ABSTRACT
In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Copper/chemistry , Nitriles/chemistry , Quinolones/chemical synthesis , Quinolones/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Animals , Catalysis , DNA Topoisomerases, Type I/chemistry , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , Male , Mice , Mice, Nude , Models, Molecular , Molecular Docking Simulation , Quinolones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Topoisomerase I Inhibitors/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
A series of C-6 or C-3' alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline 5e was a very potent EGFR kinase inhibitor with an IC(50) of 14 nM.
Subject(s)
Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Aniline Compounds/chemistry , Antineoplastic Agents/chemistry , Computer Simulation , Drug Screening Assays, Antitumor , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human cancer cells and an IC(50) value in the nanomolar range. The IC(50) values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 mumol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G(0)-G(1) and G(2)-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036-induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036-mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036-induced DNA damage activated ataxia telangiectasia-mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21(WAF1) in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036-induced cell death was associated with DNA damage-mediated induction of ataxia telangiectasia-mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/metabolism , DNA Damage , DNA-Binding Proteins/metabolism , Heterocyclic Compounds, 3-Ring/pharmacology , Organoselenium Compounds/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrroles/pharmacology , Tumor Suppressor Proteins/metabolism , Animals , Apoptosis/drug effects , Ataxia Telangiectasia Mutated Proteins , Carcinoma, Renal Cell/pathology , DNA Adducts/drug effects , Drug Resistance, Neoplasm/drug effects , Enzyme Activation/drug effects , Flow Cytometry , HT29 Cells , HeLa Cells , Humans , Male , Mice , Mice, Nude , Protein Kinase C/metabolism , Protein Kinase C beta , Protein Kinase C-alpha/metabolism , Reactive Oxygen Species/metabolism , S Phase/drug effects , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
N-Substituted isatin derivatives were prepared from the reaction of isatin and various bromides via two steps. Bioactivity assay results (in vitro tests) demonstrated that some of these compounds are potent and selective inhibitors against SARS coronavirus 3CL protease with IC50 values ranging from 0.95 to 17.50 microM. Additionally, isatin 4o exhibited more potent inhibition for SARS coronavirus protease than for other proteases including papain, chymotrypsin, and trypsin.