Sulfur-containing aminoacid derivatives of cholchicine and cholchamine and derivatives of isothiouronium and mercaptoethylamine

Abstract

New sulfur-containing delqvatives of cholchicine and cholchamine n4th reduced toxicity and preserved pharmacological properties (cytostatic activity for human cancer cells) are prepared. The ability of the new compotolds to affect radiation treamwnt is studied, enabling cholchicine derivatives with more significant radio-sensitizing properties to be found.The antimitofic and radio-sensitizing properties of cholchicine are responsible for the interest in synthesizing less toxic analogs that surpass the starting compound in activity. We have used sulfur-containing aminoacids and certain aminothiols to modify cholchicine and cholchamine and have measured their ability to affect radiological treatments [1, 2].The reaction of cholchicine and aminoacids to produce N-cholchicidyl derivatives has been studied by Kiselev [3]. It was noted that the reaction with acidic and monobasic aminoacids occurs only in the presence of base, which is needed to destroy the aminoacid zwitter-ion. A 20-fold excess of aminoacid is used. For basic aminoacids (arginine, lysine, ornithine), the condensation occurs in the presence of a small excess of aminoacid without base. The terminal amino group is substituted.We used a milder base, potash, to destroy the aminoacid zwitter-ions for the reactions of cholchicine and cholchamine with S-containing aminoacids. The strong base NaOH destroys the S-containing aminoacids and hydroly-zcs part of the starting cholchicine and cholchamine. The aminoacids were used in a 2-10-1old excess. The reaction was perlbrmed in aqueous alcohol at room temperature lor 4-6 d or with heating to 100~ lor 6-10 h. The products were isolated by CHCI 3 extraction with subsequent purification by column chromatography. The yields under the above conditions were 60-80%.The lbllowing S-containing aminoacid derivatives of cholchicine (1) and cholchamine (2) were prepared: 10desmethoxy-10-N-methioninocholchicine (3), 10-desmethoxy-10-N-methioninocholchamine (4), 10-desmethoxy-10-Ncystinodicholchicine (5), 10-desmethoxy-10-N-cystinodicholchamine (6), 10-desmethoxy-10-N-cysteinocholchicine (7), 10desmethoxy-10-N-cysteinocholchamine (8).The amino groups of methionine and cystine substitute for the methoxy groups in the tropolone ring of the alkaloids. The condensation with cysteine is expected to occur also at the sullhydryl group of the aminoacid, which is highly reactive. For example, it has been suggested [4, 5] that the mechanism of action of cholchicine involves binding to SH groups of tubulins, proteins of the mitotic system, or cleavage of S-S bonds of the proteins, thereby disturbing the sullhydryl---disulfide equilibrium in tubulins 161.However, sulthydryl groups were qualitatively observed during the analysis of cysteine derivatives of both cholchicine and cholchmnine. Quantitative analysis showed close to 100% of the SH group content in preparations stored for a long time in air. The products from the reaction ofcholchicine and cholchamine with cystine do not color a solution of iodine and do not react with nitropruss...

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