title: Heterocyclic and phenyl double-bond-locked combretastatin analogues possessing potent apoptosis-inducing activity in HL60 and in MDR cell lines.
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 microM) 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. smd@dns.unife.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Grisolia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Marinella
authors.initials: M
authors.lastname: Roberti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rondanin
authors.forename: Laura
authors.initials: L
authors.lastname: Piccagli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baruchello
authors.forename: Marcello
authors.initials: M
authors.lastname: Rossi
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Invidiata
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Jung
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Nicola
authors.initials: N
authors.lastname: Gebbia
authors.forename: Lucia
authors.initials: L
authors.lastname: Crosta
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Abbadessa
authors.forename: Antonietta
authors.initials: A
authors.lastname: Di Cristina
authors.forename: Luisa
authors.initials: L
authors.lastname: Dusonchet
authors.forename: Maria
authors.initials: M
authors.lastname: Meli
authors.forename: Manlio
authors.initials: M
authors.lastname: Tolomeo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D007555:Isoxazoles; D011725:Pyridines; D013267:Stilbenes; C058728:fosbretabulin