Natural product-inspired synthesis of coumarin–chalcone hybrids as potential anti-breast cancer agents

Abstract

Twelve novel neo-tanshinlactone–chalcone hybrid molecules were constructed through a versatile methodology involving the Horner–Wadsworth–Emmons (HWE) olefination of 4-formyl-2H-benzo [h]chromen-2-ones and phosphonic acid diethyl esters, as the key step, and evaluated for anticancer activity against a series of four breast cancers and their related cell lines, viz. MCF-7 (ER + ve), MDA-MB-231 (ER-ve), HeLa (cervical cancer), and Ishikawa (endometrial cancer). The title compounds showed excellent to moderate in vitro anti-cancer activity in a range of 6.8–19.2 µM (IC50). Compounds 30 (IC50 = 6.8 µM and MCF-7; IC50 = 8.5 µM and MDA-MB-231) and 31 (IC50 = 14.4 µM and MCF-7; IC50 = 15.7 µM and MDA-MB-231) exhibited the best activity with compound 30 showing more potent activity than the standard drug tamoxifen. Compound 30 demonstrated a strong binding affinity with tumor necrosis factor α (TNF-α) in molecular docking studies. This is significant because TNFα is linked to MCF-7 cancer cell lines, and it enhances luminal breast cancer cell proliferation by upregulating aromatase. Additionally, virtual ADMET studies confirmed that hybrid compounds 30 and 31 met Lipinski’s rule; displayed high bioavailability, excellent oral absorption, favorable albumin interactions, and strong penetration capabilities; and improved blood–brain barrier crossing. Based on the aforementioned results, compound 30 has been identified as a potential anti-breast cancer lead molecule.

A Promising Therapeutic Scaffold Fusing Chalcone/Coumarin Targeting Colorectal Cancer: Design, Synthesis, Biological and ADME‐tox Modelling

“…Thereon, different studies have been reported with coumarin and chalcone derivatives, showing the great potential of these two pharmacophores containing methoxy groups, highlighting the properties in different biological models, including colorectal cancer [31,56] . Besides, Alhakamy and colleagues [57] also reported the in vitro anticancer activity of different coumarin‐chalcone hybrids. They showed two active molecules with methoxy substituents at the 3′, 5′ positions of the aroyl rings, with IC 50 values in the range of 6.8 μM and 17.2 μM on breast cancer cells (MCF‐7 and MDA‐MB‐231).…”

Effect of 2‐methoxyestradiol on mammary tumor initiation and progression

“… 7 , 8 Similar to 2‐ME, benzopyran derivatives, such as K‐1 compound exert their anti‐estrogenic effects by competitively inhibiting oestradiol binding to estrogen receptors. 9 , 10 , 11 This shared mechanism of action underscores their potential as therapeutic agents in BC by mitigation of estrogen‐driven tumor growth and progression. 12 , 13 Numerous studies in BC, both in vitro and in vivo.…”

“…2‐Methoxyestradiol (2‐ME) targets the colchicine‐binding site in tubulin and alters polymerization kinetics hindering tumor vascularization and growth 7,8 . Similar to 2‐ME, benzopyran derivatives, such as K‐1 compound exert their anti‐estrogenic effects by competitively inhibiting oestradiol binding to estrogen receptors 9–11 . This shared mechanism of action underscores their potential as therapeutic agents in BC by mitigation of estrogen‐driven tumor growth and progression 12,13 .…”

Dietary isothiocyanates and anticancer agents: exploring synergism for improved cancer management

“…One of the critical challenges in cancer therapy is the development of resistance to chemotherapeutic agents ( 22 , 23 ). Studies have shown that SFN can sensitize cancer cells to various anticancer drugs, thereby potentially overcoming resistance mechanisms.…”

“…One significant impact of isothiocyanates (ITCs) on cancer therapy is their potential to combat chemoresistance, a major obstacle in effective cancer treatment. Chemoresistance, where cancer cells develop mechanisms to resist the effects of chemotherapy, often leads to diminished treatment effectiveness ( 22 , 23 ). ITCs, notably SFN, have been shown to induce chemosensitization in cancer cells.…”