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Published on: February 9, 2021
Design, synthesis, and validation of novel nitrogen-based chalcone analogs against triple negative breast cancer
Dana Elkhalifa1, Abu Bakar Siddique2, Mohammed Qusa2
1College of Pharmacy, Qatar Health, Qatar University, Doha, Qatar.
Abstract:
Great strides have been made in triple negative breast cancer (TNBC) treatment, which represents 20% of total predicted annual US breast cancer (BC) cases. Despite the development of several therapeutics, TNBC patients have poor overall survival rate, compared to other BC patients, justifying the urgent need to discover new entities for use to control TNBC. Chalcones are important natural products with diverse bioactivities including anticancer effects. This study aimed to design, synthesize and validate novel chalcone leads as potential therapies for TNBC. Fourteen novel chalcone analogs were designed and synthesized comprising alicyclic amines (pyrrolidine, morpholine and piperidine) or nitrogen mustard (Bis-(2-chloroethyl) amine) substituents. Among them, compound 14((E)-3-(4-(Bis(2-chloroethyl) amino) phenyl)-1-(3-methoxyphenyl) prop-2-en-1-one) was identified as the most effective against TNBC and other BC phenotypes, with anti-proliferative IC50 values ranging between 3.94 and 9.22 μM against the TNBC cell lines MDA-MB-231 and MDA-MB-468, as well as against the estrogen positive MCF-7 cell line. Chalcone 14 effectively suppressed the colony formation capacity of MDA-MB-231, MDA-MB-468, and MCF-7 cell lines at 5 and 10 μM treatment concentrations. Furthermore, compound 14 has significantly inhibited cell invasion and migration of MDA-MB-231 and MCF-7 BC cell lines. Additionally, compound 14 had significantly promoted apoptosis by upregulating BAX and downregulating Bcl-2 proteins. Compound 14 induced significant cell cycle arrest of TNBC cells at the G2/M phase. It also induced a reversal of Epithelial Mesenchymal Transition (EMT) by upregulating the epithelial markers E-cadherin and Pan-cadherin and downregulating FAK. Furthermore, it had dramatically diminished new vessel formation (vasculogenesis) in chick chorioallantoic membrane (CAM) model by 60.20 ± 8.47%. Chalcone 14 inhibited 46.41 ± 0.71% of the TNBC MAD-MB-231 cells growth in a nude mouse orthotopic xenograft model in comparison with vehicle control treated animals. Collectively, this study results propose chalcone 14 as a promising lead molecule for the control of TNBC as well as other breast cancer phenotypes.
Insights
Novel chalcone compound 14 effectively targets triple-negative breast cancer (TNBC) and other breast cancer phenotypes. This promising therapy inhibits proliferation, invasion, and vasculogenesis while promoting apoptosis and reversing epithelial-mesenchymal transition.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) accounts for 20% of US breast cancer cases, with a poorer survival rate than other subtypes.
- Existing treatments have limitations, highlighting the need for novel therapeutic agents.
- Chalcones, natural products with known bioactivities, offer potential anticancer properties.
Purpose of the Study:
- To design, synthesize, and validate novel chalcone analogs as potential therapies for TNBC.
- To identify lead compounds with significant anti-cancer activity against various breast cancer phenotypes.
- To investigate the mechanism of action of the most effective chalcone derivative.
Main Methods:
- Synthesis of fourteen novel chalcone analogs containing alicyclic amines or nitrogen mustard substituents.
- In vitro evaluation of anti-proliferative activity (IC50) against TNBC (MDA-MB-231, MDA-MB-468) and MCF-7 cell lines.
- Assessment of effects on colony formation, cell invasion, migration, apoptosis (BAX, Bcl-2), cell cycle (G2/M phase), and epithelial-mesenchymal transition (EMT).
- In vivo studies including chick chorioallantoic membrane (CAM) assay for vasculogenesis and nude mouse orthotopic xenograft model for tumor growth inhibition.
Main Results:
- Compound 14 ((E)-3-(4-(Bis(2-chloroethyl) amino) phenyl)-1-(3-methoxyphenyl) prop-2-en-1-one) demonstrated the highest efficacy.
- Compound 14 exhibited anti-proliferative IC50 values between 3.94 and 9.22 μM against tested cell lines.
- It suppressed colony formation, inhibited cell invasion and migration, promoted apoptosis, induced G2/M cell cycle arrest, and reversed EMT.
- Compound 14 significantly reduced new vessel formation in the CAM model (60.20%) and inhibited TNBC tumor growth in mice (46.41%).
Conclusions:
- Chalcone 14 is identified as a potent lead molecule for TNBC and other breast cancer types.
- The compound exerts its effects through multiple mechanisms, including apoptosis induction and EMT reversal.
- Further development of chalcone 14 holds promise for novel breast cancer therapies.
