Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

Cudraisoflavone J (1), isolated from Cudrania tricuspidata, is a potent neuroprotective compound with a chiral center. Herein, we report the first total synthesis of racemic cudraisoflavone J (1) using a Claisen rearrangement and a Suzuki coupling reaction as the key steps. Racemic secondary alcohol was kinetically resolved to give (+)-and (−)-cudraisoflavone J with up to 97 and 88% enantiomeric excess, respectively. The modified Mosher's method was used to elucidate the absolute configuration of naturally occurring cudraisoflavone J.Cudrania tricuspidata (Carr.) Bur. ex Lavallee, which is a perennial plant of the family Moraceae, is widely used in east Asia as a traditional medicine or health supplement. 1 In China, C. tricuspidata has been used in the treatment of eczema, mumps, tuberculosis, contusions, and acute arthritis since ancient times. 2 In Korea, its edible fruits have been made into juices, jams, alcoholic beverages, dietary supplements, and other health products. 3,4 The immense medicinal and economic value of C. tricuspidata has encouraged numerous studies of its phytochemical and pharmacological activities. 5−7 Flavonoids, including flavones, flavanones, and isoflavones, are considered to be the major bioactive constituents of C. tricuspidata, exhibiting notable anti-inflammatory, 8,9 antioxidative, 10 antitumor, 11 hepatoprotective, 12 neuroprotective, 13,14 and antiobesity 15,16 effects. In 2015, Lee and co-workers isolated a group of isoflavones from the fresh fruits of C. tricuspidata and found that they featured 3-hydroxy-2,2dimethyldihydropyran groups substituted on their aromatic rings, as shown in Figure 1. Among these, cudraisoflavone J had the most potent activity against 6-hydroxydopamine (6-OHDA)-induced cell death in human neuroblastoma SH-SY5Y cells, with an EC 50 value of 0.5 μM. 17 This suggested that cudraisoflavone J could be considered a candidate for further research into using it for therapeutic purposes to treat neurodegenerative diseases, such as Parkinson's disease. To the best of our knowledge, neither the total synthesis nor the

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