title: Replacement of the lactone moiety on podophyllotoxin and steganacin analogues with a 1,5-disubstituted 1,2,3-triazole via ruthenium-catalyzed click chemistry.
abstract: Steganacin and podophyllotoxin are two naturally occurring lignans first isolated from plant sources, which share the capability to disrupt tubulin assembly. Although not strictly essential for its activity, the lactone ring on both structures represents Achilles' heel, as it is a potential site of metabolic degradation and epimerization on its C2 carbon brings about a significant loss in potency. In the present manuscript, we have used the ruthenium-catalyzed [3+2] azide-alkyne cycloaddition, a click-chemistry reaction, to replace the lactone ring with a 1,5-disubstituted triazole in few synthetic steps. The compounds were cytotoxic, although to a lesser degree compared to podophyllotoxin, while retaining antitubulin activity. The present structures might therefore represent a good platform for the fast generation of metabolically stable compounds with few stereogenic centers that might be of value from a medicinal chemistry point of view.
authors.affiliation: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center, Università degli Studi del Piemonte Orientale A Avogadro, Via Bovio 6, 28100, Novara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Imperio
authors.forename: Tracey
authors.initials: T
authors.lastname: Pirali
authors.forename: Ubaldina
authors.initials: U
authors.lastname: Galli
authors.forename: Francesca
authors.initials: F
authors.lastname: Pagliai
authors.forename: Laura
authors.initials: L
authors.lastname: Cafici
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorba
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Gian Cesare
authors.initials: GC
authors.lastname: Tron
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D017705:Lignans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D012428:Ruthenium / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry; D014404:Tubulin / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D017705:Lignans; D014230:Triazoles; D014404:Tubulin; C002858:steganacin; D012428:Ruthenium; D011034:Podophyllotoxin; D015107:4-Butyrolactone