Discovery of new cinnamic derivatives as anti-inflammatory agents for treating acute lung injury in mice.

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% for  IL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI.

Discovery of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine as an effective molecular skeleton to develop reversible/irreversible pan-HER inhibitors.

Pan-HER inhibitors exhibit extensive biological activity and offer unique advantages and usually bind to targets in an irreversible manner. Owing to the off-target toxicity of irreversible inhibitors, reversible pan-HER inhibitors are desirable. Herein, we describe the process of N-(ring structure fused phenyl)quinazoline-4-amine-based design, synthesis, and biological evaluation of pan-HER inhibitors in vitro and in vivo. Compound C5, with the molecular skeleton of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine, displayed irreversible binding just like other effective pan-HER inhibitors. To our surprise, compound C6, which possessed the same skeleton, was found to be a high-strength reversible pan-HER inhibitor. This compound was capable of inhibiting HER1s (such as EGFR T790M/L858R and WT), HER2, and HER4 and can be considered as a breakthrough in the development of pan-HER inhibitors. Altogether, N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine can serve as an effective molecular skeleton for developing both reversible and irreversible pan-HER inhibitors in the following discovery of antitumor drugs.

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs.

Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

Pharmacological inhibition of MyD88 suppresses inflammation in tubular epithelial cells and prevents diabetic nephropathy in experimental mice.

Emerging evidence shows that chronic inflammation mediated by toll-like receptors (TLRs) contributes to diabetic nephropathy. Myeloid differentiation primary-response protein-88 (MyD88) is an essential adapter protein of all TLRs except TLR3 in innate immunity. It is unclear whether MyD88 could be a therapeutic target for diabetic nephropathy. Here, we used a new small-molecule MyD88 inhibitor, LM8, to examine the pharmacological inhibition of MyD88 in protecting kidneys from inflammatory injury in diabetes. We showed that MyD88 was significantly activated in the kidney of STZ-induced type 1 diabetic mice in tubular epithelial cells as well as in high glucose-treated rat tubular epithelial cells NRK-52E. In cultured tubular epithelial cells, we show that LM8 (2.5-10 µM) or MyD88 siRNA attenuated high-concentration glucose-induced inflammatory and fibrogenic responses through inhibition of MyD88-TLR4 interaction and downstream NF-κB activation. Treatment with LM8 (5, 10 mg/kg, i.g.) significantly reduced renal inflammation and fibrosis and preserved renal function in both type 1 and type 2 diabetic mice. These renoprotective effects were associated with reduced MyD88-TLR4 complex formation, suppressed NF-κB signaling, and prevention of inflammatory factor expression. Collectively, our results show that hyperglycemia activates MyD88 signaling cascade to induce renal inflammation, fibrosis, and dysfunction. Pharmacological inhibition of MyD88 may be a therapeutic approach to mitigate diabetic nephropathy and the inhibitor LM8 could be a potential candidate for such therapy.

Design, synthesis and bioactivity evaluation of fisetin derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury.

Acute lung injury (ALI) refers to a common and life-threatening disease attributed to inflammation. However, effective drug treatments have been rare for ALI. Natural products have been considered as a vital source of drug discovery which indicates that it's a workable method to find new anti-inflammatory drugs in natural products. Inspired by the various biological activities of fisetin, we reported the design and synthesis of a series of fisetin derivatives which were also evaluated for their anti-inflammatory activities in J774A.1 macrophages. Most of the obtain derivatives could effectively inhibit the release of IL-6 and TNF-α in vitro experiments without cytotoxicity. The most promising compound 5b exhibited significant in vivo anti-inflammatory activity in the model of LPS-induced ALI in mice. On the whole, this study could provide novel candidates for the treatment of ALI.

Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment.

In this study, a series of pyrrolo [2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment were synthesized and their biological activity were tested. Most of the target compounds displayed moderate to excellent activity against one or more cancer cell lines and low activity against human normal cell LO2 in vitro. The most promising compound 51, of which the IC50 values were 0.66 µM, 0.38 µM and 0.44 µM against cell lines A549, Hela and MCF-7, shown more remarkable activity and better apoptosis effect than the positive control Cabozantinib. The structure-activity relationships (SARs) indicated that double-EWGs (such as R3 = 2-Cl-4-CF3) on the terminal phenyl rings was a key factor in improving the biological activity. In addition, the further research on compound 51 mainly included c-Met kinase activity and selectivity, concentration dependence, and molecular docking.

Myeloid Differentiation Primary Response Protein 88 (MyD88): The Central Hub of TLR/IL-1R Signaling.

Myeloid differentiation primary response protein 88 (MyD88) is a ubiquitously expressed cytoplasmic adaptor protein that plays a central role in the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. TLR/IL-1R pathways regulate the proliferation and differentiation of cells involved in the innate and adaptive immunity. Although the general TLR/IL-1R activation cascade is well understood, the molecular mechanisms involving MyD88 have only begun to surface in the past decade. In this review, we explore MyD88 structural biology, the role of posttranslational modifications (PTMs), and the recent developments in MyD88 inhibitor discovery and use. We also highlight the potential application of MyD88-targeted therapies in human diseases.

Development of 2-amino-4-phenylthiazole analogues to disrupt myeloid differentiation factor 88 and prevent inflammatory responses in acute lung injury.

Myeloid differentiation primary response protein 88 (MyD88), an essential adapter protein used by toll-like receptors (TLR), is a promising target molecule for the treatment of respiratory inflammatory diseases. Previous studies explored the activities of novel 2-amino-4-phenylthiazole analogue (6) in inflammation-induced cancer, and identified the analogue as an inhibitor of MyD88 toll/interleukin-1 receptor (TIR) homology domain dimerization. Here, we describe the synthesis of 47 new analogues by modifying different sites on this lead compound and assessed their anti-inflammatory activities in lipopolysaccharide-induced mouse primary peritoneal macrophages (MPMs). The most promising compound, 15d, was found to effectively interact with MyD88 protein and prevented formation of the MyD88 homodimeric complex. Furthermore, 15d showed in vivo anti-inflammatory activity in LPS-caused model of acute lung injury. This work provides new candidates as MyD88 inhibitors to combat inflammation diseases.

Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury.

Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.