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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Naphthoquinone-Quinolone Hybrids with Antitumor Effects on Breast Cancer Cell Lines—From the Synthesis to 3D-Cell Culture Effects
Author
Vanessa da Gama Oliveira 1   VIAFID ORCID Logo  ; Muxfeldt, Marcelly 2 ; Mariana Muniz da Paz 3 ; Mayra Silva Coutinho 4   VIAFID ORCID Logo  ; dos Santos, Raissa Eduardo 3 ; Giulia Diniz da Silva Ferretti 5 ; Danielly C Ferraz da Costa 6 ; Pedro Fonseca Regufe 4 ; Gama, Ivson Lelis 7 ; Fernanda da Costa Santos Boechat 4 ; Emersom Silva Lima 8   VIAFID ORCID Logo  ; Ferreira, Vitor Francisco 9   VIAFID ORCID Logo  ; de Moraes, Marcela Cristina 4   VIAFID ORCID Logo  ; Maria Cecília Bastos Vieira de Souza 4   VIAFID ORCID Logo  ; Pedro Netto Batalha 4   VIAFID ORCID Logo  ; Luciana Pereira Rangel 3   VIAFID ORCID Logo 

 Instituto Nacional de Infectologia, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, RJ, Brazil; [email protected]; Instituto de Química, Universidade Federal Fluminense, Niteroi 24020-141, RJ, Brazil; [email protected] (M.S.C.); [email protected] (P.F.R.); [email protected] (I.L.G.); [email protected] (F.d.C.S.B.); [email protected] (M.C.d.M.); [email protected] (M.C.B.V.d.S.) 
 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; [email protected] (M.M.); [email protected] (M.M.d.P.); [email protected] (R.E.d.S.); Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus 69067-005, AM, Brazil; [email protected] 
 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; [email protected] (M.M.); [email protected] (M.M.d.P.); [email protected] (R.E.d.S.) 
 Instituto de Química, Universidade Federal Fluminense, Niteroi 24020-141, RJ, Brazil; [email protected] (M.S.C.); [email protected] (P.F.R.); [email protected] (I.L.G.); [email protected] (F.d.C.S.B.); [email protected] (M.C.d.M.); [email protected] (M.C.B.V.d.S.) 
 Instituto de Bioquimica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; [email protected] 
 Instituto de Nutrição, Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20550-013, RJ, Brazil; [email protected] 
 Instituto de Química, Universidade Federal Fluminense, Niteroi 24020-141, RJ, Brazil; [email protected] (M.S.C.); [email protected] (P.F.R.); [email protected] (I.L.G.); [email protected] (F.d.C.S.B.); [email protected] (M.C.d.M.); [email protected] (M.C.B.V.d.S.); Faculdade da Amazônia Legal, Colider 78500-000, MT, Brazil 
 Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus 69067-005, AM, Brazil; [email protected] 
 Faculdade de Farmácia, Universidade Federal Fluminense, Niteroi 24020-141, RJ, Brazil; [email protected] 
First page
6490
Publication year
2024
Publication date
2024
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3072355014
Copyright
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.