TNFα and related inflammatory factor antibody drugs have been orchestrated for the treatment of inflammatory bowel disease (IBD). However, antibody drugs elicited inevitable disadvantages and small molecule drugs are in an urgent need. Herein, we described the discovery, design, synthesis, and SAR studies from furanone glycoside compound (hit) isolated from to (lead).
View Article and Find Full Text PDFIn view of the serious adverse reactions and clinical toxicity of first line therapy 5-fluorouracil and lack of small molecule therapeutics in colorectal cancer chemotherapy, a series of natural scaffold-based 3-arylindanone derivatives (9a-q) were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine site. The most potent colchicine binding site inhibitor (CBSI), , exhibited 14-38 times more dominant anti-proliferative activity against three colon cancer cell lines than 5-fluorouracil. Particularly, showed higher selectivity against human normal cells compared with 5-fluorouracil and colchicine, and displayed negligible cardiotoxicity through hERG assessment.
View Article and Find Full Text PDFTumor necrosis factor α (TNF-α) has been demonstrated to be a therapeutic target for autoimmune diseases. However, this biological therapy exhibits some inevitable disadvantages, such as risk of infection. Thus, small-molecule alternatives by targeting TNF-α production signaling pathway are still in demand.
View Article and Find Full Text PDFIschemic stroke is a complex systemic disease characterized by high morbidity, disability, and mortality. The activation of the presynaptic adenosine A and A receptors modifies a variety of brain insults from excitotoxicity to stroke. Therefore, the discovery of dual A/A adenosine receptor (AR)-targeting therapeutic compounds could be a strategy for the treatment of ischemic stroke.
View Article and Find Full Text PDFObjective: Although benzene is a confirmed environmental carcinogen, the mechanism of its carcinogenicity remains largely unclear. The suggested oncogene, miR-221, is elevated and plays important roles in various tumors, but its role in benzene-induced carcinogenesis remains unknown.
Methods: In the present study, we constructed hydroquinone (HQ, a representative metabolite of benzene with biological activity)-transformed malignant cell line (16HBE-t) and analyzed the level of miR-221 in it with qRT-PCR.
The discovery of IDO1 and HDAC1 dual inhibitors may provide a novel strategy for cancer treatment by taking advantages of both immunotherapeutic and epigenetic drugs. In this paper, saprorthoquinone () and 13 of its analogues from Hance were investigated for their SAR against IDO1, the results demonstrated the -quinone was a key pharmacophore. Then a series of IDO1 and HDAC dual inhibitors connected by appropriate linkers were designed, synthesized, and evaluated from the hit compound saprorthoquinone ().
View Article and Find Full Text PDFColorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death around the world. The current treatments of CRC exhibited high occurrence rate of side effects. Docetaxel (DTX), an important drug widely used in cancer chemotherapy, showed serious toxicity in CRC.
View Article and Find Full Text PDFAn efficient approach to obtain functionalized rhodanines was developed through a base-assisted one-pot coupling and continuous cyclization of a primary amine, carbon disulfide, and methyl (2-chloroacetyl)carbamate. This conversion tolerates a broad range of functional groups and can be used to scale the preparation of -substituted rhodanines in excellent yields.
View Article and Find Full Text PDFThe emergence and worldwide prevalence of New Delhi metallo-β-lactamase 1 (NDM-1) expressing Gram-negative bacteria with resistance against most β-lactam antibiotics pose a serious threat to human health. However, no NDM-1 inhibitors are clinically approved at present. Herein, based on the lead compound captopril, a series of compounds were designed, synthesized, and evaluated for NDM-1 inhibitory activities.
View Article and Find Full Text PDFAn efficient and mild zinc-mediated decarboxylative alkylation of gem-difluoroalkenes with N-hydroxyphthalimide (NHP) esters, to give monofluoroalkenes in moderate to excellent yields with high Z-selectivity is reported. The reaction tolerates a broad range of functional groups and can be easily scaled up, which thus may pave the way for its further applications in medicinal chemistry and materials science.
View Article and Find Full Text PDFThe synthesis of enantiomerically pure 3-aryl substituted indanones is developed using an enantioselective sulfoxide-based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para-tolyl sulfoxide-containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)-isopaucifloral F, (+)-quadrangularin A, and (+)-pallidol.
View Article and Find Full Text PDF3FDT, an analog of docetaxel with a blocked metabolism at its 3'-N-tert-butyloxyl group with three fluorine atoms, exhibits more potent cytotoxicity than docetaxel both with human cancer cell line SK-OV-3 in vitro and with human non-small cell lung cancer A549 xenografts in vivo. To further develop pharmacodynamically and pharmacokinetically favorable fluorinated docetaxel analogs as anticancer agents, we chose 3FDT as the model compound to identify the metabolites of 3FDT in RLMs, rats, and HLMs and the cytochrome P450 enzymes responsible for the metabolism of 3FDT. Our findings indicated that the major metabolic site switched from the C3' appendage for docetaxel to the taxane ring for 3FDT, and the main metabolizing P450 enzymes switched from CYP3A to CYP3A4 and CYP2E1.
View Article and Find Full Text PDFTo develop novel anti-inflammatory agents with improved pharmaceutical profiles, twenty-eight novel sesquistilbene indanone analogues were synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Among these compounds, compound 11k was found to be one of the most potent analogues in inhibiting NO production in LPS-stimulated RAW264.
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