Synthesis and biological effects of novel thiocolchicines. 3. evaluation of N-acyldeacetylthiocolchicines, N-(alkoxycarbonyl)deacetylthiocolchicines, and O-ethyldemethylthiocolchicines. New synthesis of thiodemecolcine and antileukemic effects of 2-demethyl- and 3-demethylthiocolchicine

Abstract

Novel and known analogues of thiocolchicine were evaluated in vitro in a tubulin binding assay and in vivo in mice for acute toxicity and in the P388 lymphocytic leukemia assay. This evaluation included N-acyldeacetylthiocolchicines, N-(alkoxycarbonyl)deacetylthiocolchicines, thiodemecolcine and its methyl carbamate, and O-ethyl ethers of demethylthiocolchicines. Selective ether cleavage of thiodemecolcine with concentrated sulfuric acid at 50 degree C afforded the 2-demethyl congener, characterized as its N,O-diacetyl derivative. Several of the compounds showed high potency in the tubulin binding assay, matching the potency of colchicine. Several N-(alkoxycarbonyl)deacetylcolchicines (carbamates) exhibited strong binding affinity to tubulin but had only weak activities against the P388 tumor system, suggesting that other factors besides tubulin binding may be important for the biological effects. The compounds potent in the tubulin binding assay and in the P388 leukemia assay in mice were generally also toxic to mice in the acute toxicity test, showing thus a similar behavior of thiocolchicines to that observed earlier with colchicines. A considerable amount of data collected for 2-demethyl- and 3-demethylthiocolchicine suggests that the latter represents a broad-spectrum antitumor agent of considerable promise and possibly a less toxic substitute for colchicine.

Colchicine analogues: Effect on amyloidogenesis in a murine model and, in vitro, on polymorphonuclear leukocytes

“…The methods of preparation of the analogues were previously described [7]. The methods of preparation of the analogues were previously described [7].…”

“…Extracts of colchicum autumnale were used in acute gouty arthritis over 200 years ago. The antimitotic potential of this preparation, suggested by some interesting animal experiments [7] could not be explored in man due to its very narrow therapeutic toxic ratio. There is also preliminary evidence of its therapeutic potential in 630 slowing liver fibrosis [3,4], in Behcet's disease [5] and in recurrent idiopathic pericarditis [6].…”

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

“…Among them, the 10-thiomethyl analogues of colchicine and derivatives have been reported to be less toxic and presenting a better therapeutic index. Among them, 3-demethylthiocolchicine has been presented as a broad-spectrum antitumor agent of considerable promise and possibly with a less toxicity [19] . Indeed, 3-demethylcolchicine and 3-demethylthiocolchicine (3-demethyl-10-thiomethylcolchicine) and their glucosides have been shown to possess superior pharmacological properties, accompanied by decreased toxicity.…”

Design, Synthesis, and Antitumor Activity of 4-Halocolchicines and Their Pro-drugs Activated by Cathepsin B

“…To solve this problem, many groups have poured much effort into the development of colchicine derivatives having high potency and reduced toxicity. [2][3][4][5][6][7][8][9][10][11] In our previous study of the alkaloidal constituents in the aerial parts of Gloriosa rothschildiana, we isolated a new colchicinoid, gloriosamine A (2), which is the first example of natural colchicinoid having a substituent at the C-4 position. 12 Moreover, preliminary biological evaluation showed that gloriosamine A (2) demonstrated significant cytotoxicity to A549 human lung adenocarcinoma cell line.…”