Design and synthesis of naphthylchalcones as novel anti-leukaemia agents

• Published in: Bioorganic chemistry Vol. 117; p. 105348
• Main Authors: Leitão, Emília P.T., Ascenso, Osvaldo S., Santos de Almeida, Tania, González, Ignacio, Hernández, Inmaculada, Quintana, José, Estévez, Francisco, Rijo, Patrícia
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.12.2021; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry & Molecular Biology; Caspases; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Chalcone - analogs & derivatives; Chalcone - chemical synthesis; Chalcone - pharmacology; Chalcones; Chemistry; Chemistry, Organic; Claisen-Schmidt condensation. cytotoxicity; Drug Design; Drug Screening Assays, Antitumor; Flavanones; Humans; Leukemia - drug therapy; Life Sciences & Biomedicine; Physical Sciences; Science & Technology; Flavanones; Chalcones; Caspases; Claisen-Schmidt condensation. cytotoxicity; Apoptosis; CHALCONE; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105348

[Display omitted] •Synthesis of a series of hydroxylated chalcone derivatives substituted on a phenyl ring A and B.•Structure-activity relationship of naphthylchalcones prepared by Claisen–Schmidt condensation.•The naphthylchalcone with a methoxy group in position 6́ of the A ring is a promising anti-leukaemia drug. A series of new hydroxylated chalcone derivatives with different substitution patterns on a phenyl ring A and B, were prepared by Claisen–Schmidt condensation in an aqueous alkaline base. The antiproliferative activity of the studied compounds was evaluated against the human leukaemia cell line U-937. The structure–activity relationship of these naphthylchalcones was investigated by the introduction of one methoxy or two methyl groups on the A ring, the introduction of a methoxy group on the naphthyl ring or by varying the position of the methoxy group on the A ring. The results revealed that the naphthylchalcone containing a methoxy group in position 6́ of the A ring was the most cytotoxic compound, with an IC50 value of 4.7 ± 0.5 μM against U-937 cells. This synthetic chalcone induced S and G2-M cell cycle arrest, a time-dependent increase in sub-G1 ratio and annexin-V positive cells, caspase activation and poly(ADP-ribose) polymerase cleavage. Apoptosis induction was blocked by a pan-caspase inhibitor and by the selective caspase-3/7 inhibitor and attenuated by the inhibition of c-jun N-terminal kinases / stress-activated protein kinases (JNK/SAPK) and phosphoinositide 3-kinase. The structure–activity relationship of naphthylchalcones against human leukaemia cells reveals that the major determining in cytotoxicity is the presence of a methoxy group in position 6́ of the A ring that suggest the potential of this compound or derivatives in the development of new anti-leukaemia drugs.