Structure-anti-leukemic activity relationship study of ortho-dihydroxycoumarins in U-937 cells: key role of the ¦Ä-lactone ring in determining differentiation-inducing potency and selective pro-apoptotic action.

RAMIRO VÁZQUEZ.; MARÍA E. RIVEIRO.; MÓNICA VERMEULEN.; ELIANA ALONSO, ; CAROLINA MONDILLO.; ,NATALIA GÓMEZ.; GRACIELA FACORRO,; LIDIA PIEHL.; ALBERTINA MOGLIONI.; NATALIA FERNÁNDEZ.; ALBERTO BALDI, ; CARINA SHAYO.; CARLOS DAVIO.

BIOORGANIC & MEDICINAL CHEMISTRY.

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2012 vol. 20 p. 5537 - 5549

0968-0896

a b s t r a c t 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 d-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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. open-chain coumarin analogues) and 1,2-pyrones (representative of the d-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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. ortho-dihydroxycoumarins (o-DHC) derivatives, cinnamic acid derivatives (as open-chain coumarin analogues) and 1,2-pyrones (representative of the d-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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. d-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 d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. o-DHC required to induce leukemic cell differentiation and apoptosis in U-937 cells. Our results show for the first time that the d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. d-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. of novel chemotherapeutic agents. pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. of novel chemotherapeutic agents. 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. of novel chemotherapeutic agents. o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. 2012 Elsevier Ltd. All rights reserved2012 Elsevier Ltd. All rights reserved