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.
Subject(s)
Apoptosis/drug effects , Lactones/chemistry , Leukocytes, Mononuclear/drug effects , 4-Hydroxycoumarins/chemical synthesis , 4-Hydroxycoumarins/chemistry , 4-Hydroxycoumarins/pharmacology , Cell Cycle/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Cinnamates/chemical synthesis , Cinnamates/chemistry , Cinnamates/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Jurkat Cells , Leukocytes, Mononuclear/cytology , Pyrones/chemical synthesis , Pyrones/chemistry , Pyrones/pharmacology , Structure-Activity Relationship , U937 CellsABSTRACT
The antioxidant activity of 4-hydroxycoumarin synthetic derivatives and 4-methylumbelliferone were determined taking 4-hydroxycoumarin as the reference compound. Six 3-aryl-4-hydroxycoumarin derivatives were synthesized from 4-hydroxycoumarin as precursor in order to evaluate changes in their antioxidant properties due to C3-aryl substituent nature. Free radical scavenging capacities of these compounds against two different species DPPH(·) and ABTS(·+) and the protecting ability towards the ß-carotene-linoleic acid co-oxidation enzymatically induced by lipoxygenase were measured. In addition, the relationship between the activities of these molecules against DPPH radical and the bond dissociation energy of O-H (BDE) calculated using methods of computational chemistry was evaluated.