Journal
BIOORGANIC CHEMISTRY
Volume 117, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105348
Keywords
Chalcones; Flavanones; Claisen-Schmidt condensation. cytotoxicity; Apoptosis; Caspases
Funding
- Hovione
- Fundacao para a Ciencia e Tecnologia [RECI/BBB-BQB/0230/2012]
- Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [UIDB/04567/2020, UIDP/04567/2020]
- Fundação para a Ciência e a Tecnologia [UIDB/04567/2020] Funding Source: FCT
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A series of hydroxylated chalcone derivatives with different substitution patterns were prepared, and it was found that the naphthylchalcone containing a methoxy group in position 6 ' of the A ring exhibited the highest cytotoxicity against human leukaemia cells.
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 6 ' of the A ring was the most cytotoxic compound, with an IC50 value of 4.7 +/- 0.5 mu M against U-937 cells. This synthetic chalcone induced S and G2-M cell cycle arrest, a time-dependent increase in sub-G(1) 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 Nterminal 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 6 ' of the A ring that suggest the potential of this compound or derivatives in the development of new anti-leukaemia drugs.
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