Introduction. Heliomycin (resistomycin) is an antibiotic with broad-spectrum biological activity. However, its poor water solubility and the lack of feasible strategies for chemical modification have limited its potential as a drug scaffold. Recent advances in the design and synthesis of heliomycin-based compounds yielded water-soluble derivatives with strong i-motif stabilization and notable antitumor activity. This study investigates the effects of the heliomycin derivative LCTA-2614 on both hormone-dependent and hormone-independent breast cancer cell lines.

Methods. Aminoalkylamine side chains were introduced at positions 3, 5, and 7 of heliomycin through nucleophilic substitution of alkoxy groups, enabling the synthesis of a previously undescribed series of water-soluble derivatives. Biological activity was assessed using the MTT assay, flow cytometry, and immunoblotting.

Results. Heliomycin exhibited potent antiproliferative activity across breast cancer cell lines of various molecular subtypes, with half-maximal inhibitory concentrations (IC₅₀) of 0.65±0.03 μM in MCF7, 0.79±0.01 μM in HCC1954, and 0.95±0.01 μM in MDA-MB-231 cells. The derivative LCTA-2614 showed comparable efficacy, with IC₅₀ values of 0.86±0.03 μM in MCF7, 0.60±0.03 μM in HCC1954, and 0.68±0.01 μM in MDA-MB-231. Importantly, both compounds maintained their antiproliferative activity under hypoxic conditions, a known driver of chemoresistance. Additionally, LCTA-2614 induced apoptosis in hormone-dependent MCF7 cells through a p53-dependent pathway.

Conclusions. These findings highlight heliomycin derivatives as promising molecular scaffolds for the development of new chemotherapeutic agents. Their retained activity under hypoxia suggests particular potential for the treatment of solid tumors with extensive hypoxic regions. Funding. This research was partly funded by the Russian Science Foundation (agreement 25-73-20069).