The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

Stockmann, Philipp; Kuhnert, Lydia; Leinung, Wencke; Lakoma, Cathleen; Scholz, Birte; Paskas, Svetlana; Mijatović, Sanja; Maksimović-Ivanić, Danijela; Honscha, Walther; Hey-Hawkins, Evamarie

doi:10.3390/pharmaceutics15010241

Open AccessArticle

The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

by

Philipp Stockmann

¹

,

Lydia Kuhnert

^2,*

,

Wencke Leinung

^1,†

,

Cathleen Lakoma

²,

Birte Scholz

²

,

Svetlana Paskas

³,

Sanja Mijatović

³,

Danijela Maksimović-Ivanić

³

,

Walther Honscha

² and

Evamarie Hey-Hawkins

^1,*

¹

Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany

²

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany

³

Department of Immunology, Institute for Biological Research “Siniša Stanković”, Belgrade University, 11060 Belgrade, Serbia

^*

Authors to whom correspondence should be addressed.

^†

Current address: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.

Pharmaceutics 2023, 15(1), 241; https://doi.org/10.3390/pharmaceutics15010241

Submission received: 2 December 2022 / Revised: 29 December 2022 / Accepted: 5 January 2023 / Published: 10 January 2023

(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)

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Abstract

The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents’ pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.

Keywords: multidrug resistance; drug discovery; synthesis; structure-activity relationship; in silico modeling; carborane; ABCG2; breast cancer resistance protein

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MDPI and ACS Style

Stockmann, P.; Kuhnert, L.; Leinung, W.; Lakoma, C.; Scholz, B.; Paskas, S.; Mijatović, S.; Maksimović-Ivanić, D.; Honscha, W.; Hey-Hawkins, E. The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. Pharmaceutics 2023, 15, 241. https://doi.org/10.3390/pharmaceutics15010241

AMA Style

Stockmann P, Kuhnert L, Leinung W, Lakoma C, Scholz B, Paskas S, Mijatović S, Maksimović-Ivanić D, Honscha W, Hey-Hawkins E. The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. Pharmaceutics. 2023; 15(1):241. https://doi.org/10.3390/pharmaceutics15010241

Chicago/Turabian Style

Stockmann, Philipp, Lydia Kuhnert, Wencke Leinung, Cathleen Lakoma, Birte Scholz, Svetlana Paskas, Sanja Mijatović, Danijela Maksimović-Ivanić, Walther Honscha, and Evamarie Hey-Hawkins. 2023. "The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors" Pharmaceutics 15, no. 1: 241. https://doi.org/10.3390/pharmaceutics15010241

APA Style

Stockmann, P., Kuhnert, L., Leinung, W., Lakoma, C., Scholz, B., Paskas, S., Mijatović, S., Maksimović-Ivanić, D., Honscha, W., & Hey-Hawkins, E. (2023). The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors. Pharmaceutics, 15(1), 241. https://doi.org/10.3390/pharmaceutics15010241

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The More the Better—Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors

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