Replacement of the lactone moiety on podophyllotoxin and steganacin analogues with a 1,5-disubstituted 1,2,3-triazole via ruthenium-catalyzed click chemistry.
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.
Imperio
Daniela
D
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.
Pirali
Tracey
T
Galli
Ubaldina
U
Pagliai
Francesca
F
Cafici
Laura
L
Canonico
Pier Luigi
PL
Sorba
Giovanni
G
Genazzani
Armando A
AA
Tron
Gian Cesare
GC
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
D000970:Antineoplastic Agents; D007783:Lactones; D017705:Lignans; D014230:Triazoles; D014404:Tubulin; C002858:steganacin; D012428:Ruthenium; D011034:Podophyllotoxin; D015107:4-Butyrolactone