Naphthoquinone-Quinolone Hybrids with Antitumor Effects on Breast Cancer Cell Lines-From the Synthesis to 3D-Cell
Vanessa da Gama Oliveira1,2, Marcelly Muxfeldt3,4, Mariana Muniz da Paz3
1Instituto Nacional de Infectologia, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, RJ, Brazil.
Abstract:
Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.
Insights
Novel 1,4-naphthoquinone/4-quinolone hybrids show potent and selective anticancer activity against breast cancer cell lines. These compounds demonstrate promising efficacy and reduced toxicity compared to doxorubicin, suggesting potential for new breast cancer chemotherapy treatments.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Breast cancer is a leading cause of cancer mortality worldwide, with diverse molecular subtypes necessitating tailored therapies.
- Current treatments face challenges of toxicity and limited effectiveness, driving the search for novel therapeutic agents.
Purpose of the Study:
- To investigate the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrid compounds against breast cancer cell lines.
- To evaluate the selectivity, efficacy, and preliminary pharmacokinetic properties of these novel compounds.
Main Methods:
- Synthesis and in vitro cytotoxicity testing of 1,4-naphthoquinone/4-quinolone hybrids against Luminal and triple-negative breast cancer (TNBC) cell lines.
- Comparison of compound potency and selectivity indices (SI) against doxorubicin and a precursor compound.
- Mechanistic studies including apoptosis induction and clonogenic assays, 3D cell culture models, and in silico pharmacokinetic predictions (SwissADME).
Main Results:
- Synthesized compounds exhibited selective cytotoxicity against Luminal and TNBC cells, comparable in potency to doxorubicin.
- Derivatives showed superior selectivity indices (SI) compared to doxorubicin, indicating lower toxicity to non-tumor cells.
- Compounds 11a and 11b demonstrated improved IC50 values and SI compared to the precursor and reference compounds.
- Mechanistic studies confirmed apoptosis induction, inhibition of clonogenic potential, and efficacy in 3D models.
- In silico analysis predicted favorable drug-likeness properties for the compounds.
Conclusions:
- Novel 1,4-naphthoquinone/4-quinolone hybrids possess significant anticancer potential for breast cancer chemotherapy.
- These compounds offer a promising balance of selectivity and efficacy, with potential for reduced toxicity.
- Further development of these hybrid compounds is warranted for their therapeutic utility in breast cancer treatment.
