A series of benzimidazo[2,1-a]isoquinolines with carboxamide side chains at the 1-, 6-, 9- and 11-positions were prepared, in order to study the biological effects of varying the position of the side chain in this tetracyclic series. The 6-, 9- and 11-analogues were obtained by modifications to published chemistry. The 1-carboxamide analogue was obtained via a one-pot isocoumarin/isoquinolone conversion of 3-methylisocoumarin-8-carboxylic acid with o-phenylenediamine in buffered aqueous acid, which gave the required 1-acid. The compounds were evaluated in a panel of cell lines in culture. The 6-carboxamides, where the side chain is attached to one of the central rings, were not active, but the 1- and 11-carboxamides, where the side chain is attached to one of the terminal rings off the chromophore short axis, were reasonably cytotoxic (IC50s < 1 microM). Overall, the structure-activity relationships are broadly in line with those seen with other tri- and tetracyclic carboxamides, and are consistent with recent crystal structure studies of acridine-4-carboxamides bound to DNA. The most potent 1-carboxamide was highly active in vivo against s.c. colon 38 tumours in mice, providing a growth delay of 12 days.
Download full-text PDF |
Source |
|---|
Publication Analysis
Top Keywords
Similar Publications
Small molecules that targeting p53 Y220C protein: mechanisms, structures, and clinical advances in anti-tumor therapy.
Mol Divers
January 2025
School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, People's Republic of China.
The p53 protein is regarded as the "Guardian of the Genome," but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets.
View Article and Find Full Text PDFCryo-EM reconstruction of yeast ADP-actin filament at 2.5 Å resolution. A comparison with vertebrate F-actin.
Structure
January 2025
Molecular Microbiology, School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK. Electronic address:
The core component of the actin cytoskeleton is the globular protein G-actin, which reversibly polymerizes into filaments (F-actin). Budding yeast possesses a single actin that shares 87%-89% sequence identity with vertebrate actin isoforms. Previous structural studies indicate very close overlap of main-chain backbones.
View Article and Find Full Text PDFDiscovery of novel tris-1,2,3-triazole-based hybrids as VEGFR2 inhibitors with potent anti-proliferative and cytotoxicity through apoptosis induction.
Bioorg Chem
January 2025
Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002 Saudi Arabia. Electronic address:
The discovery of novel anti-cancer drugs motivated us to synthesize a new series of triple 1,2,3-triazole-based arm scaffolds featuring distinct un functionalized alkyl and/or aryl side chains with possible anti-cancer action using the click chemistry approach under both conventional and green microwave irradiation (MWI) methods. The Cu(I) catalyzed cycloaddition reaction of targeted tris-alkyne with un functionalized aliphatic and aromatic azides has been adopted as an efficient approach for synthesizing the desired click adducts. Microwave irradiation improved the synthetic processes, resulting in higher yields and faster reaction times.
View Article and Find Full Text PDFInsight into the Structure of Antifungal Cyrmenins: Conformational Studies of Unique Dehydroamino Acid, O-Methyldehydroserine.
Int J Mol Sci
January 2025
Faculty of Chemistry and Pharmacy, University of Opole, Oleska 48, 45-052 Opole, Poland.
O-Methyldehydroserine, ΔSer(Me), is a non-standard α,β-dehydroamino acid, which occurs naturally in Cyrmenins with potential pharmaceutical application. The C-terminal part and the side chain of the ΔSer(Me) residue constitute the β-methoxyacrylate unit, responsible for antifungal activity of Cyrmenins. The short model, Ac-ΔSer(Me)-OMe, was analyzed considering the geometrical isomer Z () and E ().
View Article and Find Full Text PDFMapping O- and N-Glycosylation in Transmembrane and Interface Regions of Proteins: Insights from a Database Search Study.
Int J Mol Sci
January 2025
Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Splaiul Independenței Str., 050095 Bucharest, Romania.
Glycosylation is a critical post-translational modification that influences protein folding, stability and function. While extensively studied in extracellular and intracellular regions, glycosylation within transmembrane (TM) regions and at membrane interfaces remains poorly understood. This study aimed to map O- and N-glycosylation sites in these regions using a comprehensive database search and structural validation where possible.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!