From a Classic Approach in Cancer Chemotherapy Towards Differentiation Therapy: Acyclic and Cyclic Seven-Membered 5-Fluorouracil O,N-Acetals

Abstract

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.

Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

“…Recently, the concept of mutual prodrugs in which two different antineoplastic agents are coupled directly or by means of a spacer has become well accepted [8][9][10][11][12][13][14][15][16][17]. This technique can be used to overcome many problems including poor solubility or absorption, patient acceptability, drug instability and toxicity, and especially drug resistance [11].…”

Antiproliferative Activity, Cell‐Cycle Dysregulation, and Cellular Differentiation: Salicyl‐ and Catechol‐Derived Acyclic 5‐Fluorouracil O,N‐Acetals against Breast Cancer Cells

“…[2] Novel derivatives of 5-FU that possess a broader spectrum of antitumor activity and fewer side effects than 5-FU have been diligently sought by a number of research groups. Campos et al [3] synthesized a novel class of 5-FU-containing derivatives. The antitumor activi- ty of these 5-FU O,N-acetals was assessed against HEp human cells, showing that compound 2 is fourfold more active than 5-FU.…”

“…Compound 4 has been previously described by us. [6,3] With the idea of increasing the lipophilicity of 4, we proposed a series of bioisosteric benzannelated seven-membered O,N-acetals such as 5 a-c and 6 [7] ( Figure 1). Moreover, the preparation of a benzannelated sixmembered derivative such as 7 [7] could emphasize the significance of the biological activity of the seven-membered 5-FU O,N-acetals.…”

New Medium Oxacyclic O,N-Acetals and Related Open Analogues: Biological Activities

“…Compound 22 has been previously described by us [46,47]. On one hand, with the idea of increasing the lipophilicity of 22, we proposed a series of bioisosteric benzannelated seven-membered O,N-acetals such as 23-26.…”