demecolcine and thiocholchicine

Esterification of the phenolic group in 3-demethylthiocolchicine and exchange of the N-acetyl group with other N-acyl groups or a N-carbalkoxy group afforded many compounds which showed superior activity over the parent drug as inhibitors of tubulin polymerization and of the growth of L1210 murine leukemia cells in culture. A comparison of naturally occurring Colchicum alkaloids with thio isosters, obtained by replacing the OMe group at C(10) with a SCH3 group, showed the thio ethers to be invariably more potent in these assays. The comparison included 3-demethylthiodemecolcine prepared from 3-demethylthiocolchicine by partial synthesis. Thiation of thiocolchicine with Lawesson's reagent afforded novel thiotropolones which exhibited high antitubulin activity. Their structures are fully secured by spectral data. Colchicine and several of its analogues show good antitumor effect in mice infected with P388 lymphocytic leukemia, and all of them show high affinity for tubulin and inhibit tubulin polymerization at low concentration. Consequently, antitubulin assays with this class of compounds can serve as valuable prescreens for the initial evaluation of potential antitumor drugs.

Topics: Animals; Antineoplastic Agents; Cattle; Cell Division; Chemical Phenomena; Chemistry; Colchicine; In Vitro Techniques; Ketones; Leukemia L1210; Polymers; Protein Binding; Structure-Activity Relationship; Sulfides; Tubulin; Tumor Cells, Cultured

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.

Topics: Animals; Binding, Competitive; Chemical Phenomena; Chemistry; Colchicine; Demecolcine; Drug Evaluation; Lethal Dose 50; Leukemia P388; Leukemia, Experimental; Mice; Structure-Activity Relationship; Tubulin

The topical application of demecolcine (Colcemid, N-desacetyl methyl colchicine), N-desacetyl thiocolchicine (Thio-Colciran), and methotrexate preferably in combination, exerts a selectively destructive action on rodent (basal cell) carcinomas, solar keratoses, Bowen's disease, and keratoacanthomas, while sparing surrounding normal tissues. The former two exert their action by inhibiting mitosis in the metaphase, and the latter inhibits the commencement of mitosis by interference with the synthesis of desoxyribonucleic acid. The cosmetic results are particularly good when the ears or nose are affected, and the cure rate compares favorably with that resulting from other treatments. Although ineffective against squamous carcinomas, the fact that this form of therapy is effective for keratoacanthomas could prove a valuable additional diagnostic point between the two in doubtful cases.

Topics: Administration, Topical; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bowen's Disease; Carcinoma, Basal Cell; Colchicine; Demecolcine; Humans; Keratoacanthoma; Methotrexate; Precancerous Conditions; Skin Neoplasms; Triaziquone

Topics: Antineoplastic Agents; Busulfan; Colchicine; Demecolcine; Glycols; Leukemia; Leukemia, Myeloid