Pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents against human neuroblastoma

We report herein the evaluation of various pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multi-component Groebke–Blackburn–Bienaymé reaction to yield various pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer potential of these pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amine derivatives in the human neuroblastoma cell line, the cytotoxicity was examined using the WST-1 assay after 72 h drug exposure. A clonogenic assay was used to assess the ability of treated cells to prolif-erate and form colonies. Protein expressions (Bax, bcl-2, cleaved caspase-3, cleaved PARP-1) were analyzed using Western blotting. The colony number decrease in cells was 50.54%, 37.88% and 27.12% following exposure to compounds 2d, 2g and 4b respectively at 10 µM. We also show that treating the neuroblastoma cell line with these compounds resulted in a significant alteration in caspase-3 and PARP-1 cleavage

Search for small molecule inhibitors of the DNA repair enzymes hNEIL1 and hOGG1, potential therapeutic targets in cancer

National audienc

Discovery and characterization of inhibitors of the DNA repair enzymes hNEIL1 and hOGG1, pertinent therapeutic targets for cancer therapy

International audienc

Metal Free Formation of Various 3‑Iodo‑1<i>H</i>‑pyrrolo[3′,2′:4,5]imidazo-[1,2‑<i>a</i>]pyridines and [1,2‑<i>b</i>]Pyridazines and Their Further Functionalization

3-iodo-1<i>H</i>-pyrrolo­[3′,2′:4,5]­imidazo-[1,2-<i>a</i>]­pyridines and [1,2-<i>b</i>]­pyridazines were prepared following Groebke–Blackburn–Bienaymé MCR combined with I₂-promoted electrophilic cyclization. The flexibility of the method enables the introduction of diversity in the 2, 5, 6, and 7 positions on the resulting scaffold using commercially available starting materials. Furthermore, subsequent palladium-catalyzed reactions were successfully achieved using our iodinated derivatives

Alkyne-Azide Click Chemistry Mediated Carbanucleosides Synthesis

International audienceHitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxy carbanucleosides were synthesized based on a "click approach." Various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and cellular toxicities were evaluated on vaccinia virus. None of the synthesized compounds exhibited a significant antiviral activity

Alkyne-Azide Click Chemistry Mediated Carbanucleosides Synthesis

Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxycarbanucleosides were synthesized based on a &quot;click approach.&quot; Various alkynes were introduced on a key azido intermediate by the &quot;click&quot; 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and cellular toxicities were evaluated on vaccinia virus. None of the synthesized compounds exhibited a significant antiviral activity.</p

Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in {NMDA}-Induced Excitotoxicity

N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole derivatives of tomentosin were prepared and tested for their protective and anti-apoptotic effects in NMDA-induced excitotoxicity. Amino-tomentosin derivatives were generated through a diastereoselective conjugate addition of several secondary amines to the α-methylene-γ-butyrolactone function, while the 1,2,3-triazolo-tomentosin was prepared by a regioselective Michael-type addition carried out in the presence of trimethylsilyl azide (TMSN3) and the α-methylene-γ-lactone function. The intermediate key thus obtained underwent 1,3-dipolar Huisgen cycloaddition using a wide range of terminal alkynes. The possible effects of the derivatives on cell viability and free-radical production following NMDA treatment were measured by Water-Soluble Tetrazolium Salts (WST-1) and Dichlorofluorescein Diacetate (DCF-DA) assays, respectively. The alterations in apoptosis-related proteins were examined by Western blot technique. Our study provides evidence that synthesized triazolo- and amino-tomentosin derivatives show neuroprotective effects by increasing cellular viability, decreasing ROS production, and increasing the Bcl-2/Bax ratio in NMDA-induced excitotoxicity. The findings highlight particularly 2e, 2g, and 6d as potential regulators and neuroprotective agents in NMDA overactivation