Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-Inducing Activity in HL60 and in MDR Cell Lines

Authors:
  • GGGiuseppina Grisolia
    Giuseppina Grisolia
  • GGGiuseppe Giannini
    Giuseppe Giannini
  • MRMarinella Roberti
    Marinella Roberti
  • RRRiccardo Rondanin
    Riccardo Rondanin
  • LPLaura Piccagli
    Laura Piccagli
  • RBRiccardo Baruchello
    Riccardo Baruchello
  • MRMarcello Rossi
    Marcello Rossi
  • RRRomeo Romagnoli
    Romeo Romagnoli
  • FIFrancesco Paolo Invidiata
    Francesco Paolo Invidiata
  • MJM. Katherine Jung
    M. Katherine Jung
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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 μM) 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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