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Divergent Synthesis of Styryl–Cinnamate Hybrid Analogues Inspired by the Natural Product Salvianolic Acid F as a Premise To Investigate Their Anticancer Activity and Its Metabolomic Profiling
Author(s) -
Shard Amit,
Rawat Kiran,
Sinha Arun K.,
Padwad Yogendra,
Kumar Dinesh
Publication year - 2016
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201601104
Subject(s) - chemistry , natural product , molecule , stereochemistry , decarboxylation , combinatorial chemistry , organic chemistry , catalysis
Protecting‐group‐free synthesis of hydroxylated styryl–cinnamate hybrids (C 6 –C 2 –C 6 –C 3 unit), inspired by the natural product salvianolic acid F, was achieved by a step‐economical route involving sequential double C–C bond formation in one pot. The method involved multiple reactions (Perkin condensation/decarboxylation–Heck cross‐coupling reactions) by using simple precursors (i.e., hydroxylated benzaldehyde, arylacetic acid, and acrylic acid derivatives) in one pot and yielded the desired unnatural small hybrid molecules in varying yields of 35–65 % with E selectivity under microwave irradiation, whereas the reported conventional route for the synthesis of salvianolic acid F itself requires six steps with an overall yield of 10.0 % in addition to tedious separation of E/Z isomers that arise from a Wittig reaction. Apart from an economical synthesis and product diversity, we herein report the potential of some hybrid molecules with the catechol core to selectively inhibit glioma cells. The intrinsic mode of action of our lead molecule, involving caspase 6 and the quinonemethide pathway, is also reported on the basis of 1 H NMR spectroscopy guided metabolomic profiling. We emphatically demonstrate the role of our hybrid molecules, analogues of salvianolic acid F, in forcing glioma cells towards apoptosis by specifically perturbing the concentration of glutathione along with that of caspase 6.