title: Synthesis and antimitotic and tubulin interaction profiles of novel pinacol derivatives of podophyllotoxins.
abstract: Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.
authors.affiliation: Departamento de Química Farmacéutica, Facultad de Farmacia-CIETUS, Campus Unamuno, Universidad de Salamanca , 37007 Salamanca, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Abad
authors.forename: José L
authors.initials: JL
authors.lastname: López-Pérez
authors.forename: Esther
authors.initials: E
authors.lastname: del Olmo
authors.forename: Luis F
authors.initials: LF
authors.lastname: García-Fernández
authors.forename: Andrés
authors.initials: A
authors.lastname: Francesch
authors.forename: Chiara
authors.initials: C
authors.lastname: Trigili
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: José M
authors.initials: JM
authors.lastname: Andreu
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Arturo
authors.initials: A
authors.lastname: San Feliciano
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D008958:Models, Molecular; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D011034:Podophyllotoxin