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Pharmaceutical Chemistry Journal, Vol. 54, No. 6, September, 2020 (Russian Original Vol. 54, No. 6, June, 2020)

SYNTHESIS AND ANTITUMOR ACTIVITY OF 2-[3-(2-CHLOROETHYL)3-NITROSOUREIDO]-1,3-PROPANEDIOL (CHLONISOL) A. N. Stukov,1,* K. A. Esikov,2 L. M. Usmanova,2 N. N. Kharitonova,3 S. F. Vershinina,4 Yu. G. Zmitrichenko,1 L. V. Filatova,1 D. Kh. Latipova,1 A. L. Semenov,1 V. G. Bespalov,1 and T. Yu. Semiglazova1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 8, pp. 35 – 38, August, 2020.

Original article submitted April 28, 2020. The reaction of 2-chloroethylisocyanate and 2-amino-1,3-propanediol in MeCN–MeOH yielded 2-[3-(2-chloroethyl)ureido]-1,3-propanediol, which was nitrosated using sodium nitrite in 50% formic acid to obtain 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol (chlonisol). A single administration of chlonisol at a non-toxic dose of 15 mg/kg increased by 170% the median life expectancy of mice with P-388 leukemia and cured 100% of rats with Walker 256 carcinosarcoma. Keywords: 2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol, chlonisol, nitrosoalkylureas, alkylnitrosoureidopropanediols.

Research conducted at N. N. Petrov Research Institute of Oncology, Ministry of Health of the Russian Federation (PRIO), resulted in the synthesis of 2,5-substituted 5-amino1,3-dioxane and 2-substituted 2-amino-1,3-propanediol derivatives that were highly active as carriers of a cytotoxic functional group. Their physicochemical properties could be widely varied by changing the C2 and C5 substituents, e.g., 2,4-diethyleneimino-1,3,5-triazine. The original domestic drug dioxadet or 2,4-bis-(aziridinyl)-6-(2,2-dimethyl-5-oxymethyl-1,3-dioxan-5-yl)amino-1,3,5-triazine was created; possessed potent experimental antitumor activity; passed clinical trials; and was recommended for systemic treatment of breast, lung, and ovary cancer; for intracavity chemotherapy of malignant breast and peritoneal leakages; and for chemoembolization of primary and metastatic liver and kidney cancer [1, 2]. 1

2 3 4

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A logical extension of this research was the use of 2,5-substituted 5-amino-1,3-dioxanes and 2-substituted 2-amino-1,3-propanediols as carriers of cytotoxic moieties of another class of antitumor compounds, namely, nitrosoalkylureas. 5-Substituted 5-(N-alkyl-N-nitrosoureido)amino2,2-dimethyl-1,3-dioxanes and 2-substituted 2-(N-alkyl-Nnitrosoureido)amino-1,3-propanediols were synthesized and showed high therapeutic activity over a broad spectrum of grafted tumors [3]. The derivative 2-[3-(2-chloroethyl)-3-nitrosouriedo]1,3-propanediol (chlonisol) was selected for in-depth studies. It was registered at the Scientific Research Institute for Biological Testing of Chemical Compounds under No. 10181391 on Feb. 19, 1991. Technological synthetic methods for chlonisol were developed at PRIO in collaboration with KemKonsult LLC [4].

N. N. Petrov Research Institute of Oncology, Ministry of Health of the Russian Federation, 68 Leningradskaya St., Pesochnyi, St. Petersburg, 197758 Russia. KemKonsult LLC, 1 Be