title: 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs of combretastatin-A4.
abstract: Eleven 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs of combretastatin-A4 (CA-4) were synthesized and their cytotoxicity against the growth of two murine cancer cell lines (B16 melanoma and L1210 leukemia) in culture was determined using an MTT assay. Two 2-thioxopyrimidine analogs 8f and 9a exhibited significant activity (IC50<1 microM for L1210 and <10 microM for B16 cells). Exposure of A-10 cells to 8f and 9a produced a significant reduction in cellular microtubules in interphase cells, with an EC50 value of 4.4 and 2.9 microM, respectively, for microtubule loss. Molecular modeling studies using MacSpartan indicated that the two active 2-thioxopyrimidine analogs preferably adopt a twisted conformation, similar to CA-4, affirming that conformation and structure are connected to activity.
authors.affiliation: Department of Chemistry and the Division of Natural and Applied Sciences, Hope College, 35E, 12th street, Holland, MI 49423, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Lee
authors.forename: Ryan
authors.initials: R
authors.lastname: Davis
authors.forename: Jenna
authors.initials: J
authors.lastname: Vanderham
authors.forename: Patrice
authors.initials: P
authors.lastname: Hills
authors.forename: Hilary
authors.initials: H
authors.lastname: Mackay
authors.forename: Toni
authors.initials: T
authors.lastname: Brown
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051379:Mice; D011743:Pyrimidines / Q000737:chemistry*; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D013267:Stilbenes; C058728:fosbretabulin; C030986:pyrimidine