Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

• Published in: ChemMedChem 2018-09, Vol.13 (18), p.1909-1922
• Main Authors: Tokala, Ramya, Thatikonda, Sowjanya, Vanteddu, Usha Sree, Sana, Sravani, Godugu, Chandraiah, Shankaraiah, Nagula
• Format: Article
• Language: English
• Subjects: Acridine orange; Actin; Annexin V; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Aromatic compounds; Bax protein; Cancer; Carbolines - chemistry; Carbolines - pharmacology; Caspase; Cell cycle; Cell Proliferation - drug effects; Cells, Cultured; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - pharmacology; DNA biosynthesis; DNA intercalation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Ethidium bromide; Flow cytometry; G1 phase; heterocycles; Humans; Hybrids; Lungs; Membrane Potential, Mitochondrial - drug effects; Methylene; Molecular docking; Molecular Structure; Oxindoles - chemistry; Oxindoles - pharmacology; Poly(ADP-ribose) polymerase; Proteins; Structure-Activity Relationship; Toxicity; Tumor cell lines; Viscosity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800402

A new series of (E)‐3‐[(1‐aryl‐9H‐pyrido[3,4‐b]indol‐3‐yl)methylene]indolin‐2‐one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT‐15, HCT‐116, A549, NCI‐H460, and MCF‐7, including HFL. Among the tested compounds, (E)‐1‐benzyl‐5‐bromo‐3‐{[1‐(2,5‐dimethoxyphenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl]methylene}indolin‐2‐one (10 s) showed potent cytotoxicity against HCT‐15 cancer cells with an IC50 value of 1.43±0.26 μm and a GI50 value of 0.89±0.06 μm. Notably, induction of apoptosis by 10 s on the HCT‐15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V‐FITC/PI, DCFDA, and JC‐1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT‐15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT‐15 cancer cells led to decreased expression of anti‐apoptotic Bcl‐2 and increased protein expression of both pro‐apoptotic Bax and caspase‐3, ‐8, and ‐9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT‐15 cancer cells by 10 s in a dose‐dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular‐docking studies showed that compound 10 s has typical intercalation with DNA. Take a pop at it: A series of β‐carboline‐linked oxindole derivatives are synthesized by Knoevenagel condensation. These new compounds are evaluated for their in vitro cytotoxic activity and DNA intercalation. Most compounds show cytotoxic potential at a concentration less than 50 μm. Overall, these new hybrids have the potential to be developed as lead molecules, and suitable structural modifications may result in promising anticancer agents.