C5-Morpholinomethylation of N1-sulfonylcytosines by a one-pot microwave assisted Mannich reaction

Abstract

A fast and efficient route for introduction of methylene bridged-amine (morpholinomethyl) functionality in the C5 position of the sulfonylated cytosine nucleobase has been developed. First, novel N1-sulfonylcytosine derivatives 3-6 were prepared by the condensation of silylated cytosine with selected sulfonyl chlorides. They were subsequently transformed to 5-morpholinomethyl-N1-sulfonylcytosine derivatives (8, 12-15) using microwave irradiation. As a result of the cytosine ring opening in N1-tosylcytosine, depending on the reaction conditions, peculiar tosyl-urea derivative 9 has been isolated, which provided additional insight into reaction pathway. The influence of the C5-substituent on the antiproliferative activity has been evaluated by MTT test on U251, MCF-7 and MOLT-4 tumor cell-lines.

The transformation from 2°‐amine to 3°‐amine of cyclam ring alters the fragmentation patterns of 1‐tosylcytosine‐cyclam conjugates

“…Compound 1 contained three 2°‐amine and one 3°‐amine within the cyclam ring, and therefore, most likely the protonation occurred within cyclam macrocycle cavity at the tertiary nitrogen atom which (at least in the gas phase)—could have higher proton affinity than the primary group of the cytosine moiety . This fact led to the cleavage of the compound already at the source.…”

1,2,3-Triazole-containing flex-nucleoside analogs and sulfonamido-ribofuranoside conjugates: design, synthesis, and antiproliferative potential

“…The C5-[1,2,3]triazolyl-flex-nucleoside analogs (7)(8)(9)(10)(11)(12)(13)(14)(16)(17)(18)(19)(20), ribofuranoside conjugates (23)(24)(25)(26)(27)(28), and 5-azido-ribosylsulfonamides (31)(32)(33) were tested for their effects on the growth of the non-tumor MDCK1 (Madine-Darby canine kidney) cell line, leukemia and lymphoma cell lines: Hut78 (T-cell lymphoma), K562 (acute monocytic leukemia), Burkitt lymphoma (Raji), and carcinoma cell lines: HeLa (human cervical adenocarcinoma), CaCo-2 (human colorectal adenocarcinoma), and NCI-H358 (human non-small cell lung cancer). The obtained results, presented as the concentration achieving 50% of cell growth inhibition (IC 50 value), show that the investigated compounds influenced tumor cell growth differently depending on the cell line and the dose applied.…”

“…[1][2][3][4][5][6][7][8] In the search for new biologically active nucleobase/nucleoside mimics, structural modifications usually involving changes in the sugar and/or nucleobase domain have been widely exploited. For example, recently reported modified nucleosides in which the furanose ring has been replaced by an alternative alkyl-or aryl-SO 2 -moiety to give N1-sulfonylpyrimidines [9][10][11][12][13][14] or N9-sulfonylpurines 15,16 have revealed potent in vitro [10][11][12][13][14]17 and in vivo 18,19 antitumor activity. Additionally, introducing aromatic functionalities to the natural nucleobase can result in nucleoside mimics with new mechanisms of action.…”

“…for C 9 H 11 N 5 O 3 ÁH + [M + H] + 238.0940, found 238.0923. 5-[1-(6-Ferrocenyl-6-oxohexyl)-1H-1,2,3-triazol-4-yl]uracil(14). According to the general CuAAC procedure 6-Bromo-1-oxohexyl ferrocene (726.2 mg, 2 mmol) was used.…”

An Efficient Synthesis and In vitro Cytostatic Activity of 5-Aminosulfonyl Uracil Derivatives

“…The pyrimidine base with modification at C5 position provides the enhanced biological activity of the nucleobase and nucleoside analogs. [16][17][18] 5-Fluorouracil [19,20] and the nucleoside floxuridine [21] are frequently used for the treatment of various cancers. Uramustine [22] is used orally in the treatment of leukemia and thymine derivative HEPT is considered as a nonnucleoside reverse transcriptase inhibitor in HIV-infection therapy (Figure 1).…”