Bioorganic Chemistry最新文献

Disruptor of telomeric silencing 1-like (DOT1L) is a key hub in histone lysine methyltransferase and an attractive therapeutic target for treating hematological malignancies including acute myeloid leukemia (AML). In this study, we report the design and synthesis of a new series of adenosine derivatives as DOT1L inhibitors by accommodating a basic linker piperidine-4-ylmethyl motif to respective aryl-urea/benzimidazole scaffolds. The anti-DOT1L enzyme activity analysis demonstrated that compounds 8, 12, and 13 strongly suppressed DOT1L activity with IC₅₀ values ranging from 0.125 to 0.408 µM among all the synthetics, and the structure–activity relationships were summarized. Moreover, compound 12 possessed relatively potent DOT1L inhibitory activity by significantly reduced histone H3 di-methylation at lysine 79 (H3K79me2) level in cells. Subsequently, all the synthetics were screened against various leukemia cell lines, indicating the DOT1L active adenosine derivatives exhibited low to moderate while compound 15 showed strong cellular inhibition despite its unsuccessful DOT1L inhibition. Therefore, acknowledging the distinctive potency of compound 15 against five different leukemia cell lines, including MLL-r (MV4-11) and non-MLL-r cell lines (HL-60, HH, K562, and KG-1), with IC₅₀ values in the 0.45 ∼ 1.66 μM range and its mode of action was explored. Furthermore, compound 15 hindered histone acetylation, induced remarkable DNA damage, and triggered apoptosis. Importantly, normal T lymphocytes only showed moderate response to compound 15. These findings provide a basis for future studies on its potential application against AML.

Iron is an essential micronutrient for almost every living organism, namely pathogenic bacteria. In an infection scenario, host-pathogen competitive relationships for the element are present and Fe withholding is a well known response of the host. Also, bacterial resistance is a major concern that can compromise public health and the WHO underlines an urgent need to search for new pharmaceutical ingredients or strategies to fight opportunistic bacteria. Iron metabolism, and in particular, deprivation is a strategy that currently constitutes another option to fight bacterial infection.

In this work we report the synthesis of a new hexadentate chelator with enhanced hydrophilicity (MRHT) and the improved synthesis of two other chelators. The affinity towards charged and non-charged phospholipid bilayers was evaluated for three hexadentate chelators: MRHT, CP256 and RH8b using NMR and EPR spectroscopies. The results revealed that these structures, bearing 3,4-HPO units have a high affinity towards the hydrophilic region of the phospholipid bilayer. From the three hexadentate chelators, MRHT stood out, especially for liposomes with a charged surface, suggesting that this molecule could more efficiently compete with natural siderophores, creating an iron gradient near bacteria organisms.

In the pursuit of novel antidiabetic agents, a series of isatin-thiazole derivatives (7a-7j) were synthesized and characterized using a range of spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using both in vitro and in vivo assays. The tested compounds 7a-7j demonstrated In vitro inhibitory potential against α-glucosidase, as indicated by their IC₅₀ values ranging from 28.47 to 46.61 µg/ml as compared to standard drug acarbose IC₅₀ value of 27.22 ± 2.30 µg/ml. Additionally, compounds 7d and 7i were chosen for in vivo evaluation of their antidiabetic efficacy in streptozotocin-induced diabetic Wistar rats. These compounds exhibited significant antidiabetic activity both in vitro and in vivo, compound 7d produces therapeutic effects compared to standard pioglitazone by decreasing glycaemia and triglyceride levels in diabetic animals. Furthermore, a molecular docking study was conducted to elucidate the binding interactions of the compounds within the α-glucosidase enzyme binding pocket (PDB ID 3A47) and stability was confirmed by dynamics simulation trajectories. Thus, from the above findings, it may demonstrate that isatin-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.

A series of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles (5-1 to 5-29) were developed and characterized. Most of compounds were found to be potent for inhibiting the production of NO in LPS-induced RAW264.7 cells, of which 3-(3-(4-chlorophenyl)-6-methoxy-2-(trifluoromethyl)-4H-chromen-4-yl)-1H-indole (5-25) was the most optimal (IC₅₀ = 4.82 ± 0.34 μΜ) and was capable of significantly suppressing the release of PGE₂. The inhibitory effect of 5-25 on human recombinant COX-2 (IC₅₀ = 51.7 ± 1.3 nM) was measured and molecular docking was performed, determining 5-25 as a COX-2 inhibitor. Additionally, the interaction between 5-25 and COX-2 was determined by the CETSA technique. Then, 5-25 inhibited the degradation of IκB, the phosphorylation and nuclear translocation of NF-κB p65, and the expression of COX-2 and iNOS. Moreover, it was verified that 5-25 exhibited efficacy in rodent models of inflammation and pain, encompassing the paw edema, cotton pellet-induced granuloma, acid-induced writhing, and adjuvant-induced arthritis models. Therefore, the mechanism of 5-25 may be to bind to COX-2 and exert anti-inflammatory and analgesic effects in vitro and in vivo by suppressing the NF-κB pathway. Encouragingly, in comparison with indomethacin, 5-25 exhibited a lower ulcerative potential in rats, as manifested by generating smaller areas and fewer ulcers, less inflammatory infiltration, a lower expression of MMP-9, and less apoptosis. In conclusion, 5-25 is a candidate drug with high activity and low ulcerogenic potential, and it deserves further research for the treatment of inflammation, pain, and other symptoms in which COX-2 plays a role in their pathogenesis.

The need for targeted pest control strategies has led to the development of juvenile hormone (JH) mimics that selectively disrupt the life cycles of harmful insect species. Present study focuses on the synthesis, characterization and evaluation of sulfonyl-acetohydrazide derivatives (H1-H8) as novel JH mimics on two different insect species, with an emphasis on their insect-specific action. The yellow fever mosquito, Aedes aegypti and cabbage leaf borer, Spodoptera litura, were selected for this investigation. Our results indicate that while these compounds exhibit negligible effects on the development of Aedes aegypti, they demonstrate a potent and specific action against Spodoptera litura. The sulfonyl-acetohydrazide derivatives induced significant developmental abnormalities and increased mortality rates in Spodoptera litura larvae, leading to a marked disruption in their life cycle. Additionally, Density Functional Theory methods were employed to elucidate the electronic structure and corelate the reactivity of the synthesized compounds with the insect growth regulating activity (IGR). The DNA-binding study of synthesized JH analogs has been carried out using UV–vis spectroscopy for toxicity assessment against biomolecule DNA. All the synthesized JH analogs (H1-H8) show IGR action and exhibit better reactivity and reduced toxicity as compared to the commercial in use IGR, pyriproxyfen.

The treatment of bladder cancer is limited by low drug efficacy and drug resistance. Hence, this study aimed to screen and identify potential drug precursors and investigate their mechanism of action. A set of camptothecin derivatives showing high anti-tumor potential was selected from early-stage research or literature and synthesized to construct a compound library. A total of 135 compounds were screened in T24 and J82 cells, revealing that FL118 significantly inhibited the proliferation of GC (gemcitabine + cisplatin)-sensitive/insensitive cells. FL118 exhibited excellent penetration and killing ability in organoids and three GC-insensitive patient-derived xenografts. Chemical proteomic and docking calculations were employed to identify binding proteins, indicating that FL118 can bind into H2A.X and its entwined DNA. The results of Cellular thermal shift assay and surface plasmon resonance (K_d = 3.77E-6) support the above findings. Fluorescence localization revealed widespread binding of FL118 within the cell nucleus. Furthermore, WB showed that FL118 increased cellular DNA damage, resulting in significant cell cycle inhibition. The binding of FL118 to H2A.X hindered the damage repair process, leading to apoptosis. Controllable adverse reactions were observed in mice treated with FL118. In conclusion, FL118 may be a superior anti-bladder cancer compound that acts as a molecular glue binding to both H2A.X and DNA. The resistance mediated by the DNA damage repair to DNA damage caused by GC regimen can be reversed by FL118. This distinct mechanism of FL118 has the potential to complement existing mainstream treatment approaches for bladder cancer.

Candida auris (C. auris) has caused notable outbreaks across the globe in last decade and emerged as a life-threatening human pathogenic fungus. Despite significant advances in antifungal research, the drug resistance mechanisms in C. auris still remain elusive. Under such pressing circumstances, research on identification of new antifungal compounds is of immense interest. Thus, our studies aimed at identifying novel drug candidates and elucidate their biological targets in C. auris. After screening of several series of synthetic and hemisynthetic compounds from JUNIA chemical library, compounds C4 (butyl 2-(4-chlorophenyl)hydrazine-1-carboxylate) and C13 (phenyl 2-(4-chlorophenyl) hydrazine-1-carboxylate), belonging to the carbazate series, were identified to display considerable antifungal activities against C. auris as well as its fluconazole resistant isolates. Elucidation of biological targets revealed that C4 and C13 lead to changes in polysaccharide composition of the cell wall and disrupt vacuole homeostasis. Mechanistic insights further unravelled inhibited efflux pump activities of ATP binding cassette transporters and depleted ergosterol content. Additionally, C4 and C13 cause mitochondrial dysfunction and confer oxidative stress. Furthermore, both C4 and C13 impair biofilm formation in C. auris. The in vivo efficacy of C4 and C13 were demonstrated in Caenorhabditis elegans model after C. auris infection showing reduced mortality of the nematodes. Together, promising antifungal properties were observed for C4 and C13 against C. auris that warrant further investigations. To summarise, collected data pave the way for the design and development of future first-in-class antifungal drugs.

Resistance to proteasome inhibitors like Bortezomib is a major challenge in the treatment of multiple myeloma (MM). Proteolysis targeting chimeras (PROTACs), an emerging therapeutic approach that induces selective degradation of target proteins, offer a promising solution to overcome drug resistance. In this study, we designed and synthesized novel small-molecule PROTACs that induce 20S proteasome subunit β5 degradation as a strategy to overcome Bortezomib resistance. These 20S proteasome subunit β5 PROTACs demonstrated considerable binding affinity to 20S proteasome subunit β5 and cereblon (CRBN), effectively induced 20S proteasome subunit β5 degradation, and exhibited potent antiproliferative activity against a panel of cancer cell lines. Notably, PROTACs 12f and 14 displayed robust antitumor effects against both the pharyngeal carcinoma cell line FaDu and the Bortezomib-resistant MM cell line KM3/BTZ in vitro and in vivo with excellent safety profiles. Taken together, our findings highlight the potential of PROTACs 12f and 14 as novel 20S proteasome subunit β5-degrading agents for the treatment of pharyngeal carcinoma and overcoming Bortezomib resistance in MM.

Uncontrolled hyperglycemia leads to increased oxidative stress, chronic inflammation, and insulin resistance, rendering diabetes management harder to accomplish. To tackle these myriads of challenges, researchers strive to explore innovative multifaceted treatment strategies, including inhibiting carbohydrate hydrolases. Herein, we report alkyl-ether EGCG derivatives as potent α-amylase and α-glucosidase inhibitors that could simultaneously ameliorate oxidative stress and inflammation. 4″-C₁₈ EGCG, the most promising compound, showed multifold improvement in glycaemic management compared to acarbose, with 230-fold greater inhibition (competitive) of α-glucosidase (IC₅₀ 0.81 µM) and 3-fold better inhibition of α-amylase (IC₅₀ 3.74 µM). All derivatives showed stronger antioxidant activity (IC₅₀ 6.16–15.76 µM) than vitamin C, while acarbose showed none. 4″-C₁₈ EGCG also downregulated pro-inflammatory cytokines and showed no significant cytotoxicity up to 50 µM in primary human peripheral blood mononuclear cells (PBMC), non-cancerous cell line, 3T3-L1 and HEK 293. The in silico binding affinity analysis of 4″-C₁₈ EGCG with α-amylase and α-glucosidase was found to exhibit a good extent of interaction as compared to acarbose. In comparison to EGCG, 4″-C_n EGCG derivatives were found to remain stable in the physiological conditions even after 24 h. Together, the reported molecules demonstrated multifaceted antidiabetic potential inhibiting carbohydrate hydrolases, reducing oxidative stress, and inflammation, which are known to aggravate diabetes.