Abstract 3834: Antiproliferative activity of substituted chromone-2-carboxamides on MDA-MB-231 cells and their 3D pharmacophore models (2023)

Abstract After lung cancer, breast cancer is the second leading cause of cancer death in women in the United States, accounting for 12.5 % of all new cancer cases globally. Triple-negative breast cancer (TNBC) remains the hardest breast cancer and is difficult to treat. The current treatment option for TNBC is the surgical removal of the tumor, followed by chemotherapy. However, patients with advanced diseases respond poorly to current treatments. Therefore, discovering more effective and less toxic small drug molecules with a unique mechanism of action is one of the top priorities in drug discovery programs. Chromones have a benzo-pyrone skeleton and display interesting pharmacological activities, such as anti-cancer, anti-HIV, antiviral and anti-inflammatory, with low toxicity. In continuation of our current research work, we report the design and synthesis of substituted chromone-2-carboxamides by attaching substituted phenyl, tetrahydropyridine, and tetrahydroisoquinoline groups as anti-breast cancer agents. The starting material, substituted chromone-2-carbonyl chloride, was obtained by the acylation reaction of corresponding carboxylic acids using phosphorous pentachloride in dry cyclohexane. An equimolar amount of acyl chloride was slowly added to a stirred solution of corresponding substituted N-amino salt in dry THF in the presence of triethyl amine and refluxed at 70 °C that led to the formation of the ylides. The ylides were reduced using sodium borohydride to yield the desired substituted chromone-2-carboxamides in moderate to good yields. The synthesized compounds were characterized by NMR and elemental analysis. These compounds were evaluated for their cytotoxic effects on MBA-MB-231 ER-ve breast cancer cell lines using a Synergy HTX multi-mode reader (Bio-Tek, Winooski, VT, USA) with excitation/emission wavelength settings at 550/580. Compound MG-KKR-5-140A showed the most potent cytotoxicity with an IC50 value of 0.82 µg/mL on the MDA-MB-231 cell line. In-silico pharmacophore hypotheses were generated using GALAHAD and PHASE, and the best models with probable bioactive conformation(s) for these compounds were proposed. These confirmations and the alignments of the molecular structures give us an insight into designing compounds with better biological activity. This research was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number U54 MD007582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Suresh Eyunni, Elizabeth Mazzio, Karam F. A. Soliman. Antiproliferative activity of substituted chromone-2-carboxamides on MDA-MB-231 cells and their 3D pharmacophore models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3834.