Biological effects of modified colchicines. Improved preparation of 2-demethylcolchicine, 3-demethylcolchicine, and (+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines

Abstract

A variety of colchicine, demecolcine, and isocolchicine derivatives were examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. A qualitatively direct correlation was found between in vivo potency and toxicity; potency appeared to be less well correlated with tubulin binding. The most potent compounds were N-acylated analogues of colchicine and demecolcine. Among the monophenols, only 3-demethylcolchicine showed an appreciable effect in vitro and in vivo and was less toxic than colchicine. Improved methods were found for the preparation of 3- and 2-demethylcolchicine, which involved the use of 85% phosphoric acid and concentrated sulfuric acid, respectively. Decoupling experiments with 1H NMR proved that the double bond of dehydro-7-deacetamidocolchiceine and its derived tropolonic methyl ethers 24 and 25 was in the 5,6 position, rather than the 6,7 position formerly tentatively assigned.

Identification of Novel Metabolites of Colchicine in Rat Bile Facilitated by Enhanced Online Radiometric Detection

“…2-DMC was a gift from Dr. K. H. Lee (Natural Products Research Laboratories, University of North Carolina, Chapel Hill, NC). 1-DMC was synthesized by regioselective demethylation of colchicine (Blade-Font, 1979), and 3-DMC was synthesized from colchicoside by treatment with 85% phosphoric acid (Rösner et al, 1981). All other chemicals were HPLC or analytical grade and were obtained from Fisher Scientific Co. (Suwanee, GA), unless specified otherwise.…”

Anticancer Drug Design Based on Plant-Derived Natural Products¹

“…Of the three possible mono-demethylthiocolchicines, 1-demethylthiocolchicine (27) was the least active. (The methyl group at this position may play a role in controlling the rate of R-S isomerization for the biaryl system [48].) The didemethylated derivatives (e.g., 28) were even less active.…”

“…Thiocolchinoids with substituted benzyl amines (40)(41)(42)(43) and aroyl amides (44-46) had comparable antitubulin activity and comparable or greater cytotoxicity to those of thiocolchicine; the thiocolchicine derivative with a 4)-cyanobenzamide substituent at C(7) (44) was the most potent compound [55]. In additional modifications, we compared 26 analogs where ketone (47, thiocolchicone), hydroxy (48), and ester (49,50) groups had replaced the C-7 acetamido group [53]. Chromatographic separation followed by hydrolysis of diastereoisomeric camphanate esters allowed preparation of both enantiomeric alcohols and esters.…”

Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F Magnetic Resonance ex vivo

“…Colchicine, a major alkaloid of Colchicum autumnale and Gloriosa superba, is a drug interfering with microtubule structure both in vitro and in vivo, thereby causing cells to accumulate in mitotic arrest during the cell cycle [4]. Although the antitumor properties of many colchicinoids have been well-known [5], only one compound, N-deacetyl-N-methylcolchicine (Colcemid), has been used for the treatment of Hodgkin's lymphoma and chronic granulocitic leukemia [6]. Analogues of colchicine are currently used in therapy of Mediterranean fever [7], Behcet's disease [8], progressive scleroderma [9] and gout [10].…”