Synthesis and biological evaluation of a focused mixture library of analogues of the antimitotic marine natural product curacin A

Journal of the American Chemical Society

Volumn 122, Issue 39, 2000, Pages 9391-9395

  Wipf, Peter ^a   Reeves, Jonathan T ^a   Balachandran, Raghavan ^a   Giuliano, Kenneth A ^b   Hamel, Ernest ^c   Day, Billy W ^a  

^a UNIVERSITY OF PITTSBURGH   (United States)

^b Cellomics Inc   (United States)

^c NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLCHICINE; CURACIN A; CURACIN A DERIVATIVE; NATURAL PRODUCT; UNCLASSIFIED DRUG;

ARTICLE; DRUG EFFECT; DRUG SOLUBILITY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; GROWTH INHIBITION; HUMAN; HUMAN CELL; LYNGBYA MAJUSCULA; MICROTUBULE ASSEMBLY; MITOSIS INHIBITION; PURIFICATION;

EID: 0034605473     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja002213u     Document Type: Article

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35. The three mixtures were characterized by LC-MS using a reverse-phase (C18) column and positive ionization electrospray mass spectral detection as well as by LC NMR. Each mixture contained the six expected products in close-to-equimolar ratio, with minor amounts (ca. 15-20%) of the (E)-alkene derivatives from the Wittig reaction. No organic impurities >5% were detected. Details of the LC NMR analysis will be reported elsewhere: Wipf, P.; Reeves, J. T.; Wilkinson, P. S. Bruker Report, in press.
36. 7 Tubulin (final concentration 10 μM.; 1 mg/mL) was preincubated with drugs dissolved in DMSO (4% v/v final concentration) and monosodium glutamate (0.8 M final concentration) for 15 min at 30°C. The reaction mixture was cooled to 0°C and GTP (0.4 mM final concentration) was added. Reaction mixtures were transferred to cuvettes at 0 °C in a Beckman-Coulter 7400 spectrophotometer reading absorbance at 350 nm. Baselines at 0 °C were established and temperature was quickly raised to 30 °C (in approximately 1 min with an electronically controlled Peltier temperature controller). The change in absorbance 20 min after samples reached 30 °C was used to calculate the extent of polymerization. The change in absorbance at this time point for vehicle plus no GTP was considered 100% assembly inhibition, while the change in absorbance for GTP plus vehicle was taken as 0% inhibition. Each series of determinations included positive and negative control determinations plus one determination made with 5 μM curacin A.
37. 21, 1 mM GTP, and 0.5 mg/mL bovine serum albumin. The solutions were filtered through two stacks of DEAE-cellulose filters and the radioactivity in the filtrate was determined by scintillation spectrometry. Each series of determinations included positive controls of 1, 5, and/or 50 μM curacin A.
38. (c) Cells were plated (500-1500 cells/well depending on the cell line) in 96-well plates and allowed to attach and grow for 48 h. They were then treated with vehicle (DMSO) or drug [50, 10, 2, 0.4, and 0.08 μM (for the mixtures, these would be the summed, apparent concentrations, i.e., approximately six times the concentration of each compound); 10, 2, 0.4, 0.08, and 0.016 μM for curacin A; then 1, 0.2, 0.04, 0.008, and 0.0016 μM for 17a-e and curacin A] for the given times. One plate consisted entirely of cells used for a time zero cell number determination. The other plates contained eight wells of control cells, eight wells of medium, and each drug concentration tested in quadruplicate. Cell numbers were obtained spectrophotometrically (absorbance at 490 nm minus that at 630 nm) in a Dynamax plate reader after treatment with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium (MTS.; Owen's reagent) using N-methyldibenzopyurazine methyl sulfate (phenazine methosulfonate) as the electron acceptor.
39. 13C NMR, IR, and HRMS.
40. As a negative control, single compounds of 15mix were also resynthesized, and biological testing confirmed their lack of activity.
41. Phosphorylation of a core histone occurs during mitosis and is linked to chromosome condensation. Thus, antimitotic agents cause an accumulation of cells containing the phosphorylated form of this protein. Wei, Y.; Mizzen, C. A.; Cook, R. G.; Gorovsky, M. A.; Allis, C. D. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 7480.