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

被引:47
作者
Macchia, M
Barontini, S
Bertini, S
Di Bussolo, V
Fogli, S
Giovannetti, E
Grossi, E
Minutolo, F
Danesi, R
机构
[1] Univ Pisa, Dept Pharmaceut Sci, I-56126 Pisa, Italy
[2] Univ Pisa, Div Pharmacol & Chemotherapy, Dept Oncol Transplants & Adv Technol Med, I-56126 Pisa, Italy
[3] Univ Pisa, Dept Bioorgan Chem & Biopharm, I-56126 Pisa, Italy
[4] Bracco Imaging Spa, Dept Med, I-20134 Milan, Italy
关键词
D O I
10.1021/jm010947r
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring.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 PM, 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 C-2-ceramide, was 31.6 muM. Compounds 1 and 2 and C-2-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.
引用
收藏
页码:3994 / 4000
页数:7
相关论文
共 26 条
[1]  
AOESSENKO AV, 2000, MEMBR CELL BIOL, V13, P303
[2]   IRREVERSIBLE ENZYME INHIBITORS .77. INHIBITORS OF THYMIDINE PHOSPHORYLASE .3. HYDROPHOBIC BONDING BY 1-SUBSTITUTED URACILS CONTAINING ADDITIONAL SUBSTITUENTS AT 5 AND 6 POSITIONS [J].
BAKER, BR ;
KAWAZU, M ;
SANTI, DV ;
SCHWAN, TJ .
JOURNAL OF MEDICINAL CHEMISTRY, 1967, 10 (03) :304-&
[3]  
BIELAWSKA A, 1992, J BIOL CHEM, V267, P18493
[4]   Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine [J].
Danel, K ;
Larsen, E ;
Pedersen, EB ;
Vestergaard, BF ;
Nielsen, C .
JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (12) :2427-2431
[5]  
DANEL K, 1995, SYNTHESIS-STUTTGART, P934
[6]  
Danesi R, 1996, MOL PHARMACOL, V49, P972
[7]   Synthesis and apoptogenic activity of fluorinated ceramide and dihydroceramide analogues [J].
De Jonghe, S ;
Van Overmeire, I ;
Gunst, J ;
De Bruyn, A ;
Hendrix, C ;
Van Calenbergh, S ;
Busson, R ;
De Keukeleire, D ;
Philippé, J ;
Herdewijn, P .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (21) :3159-3164
[8]   Sphingolipid signalling domains - Floating on rafts or buried in caves? [J].
Dobrowsky, RT .
CELLULAR SIGNALLING, 2000, 12 (02) :81-90
[9]   Anti-tumoral action of cannabinoids:: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation [J].
Galve-Roperh, I ;
Sánchez, C ;
Cortés, ML ;
del Pulgar, TG ;
Izquierdo, M ;
Guzmán, M .
NATURE MEDICINE, 2000, 6 (03) :313-319
[10]   Ceramides induce a form of apoptosis in human acute lymphoblastic leukemia cells that is inhibited by Bcl-2, but not by CrmA [J].
Geley, S ;
Hartmann, BL ;
Kofler, R .
FEBS LETTERS, 1997, 400 (01) :15-18