Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-inducing activity in HL60 and in MDR Cell lines

Stefania Grimaudo, Matteo Rossi, Nicolo' Gebbia, Luisa Dusonchet, Maria Meli, Vincenzo Abbadessa, M. Katherine Jung, Ernest Hamel, Giuseppina Grisolia, Giuseppe Giannini, Marcello Rossi, Vincenzo Abbadessa, Antonietta Di Cristina, Riccardo Baruchello, Riccardo Rondanin, Stefania Grimaudo, Manlio Tolomeo, Daniele Simoni, Marinella Roberti, Romeo RomagnoliLaura Piccagli, Antonietta Di Cristina, Francesco Invidiata, Lucia Crosta

Research output: Contribution to journalArticlepeer-review

130 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)723-736
Number of pages14
JournalJournal of Medicinal Chemistry
Volume48
Publication statusPublished - 2005

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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