Sixty laying hens were carried for 20 weeks in a study designed to show the residue levels in eggs from birds maintained on feed containing 0.05, 0.15, or 0.45 ppm of lindane, heptachlor epoxide, dieldrin, endrin, and DDT in combination, and to show the rate of decline of residues in eggs during a one month withdrawal period. A rapid method for analysis of eggs based on electron capture gas chromatography and the one-step Florisil cleanup of Stemp and coworkers is described. Dieldrin and heptachlor epoxide showed the greatest propensity for storage in eggs, followed in order by endrin, p,p′-DDT, and lindane. There was a significant increase of DDE in eggs from birds fed DDT. Only lindane residues returned to the background level within the one-month withdrawal period.
Desulfurization of thiocolchicine with Raney nickel in a hydrogen atmosphere yielded tetrahydromethoxycolchicine (2), which was readily separated from unreacted thiocolchicine by chromatography and was smoothly oxidized to 10-demethoxycolchicine (colchicide) by Pd/C in refluxing toluene. Several analogues of colchicide were prepared from the corresponding thiocolchicines by this procedure. Treatment of colchicide with concentrated sulfuric acid yielded 2-demethylcolchicide. Colchicide and its analogues were found to be inactive in a tubulin-binding assay. Evidence is presented that colchicide prepared earlier from thiocolchicine with Raney nicel in aerial atmosphere was contamination with 1-2% thiocolchicine.
A method for extracting LD50 values from antitumor test data is described. A quantitative structure--activity relationship (QSAR) for 7- and 10-substituted colchicines is presented. This correlation equation closely parallels that which had been derived earlier for potency. This result indicates that attempts to modify 7- and 10-substituted colchicines in order to decrease toxicity will likely produce a simultaneous decrease in potency. Ring A modified colchicines do not obey the potency and toxicity correlations. 4-Substituted colchicines appear promising in terms of decreased toxicity, greater ILS, and a broader therapeutic range.
A quantitative structure-activity relationship (QSAR) was derived for colchicine and 14 analogues acting against P388 lymphocytic leukemia in mice. Twelve additional compounds were synthesized to reinforce and confirm the correlation. The final correlation indicates that there is a parabolic dependence of antitumor potency on the partition coefficient with log P0=1.17. When an amino nitrogen is present on the B ring, increased potency is favored by acylation of the nitrogen. The most potent compound of the series was the 7-fluoroacetamide analogue. Strong electron-withdrawing groups substituted at the 10 position of the tropolone ring destroy activity. Electron-releasing groups at position 10 improve potency slightly but have a limited effect.
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