Cancer treatment remains to be one of the biggest challenges in medical research, especially due to chemoresistance, metastasis, and tumour relapse. As conventional therapies do not provide the desired outcome, various novel approaches for tumour eradication are being investigated. The discovery and research on CSCs have shown great promise for the development of new potential therapies, consequently, different approaches for the selective pharmacological targeting of CSCs are being investigated. One notable characteristic of CSCs, particularly in breast cancer, is the overexpression of the ALDH1A3 enzyme, which oxidises aldehydes to corresponding acids. This mechanism is used to selectively mark and identify CSCs using the fluorescent substrate Aldefluor.
The present study aimed to investigate a novel approach for breast cancer treatment, through the synthesis of ALDH1A3 substrates linked to the HDAC1 inhibitor SAHA, which represents the pharmacologically active part of the compound. Upon its metabolism by upregulated ALDH1A3, the drug is expected to accumulate inside the CSCs, resulting in a selectively higher concentration of the agent and thereby leading to their eradication.
The synthesis of the ALDH1A3 substrates was based on the Aldefluor structure, which was modified with a benzaldehyde and an additional alkyne group. Following this, a SAHA conjugate incorporating an azide group was designed and subsequently coupled with the substrate to yield the final molecule. Several bioassays were conducted to evaluate the biological activity of the ALDH1A3 substrates and to measure the inhibitory effect of the SAHA conjugate on HDAC1. Results confirmed the biological activity of both compounds separately, although further modifications of the assays are required to evaluate the final compound. The research findings show great potential and represent a further step toward the development of treatment strategies targeting CSCs.
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