Synthesis and Anticancer Evaluation of Sulfur Containing 9-anilinoacridines

Abstract

Background: DNA topoisomerases are a class of enzymes that play a critical role in fundamental biological processes of replication, transcription, recombination, repair and chromatin remodeling. Amsacrine (m-AMSA), the best-known compound of 9-anilinoacridines series was one of the first DNA-intercalating agents to be considered as a Topoisomerase II inhibitor. Objective: A series of sulfur containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer activity. Methods: Cell viability was assessed by the MTT assay. The topoisomerase II inhibitory assay was performed using the Human topoisomerase II Assay kit and flow cytometry was used to evaluate the effects on cell cycle of K562 cells. Molecular docking was performed using Schrödinger Maestro program. Results: Compound 36 was found to be the most cytotoxic of the sulfide series against SW620, K562, and MCF-7. The limited SAR suggested the importance of the methansulfonamidoacetamide side chain functionality, the lipophilicity and relative metabolic stability of 36 in contributing to the cytotoxicity. Topoisomerase II α inhibitory activity appeared to be involved in the cytotoxicity of 36 through inhibition of decatenation of kinetoplast DNA (kDNA) in a concentration dependent manner. Cell cycle analysis further showed the Topo II inhibition through accumulation of K562 cells in G2/M phase of cell cycle. Docking of 36 into the Topo II α-DNA complex suggested that it may be an allosteric inhibitor of Topo II α. Conclusion: Compound 36 exhibits anticancer activity by inhibiting topoisomerase II and it could further be evaluated in in vivo models.

MG53 inhibits cellular proliferation and tumor progression in colorectal carcinoma

“…The sensitive and drug-resistant cells were trypsinized, seeded into 96 well plates and incubated for 24 h. The next day, cells were treated with 20 μl of rhMG53 at varying concentrations (0-100 μM). To assess the chemosensitizing effects of rhMG53, different concentrations of doxorubicin were added after pre-incubation with rhMG53 or verapamil for 2 h. After 68 h of treatment, MTT dye (4 mg/ml) was added and the plates were further incubated for 4 h. Subsequently, absorbance was determined at 570 nm by Opsys microplate reader (Dynex Technologies, Chantilly, VA) [36][37][38].…”