title: Structure-anti-leukemic activity relationship study of ortho-dihydroxycoumarins in U-937 cells: key role of the δ-lactone ring in determining differentiation-inducing potency and selective pro-apoptotic action.
abstract: Previous studies indicated the need of at least one phenolic hydroxyl group in the coumarin core for induction of cytotoxicity in different cell lines. Herein, we present an exhaustive structure-activity relationship study including ortho-dihydroxycoumarins (o-DHC) derivatives, cinnamic acid derivatives (as open-chain coumarin analogues) and 1,2-pyrones (representative of the δ-lactone ring of the coumarin core), carried out to further identify the structural features of o-DHC required to induce leukemic cell differentiation and apoptosis in U-937 cells. Our results show for the first time that the δ-lactone ring positively influences the aforementioned biological effects, by conferring greater potency to compounds with an intact coumarin nucleus. Most tellingly, we reveal herein the crucial role of this molecular portion in determining the selective toxicity that o-DHC show for leukemic cells over normal blood cells. From a pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents.
authors.affiliation: Laboratorio de Patología y Farmacología Molecular, Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Vuelta de Obligado 2490 (C1428ADN), Buenos Aires, Argentina; Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica-UBA, Junín 954 (C1113AAD), Buenos Aires, Argentina. ramirobioq@hotmail.com
authors.forename: Ramiro
authors.initials: R
authors.lastname: Vázquez
authors.forename: María E
authors.initials: ME
authors.lastname: Riveiro
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Eliana
authors.initials: E
authors.lastname: Alonso
authors.forename: Carolina
authors.initials: C
authors.lastname: Mondillo
authors.forename: Graciela
authors.initials: G
authors.lastname: Facorro
authors.forename: Lidia
authors.initials: L
authors.lastname: Piehl
authors.forename: Natalia
authors.initials: N
authors.lastname: Gómez
authors.forename: Albertina
authors.initials: A
authors.lastname: Moglioni
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández
authors.forename: Alberto
authors.initials: A
authors.lastname: Baldi
authors.forename: Carina
authors.initials: C
authors.lastname: Shayo
authors.forename: Carlos
authors.initials: C
authors.lastname: Davio
mesh_terms: D015110:4-Hydroxycoumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019169:Jurkat Cells; D007783:Lactones / Q000737:chemistry*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D015110:4-Hydroxycoumarins; D002934:Cinnamates; D007783:Lactones; D011753:Pyrones; C029010:cinnamic acid