Diarylether‐Amino Acid Conjugates as New Class of Anticancer Agents

• Published in: ChemistrySelect (Weinheim) 2023-07, Vol.8 (28), p.n/a
• Main Authors: Thanh Le, Thanh, Huy Vo, Vinh, Thanh Huong Le, Thi, Huy Hoang Vo, Nguyen, Loc Le, Xuan, Hong Tuoi Do, Thi, Y Vu, Thien, Hung Nguyen, Phu, Duy Vo, Duc, Le, Tin Thanh
• Format: Article
• Language: English
• Subjects: amide coupling; amino acid conjugate; anticancer; diaryl ether; SNAr reaction
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202301203

Diarylether (DE) is a privileged structure found in both natural products and synthetic compounds including small molecule drugs. We present the synthesis of a series of 13 new DE‐amino acid conjugates which were screened for cancer cells antiproliferation activity. Structure‐activity relationship suggests ester and phenyl groups in DE‐Phe‐OEt 4 c are important for the activity. Compound 4 c inhibited strongly MCF‐7 3D tumor sphere formation and have favourable calculated physical chemical properties according to Lipinski's rule of 5. Docking study suggests estrogen receptor and/ or 3a‐HSD type 3 protein could be the target(s) for anticancer activity of this class of compounds. Diarylether (DE) – amino acid conjugate such as the oral drug roxadustat represents attractive scaffold for discovery of new bioactive compounds. We designed and synthesized a series of new DE – natural amino acid conjugates which were screened for anticancer activity. Among these, the drug like phenylalanine derivative 4 c inhibited strongly MCF‐7 3D tumor sphere formation thus represents attractive scaffold for further optimization and mechanistic study.