Aim: Evaluation of the antitumor activity of the new drug Dekoglitz in animals with tumor strains of Sarcoma 45 in comparison with the drug dekocin, from which it was obtained, as well as with 5-fluorouracil and etoposide, and on ovarian tumors (OT) in comparison with the drug dekocin and identification of the effect of Dekoglitz on NA synthesis and internucleosomal DNA degradation. Methods: The study of preparations was carried out on 68 outbred rats with transplanted C-45 and OT tumors. The alkylating effect of the drugs was studied on cells tumor of Sarcoma 180. Results: The antitumor activity of dekoglitz on Sarcoma 45 was high, about 98/96%, with a remission rate of 80%. Its effect was 28-24% higher than that of dekocin. On OT, the effect of decoglitz with intraperitoneal administration reached 89/76% with a remission rate of 40%, with oral administration 96/86% with a remission rate of 60%. Conclusion: The study of the new drug Dekoglitz on animals with a tumor of Sarcoma 45 revealed its higher activity (by 20-27%) in comparison with the original Dekocin, 5-fluorouracil and etoposide with a lower level of side effects. On OT, the effect of Dekoglitz was 35-40% higher, especially after oral administration. Apparently, the great ability to suppress the synthesis of NA and carry out internucleosomal degradation and fragmentation of tumor DNA by the new drugs dekoglitz explains its antitumor efficacy, which is greater than that of Dekocin (K-18) in experiments on tumors.

546.944.615 With the aim of enhancing the cytostatic properties of the initial alkaloid, new aziridine and bis (chloroethyl) A fall in toxicity in comparison with the initial alkaloids has been reported for a series of colchicine and colcbamine derivatives [1, 2]; however, their antimm~al activity is not always retained. It is known that the introduction of alkylaling fragments (aziridine, bis(chlcxoethyl)amine, etc.) into such carrier molecules as amino acids, nucleotides, sugars, hccmones, and a number of others improves or ensures their antitumoral activity [3].We have introduced aziridine and chioroethylamine substituents into the colchicine molecule with the aim of enhancing its ant.immoral activity by cc~nbining the tubnlin-interactive effect of colchicine and the alky]ating action of the fragments introduced.10-Chloroethylamino-10-demethoxycolchicine (4) was obtained by two methods: by the reaction of colchicine with chloroethylamine hydrochloride in an alkaline medium and from lO-hydroxyethylamino-lO-demethoxycolchicine (2) by indirect chlorination.

Colchicine and its natural analog colchamine possess pronounced stathmokinetic properties, but only colchamine, which has a lower toxicity but a narrow breadth of therapeutic action, is used in oncology. Our task was to find substances with lower toxicity and retained mitosis-inhibiting activity among new analogs of these alkaloids.It is known that the introduction of amino compounds into the tropolone ring of colchicine (1) and colchamine (9) leads to a lowering of toxicity. We obtained the following derivatives: amino-(2), monoethanolamino-(3), mercaptoethylamino- (5), diethylamino-(6), chloroethylamino- (7), and dichloroethylaminocolchicine (8) and monoethanolaminocolchicine derivatives (10). The acute toxicities and mitotic indices (MIs) of these substances were determined on crypts of the intestines of mice of the C57B1/6 line. Acute toxicities were determined by the intraperitoneal (i/p) administration of the substances under study to mice weighing 20-22 g, and MIs also by the i/p administration of the preparations in doses corresponding to 1/2 LDt6" Animals were decapitated after 30 and 60 min and each hour in the course of a day, and 1 cm of the duodenum (taken 1 cm below the pyloric end of the stomach) was used for histological investigations. This section of the duodenum was fixed in Bowen's mixture and was then flooded with paraffin, and histological sections were prepared and were stained with hematoxylin-eosin. Under the microscope, the number of cells in a crypt and the number of dividing cells were counted, and the MI and mitotic activity were calculated. On average, not less than three animals were used for each point.As can be seen from Table 1, replacement of the methoxy group of the tropolone ring by various amino compounds lowered the toxicity by a factor of more than 10. The formation of hydrochlorides (4, 6) increased water solubility but doubled toxicity. An increase in the number of ethanolamine groups had practically no effect on the toxic properties. The chloroethyl-

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...

Introduction. Tropolone alkaloid -colchicine, there is very interesting object for synthesis of its derivatives, with such properties as, alkylation, a low toxicity, high antineoplastic activity and especially overcoming of multidrug resistance (MDR). We had been developed the antineoplastic preparation К-26 derivative of colchicine. К-26 has shown high cytotoxic activity on 60 lines of tumoral cells of the human in vitro, at National Institute of the Cancer of the USA (NCI). Further on the basis of К-26 its water-soluble form named term К-26w has been received. The work purpose. Studying of the mechanism of action of preparations К-26 and К-26w on: alkylating ability, mitotic activity, topoisomerase II, MDR2, р53 and colony-forming cells spleen (CFCs). Materials and methods. All researches have been carrying out by a standard technique. Studying mitotic activity of preparations was carrying out on duodenum and tumor СаРа after preparation influence. On models of a tumor of the Sarcoma 180 action of preparations has been investigated: the alkylating -on synthesis DNA/RNA, nucleosoma DNA degradation, activity topoisomerase II; on an expression MDR2 and р53 genes. Studying CFCs carry out by a standard technique on outbred mice. Results. К-26, К-26w and etoposide inhibited in cells of the Sarcoma 180: synthesis DNA/RNA on 84/65%, 95/85% and 55/35%, accordingly, in relation to the control; activity topoisomerase II on 80%, 90% and 60% accordingly. By method RT-PCR it is shown, К-26, К-26w and etoposide: inhibited an expression of MDR2 gene on 83%, 91% and 62%; increase expression р53 gene to 74%, 88% and 55%, accordingly, under the relation of the control of referential gene GARDH (100%). High ability К-26 and К-26w in an induction apoptosis tumoral cells and CFCs to 12 units is shown. Conclusion. Revealed ability К-26 and К-26w to suppress synthesis DNA/RNA activity topoisomerases, to stimulate р53, and also to suppress an expression of a multidrug resistance MDR2 gene, it explains their high antineoplastic activity which is connected with mitotic activity leading to cell fission synchronization, and radiosensitization activity. Special interest represents found at К-26w and К-26 suppression MDR2 as they are aimed for treatment of such resistant tumor as a kidney cancer. Stimulation CFCs which provides formation of haemopoetic and immune cells can protect an organism from their intensive cytotoxic action.