Water-Soluble Heliomycin Derivatives to Target i‑Motif DNA

• Published in: Journal of natural products (Washington, D.C.) Vol. 84; no. 5; pp. 1617 - 1625
• Main Authors: Tikhomirov, Alexander S, Abdelhamid, Mahmoud A. S, Nadysev, Georgy Y, Zatonsky, George V, Bykov, Eugene E, Chueh, Pin Ju, Waller, Zoë A. E, Shchekotikhin, Andrey E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 28.05.2021; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Plant Sciences; Science & Technology; EMODIN; SEQUENCES; LIGANDS; PATHWAY; STABILITY; RESISTOMYCIN; COMPLEXES; IDENTIFICATION; G-QUADRUPLEX; GENE PROMOTERS
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.1c00162

Heliomycin (also known as resistomycin) is an antibiotic with a broad spectrum of biological activities. However, low aqueous solubility and poor knowledge of its chemical properties have limited the development of this natural product. Here, we present an original scheme for the introduction of aminoalkylamine residues at positions 3, 5, and 7 of heliomycin and, using this, have prepared a series of novel water-soluble derivatives. The addition of side chains to the heliomycin scaffold significantly improves their interaction with different DNA secondary structures. One derivative, 7-deoxy-7-(2-aminoethyl)­amino-10-O-methylheliomycin (8e), demonstrated affinity, stabilization potential, and good selectivity toward i-motif-forming DNA sequences over the duplex and G-quadruplex. Heliomycin derivatives therefore represent promising molecular scaffolds for further development as DNA-i-motif interacting ligands and potential chemotherapeutic agents.