.
abstract: Current microtubule inhibitory agents used in the clinic to treat cancer have severe side effects, and development of resistance is frequent. We have evaluated the antitumor effect of a novel 30-compound library of phenoxy pyridine and phenyl sulfanyl pyridine derivatives. MTT assays revealed that, of all 30 compounds tested, compounds 2 and 3 showed the largest decrease in proliferation (low muM range) against Panc1 and HS766T human pancreatic cancer cells. Flow cytometry experiments with MCF7 breast cancer cells showed a G2/M arrest comparable to that of colcemid. Immunofluorescence staining demonstrated complete disappearance of intracellular microtubules. Tubulin assembly assays, however, showed a dose-dependent decrease in tubulin assembly with compound 3 that seemed limited to about 50% of the control reaction. With compound 2 treatment, there was only a delay in the onset of assembly, with no effect on the extent of the reaction. Taken together, our results show that these novel microtubule inhibitors have promising anticancer activity and can be potentially used to overcome paclitaxel resistance in the clinical setting.
authors.affiliation: Division of Chemical Therapeutics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
authors.forename: Ravi Kumar
authors.initials: RK
authors.lastname: Anchoori
authors.forename: Madeleine Susanne Quirine
authors.initials: MS
authors.lastname: Kortenhorst
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Taradas
authors.initials: T
authors.lastname: Sarkar
authors.forename: Gurulingappa
authors.initials: G
authors.lastname: Hallur
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Paul J Van
authors.initials: PJ
authors.lastname: Diest
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008870:Microtubules / Q000737:chemistry* / Q000187:drug effects; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D054852:Small Molecule Libraries; D014404:Tubulin
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