title: Acronycine derivatives as promising antitumor agents.
abstract: Originally isolated from an Australian plant, acronycine is an antitumor alkaloid with poor water solubility and low potency. The modest antitumor activity of this compound was markedly improved by the total synthesis of original analogs resulting in the selection of S23906-1, a diester derivative of 1,2-dihydrobenzo[b]acronycine. S23906-1 is characterized in vitro by a high potency in clonogenic assays and uncommon cell cycle pertubations. In vivo, this compound demonstrated a selectivity for human solid tumors as compared to murine transplantable tumors. The unique pharmacological profile of S23906-1 was particularly defined by a broad antitumor efficacy when administered i.v. or orally on aggressive orthotopic models of human lung, ovarian and colon models with comparable or better activity than clinically used anticancer drugs. The molecular mechanism of action of S23906-1 could involve DNA alkylation, modulation of cyclin E protein levels and inhibition of DNA synthesis leading to apoptosis. Ongoing preclinical toxicological studies will help to define the potential of this novel agent which is already considered as a valuable candidate for clinical studies.
authors.affiliation: Institut de Recherches Servier, Division de Cancérologie Expérimentale, 92150 Suresnes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilbaud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: François
authors.initials: F
authors.lastname: Tillequin
authors.forename: Michel
authors.initials: M
authors.lastname: Koch
authors.forename: John A
authors.initials: JA
authors.lastname: Hickman
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
mesh_terms: D000175:Acronine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C436732:S 23906-1; D000175:Acronine