147950-72-9Relevant academic research and scientific papers
Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors
Guan, Jian,Zhu, Xiao-Kang,Tachibana, Yoko,Bastow, Kenneth F.,Brossi, Arnold,Hamel, Ernest,Lee, Kuo-Hsiung
, p. 1956 - 1961 (2007/10/03)
Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against, various human tumor cell lines and for their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared to that of colchicine in most cell lines. The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 μg/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.
Antitumor Agents. 141. Synthesis and Biological Evaluation of Novel Thiocolchicine Analogs: N-Acyl-, N-Aroyl-, and N-(Substituted benzyl)deacetylthiocolchicines as Potent Cytotoxic and Antimitotic Compounds
Sun, Li,Hamel, Ernest,Lin, Chii M.,Hastie, Susan B.,Pyluck, Amy,Lee, Kuo-Hsiung
, p. 1474 - 1479 (2007/10/02)
Three series of novel thiocolchicine analogs, N-acyl-, N-aroyl-, and N-(substituted benzyl)deacetylthiocolchicinoids, have been synthesized and evaluated for their cytotoxicity against various tumor cell lines, especially solid tumor cell lines, and for their inhibitory effects on tubulin polymerization in vitro. Most of these compounds showed strong inhibitory effects on tubulin polymerization comparable to that obtained with thiocolchicine and greater than that obtained with colchicine. Only compounds with a long side chain at C(7) position, such as 22-24, did not inhibit tubulin polymerization. Several of the active N-aroyldeacetylthiocolchicine analogs had positive optical rotations, in contrast to the negative optical rotation observed with most colchicinoids. This property might be attributed to a reversal of biaryl configuration from the normal aS to aR. Therefore, the N-aroyl analogs were further evaluated by circular dichroism, which readily distinguishes between the aS and aR biaryl configurations. This latter technique demonstrated that the active N-aroyl analogs do have an aS configuration despite their positive optical rotations. However, comparison of 1H NMR and UV spectral data of N-(substituted benzyl)deacetylthiocolchicines with those of corresponding N-aroyldeacetylthiocolchicines suggested a different biaryl dihedral angle . The similar tubulin binding properties of these compounds suggest that a biaryl dihedral angle of 53 deg is not essential for colchicinoid-tubulin interaction. The increased cytotoxicity of N-(substituted benzyl)deacetylthiocolchicines compared to the N-aroyldeacetylthiocolchicines may be attributed to different lipophilicity, drug uptake, or drug metabolism in the tumor cells. The side chain at the C(7) position affects inhibition of tubulin polymerization and the cytotoxic activity of colchicinoids as a function of its size and its contribution to lipophilicity.
