ABSTRACT
The proto-oncogenic protein, c-KIT, plays a crucial role in regulating cellular transformation and differentiation processes, such as proliferation, survival, adhesion, and chemotaxis. The overexpression of, and mutations, in c-KIT can lead to its dysregulation and promote various human cancers, particularly gastrointestinal stromal tumors (GISTs); approximately 80-85% of cases are associated with oncogenic mutations in the KIT gene. Inhibition of c-KIT has emerged as a promising therapeutic target for GISTs. However, the currently approved drugs are associated with resistance and significant side effects, highlighting the urgent need to develop highly selective c-KIT inhibitors that are not affected by these mutations for GISTs. Herein, the recent research efforts in medicinal chemistry aimed at developing potent small-molecule c-KIT inhibitors with high kinase selectivity for GISTs are discussed from a structure-activity relationship perspective. Moreover, the synthetic pathways, pharmacokinetic properties, and binding patterns of the inhibitors are also discussed to facilitate future development of more potent and pharmacokinetically stable small-molecule c-KIT inhibitors.
Subject(s)
Gastrointestinal Neoplasms , Gastrointestinal Stromal Tumors , Humans , Gastrointestinal Stromal Tumors/genetics , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/genetics , Structure-Activity Relationship , Oncogenes , Mutation , Gastrointestinal Neoplasms/genetics , Receptor, Platelet-Derived Growth Factor alpha/geneticsABSTRACT
Parkinson's disease (PD) is a neurodegenerative disorder that causes uncontrollable movements. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, and only trials to relieve symptoms have been evaluated. Recently, we reported the total synthesis of cudraisoflavone J and its chiral isomers [Lu et al., J. Nat. Prod. 2021, 84, 1359]. In this study, we designed and synthesized a series of novel cudraisoflavone J derivatives and evaluated their neuroprotective activities in neurotoxin-treated PC12 cells. Among these compounds, difluoro-substituted derivative (13m) and prenylated derivative (24) provided significant protection to PC12 cells against toxicity induced by 6-hydroxydopamine (6-OHDA) or rotenone. Both derivatives inhibited 6-OHDA- or rotenone-induced production of reactive oxygen species and partially attenuated lipid peroxidation in rat brain homogenates, indicating their antioxidant properties. They also increased the expression of the antioxidant enzyme, heme oxygenase (HO)-1, and enhanced the nuclear translocation of Nrf2, the transcription factor that regulates the expression of antioxidant proteins. The neuroprotective effects of 13m and 24 were eliminated by Zn(II)-protoporphyrin IX, an HO-1 inhibitor, demonstrating the critical role of HO-1 in their actions. Moreover, upregulation of HO-1 was abolished by nuclear factor erythroid 2-related factor (Nrf2) knockdown, verifying that Nrf2 is an upstream regulator of HO-1. Compounds 13m and 24 triggered phosphorylation of ERK1/2, JNK, and Akt. Most importantly, 13m- and 24-induced enhancement of Nrf2 translocation and HO-1 expression was reversed by U0126 (an ERK inhibitor), SP600125 (a JNK inhibitor), and LY294002 (an Akt inhibitor). Collectively, our results show that compounds 13m and 24 exert neuroprotective and antioxidant effects through the Nrf2/HO-1 pathway mediated by phosphorylation of ERK1/2, JNK, or Akt in PC12 cells. Based on our findings, both derivatives could serve as potential therapeutic candidates for the neuroprotective treatment of PD.
Subject(s)
Neuroprotective Agents , Parkinson Disease , Animals , Rats , Antioxidants/pharmacology , Cytochrome P-450 CYP2B1/metabolism , Cytochrome P-450 CYP2B1/pharmacology , Heme Oxygenase-1/metabolism , Neuroprotective Agents/pharmacology , Neurotoxins/pharmacology , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Oxidopamine/pharmacology , Parkinson Disease/drug therapy , Platelet Aggregation Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Rotenone/pharmacologyABSTRACT
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.
Subject(s)
Discoidin Domain Receptor 1/antagonists & inhibitors , Discoidin Domain Receptor 2/antagonists & inhibitors , Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Animals , Binding Sites , Biomarkers, Tumor , Discoidin Domain Receptor 1/chemistry , Discoidin Domain Receptor 1/metabolism , Discoidin Domain Receptor 2/chemistry , Discoidin Domain Receptor 2/metabolism , Disease Management , Disease Susceptibility , Drug Design , Humans , Inflammation/drug therapy , Inflammation/etiology , Inflammation/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/etiology , Neoplasms/pathology , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/metabolism , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Structure-Activity RelationshipABSTRACT
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.
