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Heterocyclic and phenyl double-bond-locked combretastatin analogues possessing potent apoptosis-inducing activity in HL60 and in MDR cell lines

  1. Author:
    Simoni, D.
    Grisolia, G.
    Giannini, G.
    Roberti, M.
    Rondanin, R.
    Piccagli, L.
    Baruchello, R.
    Rossi, M.
    Romagnoli, R.
    Invidiata, F. P.
    Grimaudo, S.
    Jung, M. K.
    Hamel, E.
    Gebbia, N.
    Crosta, L.
    Abbadessa, V.
    Di Cristina, A.
    Dusonchet, L.
    Meli, M.
    Tolomeo, M.

  2. Author Address

    Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. R&D Sigma Tau, Pomezia, Italy. Univ Palermo, Dipartimento Farmacochim Tossicol & Biol, I-90133 Palermo, Italy. Policlin Palermo, Cattedra Ematol & Serv AIDS, Palermo, Italy. SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Natl Inst Hlth, Frederick, MD 21702 USA. Univ Palermo, Dipartimento Sci Farmacol, I-90133 Palermo, Italy Simoni, D, Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy
    1. Year: 2005
    2. Date: FEB 10
  2. Journal: Journal of Medicinal Chemistry
    1. 48
    2. 3
    3. Pages: 723-736
  4. Type of Article: Article
  1. Abstract:

    Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC50 < 1 muM) and apoptosis-inducing activity but poor antitubulin activity. The isoxazoline derivatives 18b, 20a, and 21a, demonstrated potent apoptotic activity different from that of natural CA-4. Their ability to block most cells in the G2 phase suggests that these compounds could act on targets different from the mitotic spindle. This would indicate activation of both the intrinsic and the extrinsic apoptotic pathways. The data suggest unambiguously that structural alteration of the stilbene motif of CA-4 can be extremely effective in producing potent apoptosis-inducing agents

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External Sources

  1. View record in Web of Science®
  2. WOS: 000226881300009

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