Biscoumarin–pyrimidine conjugates as potent anticancer agents and binding mechanism of hit candidate with human serum albumin

• Published in: Archiv der Pharmazie (Weinheim) 2021-01, Vol.354 (1), p.e2000181-n/a
• Main Authors: Reddy, Dinesh S., Kongot, Manasa, Singh, Vishal, Siddiquee, Md. Abrar, Patel, Rajan, Singhal, Nitin K., Avecilla, Fernando, Kumar, Amit
• Format: Article
• Language: English
• Subjects: anticancer activity; biscoumarin–pyrimidine conjugates; Brain cancer; C6 rat glioma cells; Cancer; Glioma; NMR; Nuclear magnetic resonance; protein interaction
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000181

In our continuing efforts to develop therapeutically active coumarin‐based compounds, a series of new C4–C4′ biscoumarin–pyrimidine conjugates (1a–l) was synthesized via SN2 reaction of substituted 4‐bromomethyl coumarin with thymine. All compounds were characterized using spectroscopic techniques, that is, attenuated total reflection infrared (ATR‐IR), CHN elemental analysis, and 1H and 13C NMR (nuclear magnetic resonance). In addition, the structure of compound 1d (1,3‐bis[(7‐chloro‐2‐oxo‐2H‐chromen‐4‐yl)methyl]‐5‐methylpyrimidine‐2,4(1H,3H)‐dione) was established through X‐ray crystallography. Compounds 1a–l were screened for in vitro anticancer activity against C6 rat glioma cells. Among the screened compounds, 1,3‐bis[(6‐chloro‐2‐oxo‐2H‐chromen‐4‐yl)methyl]‐5‐methylpyrimidine‐2,4(1H,3H)‐dione (1c) was identified as the best antiproliferative candidate, exhibiting an IC50 value of 4.85 μM. All the compounds (1a–l) were found to be nontoxic toward healthy human embryonic kidney cells (HEK293), indicating their selective nature. In addition, the most active compound (1c) displayed strong binding interactions with the drug carrier protein, human serum albumin, and exhibited good solution stability at biological pH conditions. Fluorescence, UV–visible spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1c with protein. New C4–C4′ biscoumarin–pyrimidine conjugates (1a–l) were synthesized via SN2 reaction of substituted 4‐bromomethyl coumarin with thymine and screened for in vitro anticancer activity against C6 rat glioma cells. 1,3‐bis[(6‐Chloro‐2‐oxo‐2H‐chromen‐4‐yl)methyl]‐5‐methylpyrimidine‐2,4(1H,3H)‐dione (1c) showed the best antiproliferative activity and strong binding interactions with the drug carrier protein, human serum albumin (HSA). All compounds (1a–l) were found to be nontoxic toward HEK239 cells.