Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues

M. Macchia, S. Barontini, S. Bertini, V. Di Bussolo, S. Fogli, E. Giovannetti, E. Grossi, F. Minutolo, R. Danesi

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Scopus)

Abstract

A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies. In this study we report the first example of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring. The evaluation of their biologic activity on CCRF-CEM human leukemia cells demonstrated that the most active was compound 1 followed by compound 2 (mean 50% inhibition of cell proliferation [IC50] 1.7 and 7.9 μM, respectively), while compounds 3 and 4 were inactive, as were uracil, thiouracil, and 5,6-dimethyluracil, the pyrimidine moieties of compounds 1-4. For comparison, the IC50 of the reference substance, the cell-permeable C2-ceramide, was 31.6 μM. Compounds 1 and 2 and C2-ceramide were able to trigger apoptosis, as shown by the occurrence of DNA and nuclear fragmentation, and to release cytochrome c from treated cells. The treatment of female CD-1 nu/nu athymic mice bearing a WiDr human colon xenograft with the most active compound 1 at 2, 10, 50, and 200 mg/kg ip daily for 10 days resulted in an antitumor effect that was equivalent at 50 mg/kg or superior (200 mg/kg) to that of cyclophosphamide, 20 mg/kg ip daily, delivered on the same schedule, with markedly lower systemic toxicity. In conclusion, the present study demonstrates that the new ceramide analogues 1 and 2 are characterized by in vitro and in vivo antitumor activity and low toxicity.

Original languageEnglish
Pages (from-to)3994-4000
Number of pages7
JournalJournal of Medicinal Chemistry
Volume44
Issue number23
DOIs
Publication statusPublished - 8 Nov 2001

Cite this