Chabin R M, Hastie S B
Department of Chemistry, State University of New York, Binghamton 13901.
Biochem Biophys Res Commun. 1989 Jun 15;161(2):544-50. doi: 10.1016/0006-291x(89)92633-8.
Thiocolchicine, a colchicine analog in which the C-10 methoxy is replaced with a thiomethyl moiety, was shown to bind with high affinity to the colchicine site on tubulin (Ka = 1.07 +/- 0.14 x 10(6) M-1 at 23 degrees C). Like colchicine, the association kinetics were biphasic, and the rate constants of both phases were temperature dependent. The rate constant of the fast phase of the association was 4 times greater than the rate constant for colchicine binding, and the activation energy was lower (19.1 +/- 1.8 kcal/mol). X-ray crystallographic analysis shows that thiocolchicine displays greater puckering of the tropone C ring than colchicine (Koerntgen, C. and Margulis, T. N. (1977) J. Pharm. Sci. 66, 1127-1131.). These results indicate that the conformation of the C ring may have little effect on the energetics of colchicinoids binding to tubulin.
硫秋水仙碱是一种秋水仙碱类似物，其中C-10甲氧基被硫甲基部分取代，已证明它能以高亲和力与微管蛋白上的秋水仙碱位点结合（23℃时的解离常数Ka = 1.07 +/- 0.14 x 10(6) M-1）。与秋水仙碱一样，结合动力学是双相的，且两个阶段的速率常数均与温度有关。结合快速阶段的速率常数比秋水仙碱结合的速率常数大4倍，且活化能更低（19.1 +/- 1.8千卡/摩尔）。X射线晶体学分析表明，硫秋水仙碱的卓酚酮C环比秋水仙碱具有更大的褶皱（科尔恩特根，C.和马尔古利斯，T.N.（1977年）《药物科学杂志》66，1127 - 1131）。这些结果表明，C环的构象可能对秋水仙碱类药物与微管蛋白结合的能量学影响很小。
