Abstract
A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.
Keywords:
G-Quadruplex; carbonic anhydrase; multitarget-directed ligands; tumours.
MeSH terms
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Antigens, Neoplasm / metabolism
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Carbonic Anhydrase IX* / antagonists & inhibitors
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Carbonic Anhydrase IX* / metabolism
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Carbonic Anhydrase Inhibitors* / chemical synthesis
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Carbonic Anhydrase Inhibitors* / chemistry
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Carbonic Anhydrase Inhibitors* / pharmacology
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Carbonic Anhydrases* / metabolism
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug*
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Drug Screening Assays, Antitumor*
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G-Quadruplexes* / drug effects
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HeLa Cells
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Humans
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Ligands
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Models, Molecular
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Molecular Structure
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Structure-Activity Relationship
Substances
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Carbonic Anhydrase Inhibitors
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Antineoplastic Agents
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Carbonic Anhydrase IX
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Carbonic Anhydrases
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Ligands
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CA9 protein, human
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Antigens, Neoplasm
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carbonic anhydrase XII
Grants and funding
The authors acknowledge the financial support from: (i) Fondazione Intesa San Paolo [B/2021/0168] to PG; (ii) Fondazione Italiana per la Ricerca sul Cancro [IG 26313] and Ministero dell’Università e della Ricerca [PRIN P2022EPH87] to AR; Ministero dell’Università e della Ricerca [PRIN 2022HMJLN] to AN. ADP is the recipient of a postdoc fellowship from Fondazione Italiana per la Ricerca sul Cancro [26644]. SB acknowledges the Research Institute of the University of Bucharest for the ICUB Fellowship for Young Researchers.