title: Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic β-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress.
abstract: Pancreatic insulin-producing β-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of β-cell dysfunction and death. In diabetes, a major cause for the decline in β-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of β-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects β-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 μM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet β-cells. We showed that 9c protects β-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis.
authors: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation , 825 NE 13th Street, Oklahoma City, Oklahoma 73104, United States.
authors: Hongliang
authors: H
authors: Duan
authors: Natural Product Research Center, Korea Institute of Science and Technology , 679 Saimdang-ro, Gangneung, Gangwon-do 210-340, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST) , Daejeon 305-333, Republic of Korea.
authors: Jae Wook
authors: JW
authors: Lee
authors: Natural Product Research Center, Korea Institute of Science and Technology , 679 Saimdang-ro, Gangneung, Gangwon-do 210-340, Republic of Korea.
authors: Sung Won
authors: SW
authors: Moon
authors: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation , 825 NE 13th Street, Oklahoma City, Oklahoma 73104, United States.
authors: Daleep
authors: D
authors: Arora
authors: Department of Medicine, Division of Endocrinology, Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center , 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104, United States.
authors: Yu
authors: Y
authors: Li
authors: Department of Physiology, The University of Oklahoma Health Science Center , 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104, United States.
authors: Hui-Ying
authors: HY
authors: Lim
authors: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation , 825 NE 13th Street, Oklahoma City, Oklahoma 73104, United States.|Department of Medicine, Division of Endocrinology, Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center , 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104, United States.
authors: Weidong
authors: W
authors: Wang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: C000621119:(1-(4-((4-methoxybenzyl)amino)quinazolin-2-yl)piperidin-2-yl)methanol; D007004:Hypoglycemic Agents; D010880:Piperidines; D011799:Quinazolines