title: Novel combretastatin analogues endowed with antitumor activity.
abstract: We studied the anticancer activity of a series of new combretastatin derivatives with B-ring modifications. The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and of a phenolic moiety in B-ring. We selected the benzo[b]thiophene and benzofuran combretastatin analogues 11 (ST2151) and 13 (ST2179) and their phosphate prodrugs (29 and 30) for their high antitumor activity in in vitro and in vivo models. Cell exposure to IC50 of 11, 13, and CA-4 led to the arrest of various cell types in the G2/M phase of the cell cycle and induction of apoptosis. Mainly, 11 and 13 induced the formation of multinucleated cells with abnormal chromatin distribution, with only a minimal effect on the microtubule organization, with respect to CA-4. Interestingly, both the pharmacokinetic profile of 29 and its in vivo antitumor effect and those of 30, active even after oral administration, suggest additional pharmacological differences between these compounds and CA-4P.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy. smd@unife.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baruchello
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rondanin
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzi
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Pavani
authors.forename: Domenico
authors.initials: D
authors.lastname: Alloatti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Marcella
authors.initials: M
authors.lastname: Marcellini
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Mario B
authors.initials: MB
authors.lastname: Guglielmi
authors.forename: Federica
authors.initials: F
authors.lastname: Bucci
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001704:Biopolymers; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D003078:Colchicine / Q000737:chemistry; D042783:Endothelial Cells / Q000187:drug effects / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D010755:Organophosphates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D001632:Bibenzyls; D001704:Biopolymers; D010755:Organophosphates; D011355:Prodrugs; D013267:Stilbenes; D013876:Thiophenes; D014404:Tubulin; C040105:combretastatin; D003078:Colchicine