ABSTRACT
Our previous studies have shown that several 7-substituted-4-imidazolylflavans are potent inhibitors of aromatase. These compounds were designed considering the anti-aromatase effect of some natural flavonoids and the importance of an azole ring for synthetic inhibitors such as letrozole or anastrozole towards binding to the heme iron of aromatase. In this study, we report the optimization of these lead compounds by the modulation of flavan A ring. The resulting 7,8-benzo-4-imidazolylflavans were tested in order to assess their ability to inhibit aromatase. Biological data concerning enantiomers obtained from the chiral separation of the racemate compound 4-imidazolyl-7-methoxyflavan are also presented.
Subject(s)
Aromatase Inhibitors/pharmacology , Aromatase/metabolism , Flavonoids/pharmacology , Imidazoles/pharmacology , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Dose-Response Relationship, Drug , Flavonoids/chemical synthesis , Flavonoids/chemistry , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Some natural compounds such as flavonoids are known to possess a moderate inhibitory activity against aromatase, this enzyme being an interesting target for hormone-dependent breast cancer treatment. It has been demonstrated that the modulation of flavonoid skeleton could increase anti-aromatase effect. Therefore, new 7,8-benzoflavanones were synthesized and tested for their activity toward aromatase inhibition. It was observed that the introduction of a benzo ring at position C-7 and C-8 on flavanone skeleton led to new potent aromatase inhibitors, the resulting 7,8-benzoflavanones being until nine times more potent than aminogluthetimide (the first aromatase inhibitor used clinically).
Subject(s)
Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/pharmacology , Benzene/chemistry , Flavanones/chemical synthesis , Flavanones/pharmacology , Anastrozole , Aromatase Inhibitors/chemistry , Cyclization , Flavanones/chemistry , Humans , Hydrogen Bonding , Letrozole , Microsomes/drug effects , Microsomes/enzymology , Molecular Structure , Nitriles/chemistry , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
A series of 4-imidazolylflavans having a variety of substituents on the 2-phenyl ring was synthesized and investigated for their inhibitory effect against aromatase. Structure-activity relationships of these compounds were determined. An additional chlorine atom or a cyano group at the 4' position did not enhance aromatase inhibition as well as a 3'-hydroxyl group. The influence of an additional 4'-hydroxyl group depends on the substitution pattern of A ring. Among these molecules, 4'-hydroxy-4-imidazolyl-7-methoxyflavan is only 2.2-fold less active than the letrozole (as assessed by IC50 values). Letrozole is used as the first-line therapy for metastatic breast cancer.
Subject(s)
Aromatase Inhibitors , Flavonoids , Imidazoles , Aromatase/chemistry , Aromatase/drug effects , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/pharmacology , Flavonoids/chemical synthesis , Flavonoids/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Microsomes/drug effects , Microsomes/enzymology , Molecular Conformation , Placenta/enzymology , Structure-Activity RelationshipABSTRACT
Aromatase is a target of pharmacological interest for the treatment of estrogen-dependent cancers. Azole derivatives such as letrozole or anastrozole have been developed for aromatase inhibition and are used for the treatment of breast tumors. In this paper, four 4-triazolylflavans were synthesized and were found to exhibit moderate to high inhibitory activity against aromatase.
Subject(s)
Antineoplastic Agents/chemical synthesis , Aromatase Inhibitors/chemical synthesis , Flavones/chemical synthesis , Triazoles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Flavones/chemistry , Flavones/pharmacology , Humans , In Vitro Techniques , Microsomes/drug effects , Microsomes/enzymology , Placenta/ultrastructure , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Two 4-imidazolylflavans were synthesized and their relative stereochemistry was established by 1H and 13C NMR data. These compounds were tested for their activity to inhibit aromatase. It was observed that the introduction of an imidazolyl group at carbon 4 on flavan nucleus led to potent molecules.
Subject(s)
Aromatase Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Flavonoids/chemical synthesis , Flavonoids/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Aromatase/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Female , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Placenta/enzymology , Pregnancy , Protons , Stereoisomerism , Structure-Activity RelationshipABSTRACT
PURPOSE: Aromatase inhibitors are known to prevent the conversion of androgens to estrogens and play a significant role in the treatment of estrogen dependent diseases such as breast cancer. Some flavonoids have been reported as potent aromatase inhibitors; therefore, in an effort to develop novel anti breast cancer agents, B ring substituted flavanones with a 7-methoxy group on A ring were synthesized and tested to assess their ability to inhibit aromatase activity and to determine the optimal B ring substitution pattern. METHODS: A series of flavanones was prepared by cyclisation of 2'-hydroxychalcones previously obtained by Claisen-Schmidt condensation and the aromatase inhibitory activity of these compounds was investigated using human placental microsomes and radiolabeled [1,2,6,7-(3)H]-androstenedione as substrate. RESULTS: Almost all flavanones exhibited inhibitory effect on the aromatase activity but their potency was dependent on their B ring substitution pattern. Hydroxylation at position 3' and/or 4' enhanced the anti-aromatase activity; thus, 3',4'-dihydroxy-7-methoxyflavanone was found to be twice more potent than aminoglutethimide, the first aromatase inhibitor clinically used. CONCLUSIONS: These results indicated that these flavanones could be considered as potential anti breast cancer agents through the inhibition of aromatase activity and allowed us to select some of these compounds as skeleton for the development of flavonoid structurally-related aromatase inhibitors.
Subject(s)
Aromatase Inhibitors , Flavonoids/chemical synthesis , Flavonoids/pharmacology , Aromatase/metabolism , Humans , Microsomes/drug effects , Microsomes/enzymologyABSTRACT
Two (E)-pyridinyl-substituted flavanone derivatives were synthesized and UV irradiation of these compounds afforded a Z-enriched mixture. These products were tested for their ability to inhibit the cytochrome P450 aromatase. It was observed that the introduction of a pyridinylmethylene group at carbon 3 on flavanone nucleus led to a significant increase of aromatase inhibitory effect. Moreover, configuration had a substantial influence on the aromatase inhibitory activity since (E)-isomers were found to be more active than (Z)-isomers.
