Antitumor Agents. 185. Synthesis and Biological Evaluation of Tridemethylthiocolchicine Analogues as Novel Topoisomerase II Inhibitors

Abstract

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 microg/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.

Identification of 4-isopropyl–thiotropolone as a novel anti-microbial: regioselective synthesis, NMR characterization, and biological evaluation

“…The purities of nal compounds were 95% or greater. NMR spectra was recorded on a Bruker NMR 400 MHz Avance III spectrometer operating at 400 MHz for 1 H NMR and 100 MHz for 13 C NMR. Chemical shis are given in part per million (ppm) relative to tetramethylsilane (TMS), coupling constants J are given in Hertz.…”

“…Compound 13 C, COSY, HSQC, and HMBC spectra revealed the presence of a singlet proton H-7 (d C /d H 137.7/7.05, C-7). This proton shows two bond correlations with C-1 (d C 179.1) and C-6 (d C 157.3) and strong three bond correlations with C-2 (d C 154.5) and C-8 (d C 38.3).…”

“…We were able to fully assign the chemical shis of the major tautomer 10A ( Table 2). The analysis of 1 H, 13 3 as a mixture of two tautomers 11A (z96%) and 11B (z4%). We were able to fully assign the chemical shis of the major tautomer 11A (Table 3).…”

Colchicine: A Promising Drug in Clinical Translation, A Minireview Focused on Cardiovascular Diseases

“…Thiocolchicine exerts its effect through interaction with tubulin at the same site as colchicine but probably with higher efficacy and affinity [21] as well as the other derivative N-acetylcolchinol O-methyl ether (NCME) [22] . Finally, numerous derivatives have been proposed with a promising feature [23,24] and some of more deeply modified derivatives have lost the tubulin interaction but are able of topoisomerase II inhibition [25] . Similarly, some of the 7-O-substituted deacetamidothiocolchicine derivatives could exert stronger antiproliferative effect in some in vitro studies [26] .…”

Anticancer Drug Design Based on Plant-Derived Natural Products¹

“…(1) The three methoxy groups in the A ring are essential for maintaining full tubulin binding affinity and ITP; all mono (e.g., 27)-, di (e.g., 28)-, and tri-demethylated (29,30) derivatives were less active than the fully A-ringmethylated parent compounds (25,26) [24]. Of the three possible mono-demethylthiocolchicines, 1-demethylthiocolchicine (27) was the least active.…”