ABSTRACT
Necroptosis is reported to play a critical role in contributing to a variety of human pathologies. The benzoxazepinone GSK'772 is a potent necroptosis inhibitor optimized using a hit from a DNA-encoded library, which is currently in phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis. In the present study, the bioisosterism strategy was applied to replace the amide and benzene ring of GSK'772 based on the co-crystal structure of GSK'772 with its binding target RIPK1. As a result, the novel thio-benzoxazepinones exhibited higher anti-necroptosis activity in a human HT-29 cell necroptosis model. The effect on anti-necroptosis activity by the chirality was significantly reduced in the thio-benzoxazepinones, which was explained by the ligand conformation calculation. Among these analogues, compound 11 (S) and 12 (R) specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.8 and 22.6 nM. They blocked necrosome formation by inhibiting the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. Collectively, the highly potent thio-benzoxazepinones represent promising lead structures for further development of necroptosis-related diseases.
Subject(s)
Drug Design , Necroptosis/drug effects , Oxazepines/pharmacology , Sulfhydryl Compounds/pharmacology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Oxazepines/chemical synthesis , Oxazepines/chemistry , Structure-Activity Relationship , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistry , Tumor Cells, CulturedABSTRACT
An efficient continuous flow sequential synthesis of diaryl ketones was achieved by coupling of aryl Grignard reagents with acyl chlorides in the bio-derived "green" solvent 2-methyltetrahydrofuran (2-MeTHF) under mild reaction conditions (ambient temperature, 1 hour), allowing a safe and on-demand generation of 2-(3-benzoylphenyl)propionitrile with a productivity of 3.16 g hour-1.
ABSTRACT
We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg(-1).
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Caffeic Acids/pharmacology , Coumaric Acids/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis/drug effects , Caffeic Acids/chemical synthesis , Caffeic Acids/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coumaric Acids/chemical synthesis , Coumaric Acids/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , HeLa Cells , Hep G2 Cells , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
In the title compound, C(23)H(17)Cl(2)F(3)N(2)O(3), the mol-ecular conformation is significantly strained: atoms O, C(=O) and C attached to the central benzene ring deviate from its plane by 0.118â (2), 0.139â (2) and 0.174â (2)â Å, respectively. In the crystal, weak C-Hâ¯O inter-actions link the mol-ecules into chains along [110]. The crystal packing exhibits short inter-molecular Clâ¯F [2.9840â (16)â Å] and Clâ¯Cl [3.2957â (12)â Å] contacts.
ABSTRACT
In the title mol-ecule, C(28)H(44)O, the two six-membered rings have a chair conformation and the two five-membered rings haveenvelope conformations. The crystal packing exhibits no short inter-molecular contacts. The absolute configuration was assigned to correspond with that of the known chiral centres in a precursor molecule, which remained unchanged during the synthesis of the title compound.
ABSTRACT
In the title mol-ecule, C(28)H(44)O, two six-membered rings have regular chair conformations, while the six-membered ring containing the C=C double bond exhibits a distorted chair conformation. The five-membered ring adopts an envelope conformation. In the crystal, weak inter-molecular C-Hâ¯O inter-actions link mol-ecules into chains along the b axis. The absolute configuration was assigned to correspond with that of the known chiral centres in a precursor mol-ecule.
ABSTRACT
A series of caffeic acid amide derivatives 2-cyano-(3-substituted phenyl)acrylamides were synthesized via Knoevenogal condensation of substituted benzaldehydes with cyanoacetamides. The structure of compound 1f was determined as E-isomer by X-ray diffractive analysis. The biological screening tests in vitro showed that compound 1b has obvious inhibitory activities against human gastric carcinoma cell line BGC-823, human nasopharyngeal carcinoma cell line KB and human hepatoma cell line BEL-7402 with IC(50) values of 5.6 microg/mL, 13.1 microg/mL and 12.5 microg/mL, respectively. Some preliminary structure-activity relationships (SAR) were also proposed which may provide a direction for further study.
Subject(s)
Acrylamides/chemical synthesis , Acrylamides/pharmacology , Caffeic Acids/chemistry , Nitriles/chemical synthesis , Nitriles/pharmacology , Acrylamides/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Nitriles/chemistry , Structure-Activity RelationshipABSTRACT
Forty caffeate analogues were synthesized via a convenient method starting from vanillin with moderate to good yields. The testing of biological activity of these compounds against HIV-1 integrase indicates that four compounds: bornyl caffeate, bornyl 2-nitrocaffeate, 5-nitrocaffeic acid and 5-nitrocaffeic acid phenethyl ester (5-nitroCAPE) possess a good HIV integrase inhibitory activity, IC(50) 19.9, 26.8, 25.0 and 13.5 microM , respectively. Twelve caffeate analogues were tested by MTT assay on growth of human hepatocellular carcinoma BEL-7404, human breast MCF-7 adenocarcinoma, human lung A549 adenocarcinoma and human gastric cancer BCG823 cell lines, respectively. And the best result is IC(50) 5.5 microM for CAPE against BEL-7404.
Subject(s)
Caffeic Acids/chemistry , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Biotin/chemistry , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme-Linked Immunosorbent Assay , HIV Integrase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical , Structure-Activity RelationshipABSTRACT
Twenty-six thiosemicarbazones (III-1-III-26) were synthesized via three steps starting from hydrazine hydrate and carbon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that compounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC50 of compound III-16 against SGC-7901 reaches to 0.032 microM.
