title: Synthesis of tetrahydronaphthalene lignan esters by intramolecular cyclization of ethyl p-azidophenyl-2-phenylalkanoates and evaluation of the growth inhibition of human tumor cell lines.
abstract: Intramolecular cyclization via nitrenium ion of 2-phenylpentanoic/2-phenylbutanoic acid esters with a terminal p-azidophenyl group gives direct access to tetrahydronaphthalene lignan esters. The p-azidophenyl-substituted butanoate led to an ethyl spirodienone carboxylate, while its homologue pentanoate gave ethyl 4-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate in good yield. In contrast, the m-azidophenyl-substituted esters suffered aromatic nucleophilic addition of trifluoromethanesulfonate. X-ray crystallography established unequivocally the end products structure, and density functional theory studies were performed to rationalize the cyclization outcome. Reaction intermediates and end products were evaluated for their capacity to inhibit in vitro growth of the cell lines MCF-7 (breast cancer), NCI-H460 (lung cancer), SF-268 (CNS cancer), and UACC-62 (melanoma). Growth inhibition of breast, lung, and CNS cancer cell lines was observed with the spirodienone carboxylate, the m-nitrophenylalkyl iodides, and p-phenyl-substituted elongated ethyl esters, namely, the p-nitrophenylpentanoate and p-aminophenylbutanoate, with the latter being also effective on the melanoma cell line.
authors.affiliation: Universidade de Lisboa, Faculdade de Ciências, Centro de Química e Bioquímica/Departamento de Química e Bioquímica (CQB/DQB), Ed. C8, Piso 5, 1749-016 Lisboa, Portugal.
authors.forename: Orlando
authors.initials: O
authors.lastname: Pinto
authors.forename: João
authors.initials: J
authors.lastname: Sardinha
authors.forename: Pedro D
authors.initials: PD
authors.lastname: Vaz
authors.forename: Fátima
authors.initials: F
authors.lastname: Piedade
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Calhorda
authors.forename: Rudolph
authors.initials: R
authors.lastname: Abramovitch
authors.forename: Nair
authors.initials: N
authors.lastname: Nazareth
authors.forename: Madalena
authors.initials: M
authors.lastname: Pinto
authors.forename: Maria S J
authors.initials: MS
authors.lastname: Nascimento
authors.forename: Amélia P
authors.initials: AP
authors.lastname: Rauter
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D006801:Humans; D017705:Lignans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D004952:Esters; D017705:Lignans; D013141:Spiro Compounds; D013764:Tetrahydronaphthalenes