Dong Jae Baek

A traceless and efficient solid-phase synthetic strategy was developed for the construction of thiazolo[4,5-b] pyridin-7(4H)-one derivatives.

We describe the first solid-phase synthesis of thiazolo [4,5-d] [1,2,3] triazin-4(3H)-one derivatives using Merrifield resin. The modular sequence involves Thorpe–Ziegler cyclization, sulfone oxidation, and disulfonate nucleophilic substitution, with each step monitored by real-time ATR-FTIR spectroscopy. Conducted under mild conditions with broad functional group tolerance, the protocol delivered a library of 40 compounds in average stepwise yields of 68–97%, requiring only simple resin washing for purification. This study demonstrates a solid-phase route to thiazolotriazinones and illustrates its applicability in heterocyclic library construction and SAR studies.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and treatment-resistant malignancy with a poor prognosis. Among the multifactorial mechanisms implicated in the progression of PDAC, oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidant defenses, has emerged as a crucial regulator of tumor behavior. While ROS can promote tumorigenesis via genomic instability, oncogenic signaling, and immune evasion, it also exhibits tumor-suppressive potential by inducing apoptosis and disrupting cancer cell metabolism. This dual role of ROS in PDAC is tightly influenced by the tumor mutational landscape, particularly KRAS gene mutations, metabolic reprogramming, and the tumor microenvironment. In PDAC, the generation of ROS promotes chemoresistance, activates hypoxia-inducible factor-1α, and facilitates desmoplastic stromal remodeling via pancreatic stellate cells and cancer-associated fibroblasts. Conversely, the therapeutic increase of ROS beyond tolerable levels induces cancer cell death through apoptosis and autophagy. This review comprehensively summarizes the dual role of ROS in PDAC, with particular emphasis on the molecular mechanisms underlying redox regulation. In addition, ROS-targeting therapeutic agents are categorized into clinically approved drugs, investigational agents, and natural compounds, and their relevance in redox biology is discussed. Finally, emerging therapeutic strategies that leverage redox vulnerabilities are outlined, and future research directions are proposed for the development of redox-modulating PDAC therapies.

Pancreatic cancer is known to be the most lethal cancer. Fewer new treatments are being developed for pancreatic cancer as compared to other cancers. The bioactive lipid S1P, which is mainly regulated by sphingosine kinase 1 (SK1) and sphingosine kinase 2 (SK2) enzymes, plays significant roles in pancreatic cancer initiation and exacerbation. S1P controls many signaling pathways to modulate the progression of pancreatic cancer through the G-coupled receptor S1PR1-5. Several papers reporting amelioration of pancreatic cancer via modulation of S1P levels or downstream signaling pathways have previously been published. In this paper, for the first time, we have reviewed the results of previous studies to understand how S1P and its receptors contribute to the development of pancreatic cancer, and whether S1P can be a therapeutic target. In addition, we have also reviewed papers dealing with the effects of SK1 and SK2, which are kinases that regulate the level of S1P, on the pathogenesis of pancreatic cancer. We have also listed available drugs that particularly focus on S1P, S1PRs, SK1, and SK2 for the treatment of pancreatic cancer. Through this review, we would like to suggest that the SK/S1P/S1PR signaling system can be an important target for treating pancreatic cancer, where a new treatment target is desperately warranted.

Allomyrina dichotoma larvae (ADL) is an insect type that is used ethnopharmacologically to treat various diseases; however, its use as an antiaging treatment has not been widely studied. Previously, we found that an ethyl acetate (EA) fraction derived from an ADL extract (ADLE) has a high polyphenol content and antioxidant properties. In this study, we identified the underlying molecular mechanism for the protective effect of the EA fraction against UVB-induced photodamage in vitro and ex vivo. UVB treatment increased intracellular reactive oxygen species levels and DNA damage; the latter of which was significantly decreased following cotreatment with the EA fraction. Biological markers of aging, such as p16^INK4a, p21^WAF1, and senescence-associated β-gal levels, were induced by UVB treatment but significantly suppressed following EA-fraction treatment. UVB-induced upregulation of matrix metalloproteinase (MMP)-1 and downregulation of COL1A1 were also reversed by EA-fraction treatment in both cells and a 3D skin model, which resulted in increased keratin and collagen deposition. Moreover, EA-fraction treatment inhibited the phosphorylation of MAPKs (p38, ERK, and JNK) and nuclear factor (NF-)-kB and decreased the levels of inflammatory cytokines in UVB-treated cells. The results indicate that an EA fraction from ADLE ameliorates UVB-induced degradation of COL1A1 by inhibiting MMP expression and inactivating the MAPK/NF-κB p65/AP-1 signaling pathway involved in this process.

Reactive oxygen species are involved in the pathogenesis of cancers and metabolic diseases, including diabetes, obesity, and fatty liver disease. Thus, inhibiting the generation of free radicals is a promising strategy to control the onset of metabolic diseases and cancer progression. Various synthetic drugs and natural product-derived compounds that exhibit antioxidant activity have been reported to have a protective effect against a range of metabolic diseases and cancer. This review highlights the development and aggravation of cancer and metabolic diseases due to the imbalance between pro-oxidants and endogenous antioxidant molecules. In addition, we discuss the function of proteins that regulate the production of reactive oxygen species as a strategy to treat metabolic diseases. In particular, we summarize the role of proteins such as nuclear factor-like 2, Sestrin, and heme oxygenase-1, which regulate the expression of various antioxidant genes in metabolic diseases and cancer. We have included recent literature to discuss the latest research on identifying novel signals of antioxidant genes that can control metabolic diseases and cancer.

FTY720 exerts an anticancer effect through the activation of protein phosphatase 2A (PP2A), which acts as a tumor suppressor, and inhibits SK1 activity. However, FTY720 taken into the body is phosphorylated by endogenous SK2. The structure of FTY720 is well‐studied as a basis for developing SK inhibitors and PP2A activators. We synthesized analogs of PF‐543 with a dimeric tail structure and reported the efficacy of SK1 inhibition. The compounds with this structure had improved anticancer activity and stability compared with PF‐543. To confirm whether the dimeric tail structure could be applied as a PP2A‐active material, we synthesized four types of compounds with a dimeric tail structure and confirmed the anticancer activity and PP2A activation in A549 non‐small cell lung cancer cells. Compounds 2 and 4 were more cytotoxic to A549 cells than RB005, and induced similar levels of cytotoxic and PP2A activation as FTY720.

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates and requires the development of highly efficacious medications that can improve the efficiency of existing treatment methods. In particular, in PDAC, resistance to conventional chemotherapy reduces the effectiveness of anticancer drugs, decreasing the therapeutic efficiency. Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SK), plays a vital role in cancer growth, metastasis, chemotherapy, and drug resistance. Focusing on the structural characteristics of mebendazole (MBZ), we studied whether MBZ would affect metastasis, invasion, and drug resistance in cancer by lowering S1P production through inhibition of SK activity. MBZ selectively inhibited SK1 more than SK2 and regulated the levels of sphingolipids. MBZ inhibited the proliferation and migration of cancer cells in other PDAC cell lines. To determine whether the effect of MBZ on cancer cell growth and migration is S1P-mediated, S1P was treated, and the growth and migration of cancer cells were observed. It was found that MBZ inhibited S1P-induced cancer cell growth, and MBZ showed a growth inhibitory effect by regulating the JAK2/STAT3/Bcl-2 pathway. The phosphorylation of focal adhesion kinase (FAK), a transcription factor that regulates migration, was inhibited by MBZ, so it was found that the effect of MBZ regulates the migration of cancer cells through the S1P/FAK/vimentin pathway. In conclusion, our study suggests that the anthelmintic MBZ can be used as a potential therapeutic agent for treating PDAC and for structural synthesis studies of its analogs.