A Unique Topoisomerase II Inhibitor with Dose-Affected Anticancer Mechanisms and Less Cardiotoxicity

Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Previously, we have carried out several rounds of structural optimizations on our in-house topo II inhibitor E17, which was shown to have superior anticancer activity and less risk of multidrug resistance (MDR). Among the newly developed acridone derivatives, 6h displayed significant anticancer efficacy with unique mechanisms of action. At low concentrations, it arrested cancer cell cycles and triggered cell apoptosis, which is similar to the action of the well-known topo II inhibitor VP16. By contrast, 6h showed significant and long-term anti-proliferative activity at relatively high concentrations, with negligible influence on apoptosis. In addition, 6h exhibited no serious cardiotoxicity compared to doxorubicin (DOXO), a widely used topo II-targeting antineoplastic drug in clinic, but with damaging myocardial side effects. Collectively, our present work has supported the therapeutic value of 6h as a promising chemotherapy for cancers.

Microwave-Assisted Regioselective Synthesis and 2D-NMR Studies of New 1,2,3-Triazole Compounds Derived from Acridone

A simple and mild protocol towards the synthesis of new 1,2,3-triazole compounds derived from acridone has been developed via regiospecific 1,3-dipolar cycloaddition reaction between 10-(prop-2-yn-1-yl)acridone derivatives and aromatic azides using CuI as a catalyst. The cycloaddition reaction has been performed using conventional as well as microwave-assisted methods. Microwave-assisted synthesis caused a significant reduction in the reaction times and improvement in the yields of all the synthesized compounds compared with the conventional method. The structure of the 1,4-disubstituted 1,2,3-triazoles has been elucidated by IR, HRMS, 1H-NMR, 13C-NMR, and 2D NMR (1H-13C HMBC, 1H-1H COSY, and 1H-1H NOESY) spectroscopies.

Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma

Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma.

Access to fused π-extended acridone derivatives through a regioselective oxidative demethylation

The oxidative demethylation of ortho-dimethoxyacridone with ceric ammonium nitrate (CAN) regioselectively furnished an ortho-quinone leaving a methoxyl unreacted, which further condensed with aromatic ortho-diamines to afford angularly fused π-extended acridone...

One-pot green synthesis of acridine alkaloid derivatives and screening of in vitro anticancer activity against Cdc25b and SHP1

Aims: To develop of anticancer active pharmaceutical intermediates. Background: Acridone derivatives possesses wide range of pharmacological activities:1) intercalate DNA 2) form covalent bond with DNA. Objective: To Screening of in vitro anticancer activity against Cdc25b and SHP1 of new acridone derivatives and preliminary study on structure-activity relationship. Materials and Methods: Synthesis of new acridone derivatives and in vitro evaluation of their anticancer activity on Cdc25b and SHP1. Natural products that contain acridine structures, such as cystodytin A and acronycine, are isolated from certain marine (tunicates & ascidians, sponges, sea anemones) and plant (bark of Australian scrub ash tree) species. Herein, we report the efficient one-pot green synthesis of twelve novel 3,4-dihydro-1 (2H) acridone derivatives, using montmorillonite K10 as the catalyst and iron/citric acid in water. Also, their inhibitory activity against Cdc25B and SHP1 is examined, in which specific derivatives show enhanced inhibitory activity compared to others. Results and Discussion: Starting from 2-nitrobenzaldehyde derivatives and 1, 3-cyclohexanedione derivatives, twelve new acridone derivatives were prepared and exhibited substantial anticancer activity against Cdc25b and SHP1 cells. Conclusion: Preliminary studies of the structure-activity relationship have shown the influence of the structural parameters and, in particular, the nature of the substituent on aromatic ring structure and cyclohexanone. Other: Further study on structure-activity relationship.

Synthesis and Application in Cell Imaging of Acridone Derivatives

Tricyclic acridone derivatives have been extensively developed as antimicrobial, antimalarial, and antitumor drugs due to their broad spectrum of drug design and biological activity. In this study, we developed a surfactant-like acridone scaffold that contained two vinylpyridines and a dodecyl pyridine chain. The acridone scaffold decorated the dodecyl pyridine chain by N-bromosuccinimide reagent. The surfactant-like core scaffold incorporated with 4-vinylpyridines at the 2- and 7-positions via a Heck coupling reaction. Subsequently, the acridone derivatives were methylated onto these pyridine groups. Here we developed two similar acridone derivatives, MedAcd12C and MedAcd12P. The MedAcd12C incorporated two pyridine groups, and MedAcd12P incorporated three pyridine groups. MedAcd12C and MedAcd12P have two identical vinylpyridines and the different anchor tails at the N10 position. Their physicochemical properties, cell compatibility, and photoluminescence were demonstrated. Although both compounds have no fluorescence emission in water solution, MedAcd12P and MedAcd12C significantly appeared with orange light emission in the cellular imaging. We suggested that the surfactant-like scaffold promoted the drugs’ self-assembly and caused the aggregation-induced emission (AIE) after cellular uptake. This innovative design endowed acridone derivatives with an AIE and traceability for cell imaging.

Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand–protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from − 8.1394 to − 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.