The neutral, colourless and optically inactive metabolite nonactin, C40H64O12, obtained from cultures of several Actinomyces strains, is a macrocyclic tetralactone (“macrotetrolide”) I of racemic nonactic acid, C10H18O4. The constitution II has been established for the latter by degradation. Crystallographic data for nonactin are reported.

Novel derivatives of 5-fluorouracil (5-FU) possessing a broader spectrum of antitumor activity and fewer toxic side effects than 5-FU have been sought. Herein, we report three different types of 5-FU O,N-acetals: a) a novel class of 5-fluorouracil-containing acyclonucleosides. The antitumor activities of such compounds were assessed against HEp human cells showing that (RS)-1-¿[3-(2-hydroxyethoxy)-1-cyclopentoxy]propyl¿-5-fluorouracil 3c is 4-fold more active than 5-FU. (RS)-1-¿[3-(2-hydroxyethoxy)-1-isopropoxy]propyl¿-5-fluorouracil 3b has important potential advantages over 5-FU because of its lower toxicity and its ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumor; b) within the cyclic prodrugs of 5-FU, a series of new ring-expanded isosteres (1,4-oxaheteroepanes) of Ftorafur were synthesized. The level of diastereoselectivity in the preparation of cis and trans 1-(3-chloromethyl)-1,4-dioxepan-5-yl)-5-fluorouracil, although modest, suggests a potentially general approach for controlling the stereochemistry of this unexplored class of reactions involving the preparation of 5-FU seven-membered O,N-acetals; c) new 5-FU acyclic analogs containing two 5-FU moieties at both ends of the molecules with a linker having two amide bonds have been designed and synthesized. These bis(5-FU-O,N-acetals) show interesting antineoplastic activities against the HT-29 cell line.

Abstract-Three new antitumour drugs containing two 5-fluorouracil moieties at both ends of the structure and a two amide bond linker were synthesized. Appropriated bis-acetal were reacted with two equivalents of 5-FU to afford the desired compounds. These drugs were evaluated for their ability to induce myogenic maturation in vitro on human rhabdomyosarcoma cells in an experimental model. Compounds 5 and 6 induced morphological and phenotypical differentiation in rhabdomyosarcoma cells at 4.5 and 3.5 mM, respectively. These new cell differentiating agents could be used as an alternative to selective destruction of undifferentiated cells. A potential role of the differentiation therapy as an alternative approach to the treatment of rhabdomyosarcomas is suggested. #

No abstract

Neoplastic cells exhibit defects in their ability to differentiate; therefore, differentiation therapy represents a viable option to control cancer growth and progression. Rhabdomyosarcomas (RMS), a malignant tumor of skeletal muscle, is the most common soft tissue sarcoma in children and is characterized by its poor response to cytotoxic treatment and significant morbidity. Since modulation of alpha-tubulin and human leukocyte antigen (HLA) class I expression has been detected during malignant transformation, we analyzed in this study the expression pattern of both kinds of proteins after the treatment with 5-FU derivatives in the human RMS RD cell line. Cytotoxic assays, scanning and transmission electron microscopy, flow cytometry and immunocytochemical analyses were used. The compounds analyzed belonged to the following three categories: (a) symmetrical bis(5-fluorouracil-1-yl) derivatives with a linker that connects the N(1) atoms of both pyrimidine moieties by means of two amide bonds; and (b) an ester with the 5-FU base. The whole structure corresponds to the terminal fragment of the molecules included in (a) and (c) 5-fluorouracil acyclonucleoside-like structures. 1-[[3-(3-Chloro-2-hydroxypropoxy)-1-methoxy]propoxy]propyl]-5-fluorouracil (2), that belongs to the class (a) produced the highest increment of tubulin and its intense capillary distribution throughout the cytoplasm. On the other hand, N,N-bis[3-(5-fluorouracil-1-yl)-3-methoxypropanoyl]-alpha,alpha;-diamino-m-xylene (5) and 2 that are included in the class (c) caused the major percentage of marked cells by the HLA class I proteins. In short, our results showed that the 5-FU derivatives increase HLA class I expression and showed greater microtubule stability with an important network of tubulin beams related with the degree of differentiation of RD cells. These results could mean a more favorable prognosis of the patients affected with these tumors.