title: Synthesis and anticancer activity of the (R,S)-benzofused 1,5-oxathiepine moiety tethered to purines through alkylidenoxy linkers.
abstract: Herein we report the design, synthesis, and anticancer activity of a series of substituted (R,S)-9-[2- or 3-(3,4-dihydro-2H-1,5-benzoxathiepine-3-yloxy)alkyl]-9H-purines. Derivatives with propylenoxy-linked 2',6'-dichloro- and 6'-bromopurines are more active than their respective ethylenoxy-linked purine conjugates. On the other hand, the compound with a propylenoxy-linked 6'-chloropurine is nearly equipotent to the corresponding ethylenoxy-linked conjugate. Our results show that bromo- and chloropurine-conjugated benzoxathiepines containing a propylenoxy linker are able to inhibit PI3 kinase (PI3K) phosphorylation in MCF-7 breast cancer cells, indicating that the activation of eIF2α, together with inhibition of the PI3K pathway, is the mechanism of action by which these compounds effect their antitumor activity in the MCF-7 cell line; apoptosis was induced in a p53-independent manner.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada c/Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Kimatrai
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-García
authors.forename: Alberto
authors.initials: A
authors.lastname: Ramírez
authors.forename: Elena
authors.initials: E
authors.lastname: Andreolli
authors.forename: Adriane
authors.initials: A
authors.lastname: Da Silveira-Gomes
authors.forename: María Angel
authors.initials: MA
authors.lastname: García
authors.forename: Antonia
authors.initials: A
authors.lastname: Aránega
authors.forename: Juan A
authors.initials: JA
authors.lastname: Marchal
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001582:Benzothiepins / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001582:Benzothiepins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D016159:Tumor Suppressor Protein p53