title: Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors.
abstract: Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O(7)-Nitrooxyethyl-O(3'),O(4')-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.
authors.affiliation: Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
authors.forename: Qi-Qin
authors.initials: QQ
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Cheng
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zheng
authors.forename: Sheng-Ming
authors.initials: SM
authors.lastname: Peng
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Zou
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D002625:Chemistry, Organic; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D047311:Luteolin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009566:Nitrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009566:Nitrates; D009569:Nitric Oxide; D000449:Aldehyde Reductase; D047311:Luteolin