| Abstract [eng] |
It is known that some natural and synthetic β'-hydroxy-α,β-unsaturated ketones and α-substituted α,β-unsaturated ketones exhibit remarkable antiproliferative activities in human solid tumor cell lines. In this concept, the main aim of the present work was dedicated to the development of synthetic approaches of these two main structural scaffolds together with their structure-anticancer activity relationship evaluation. It was found that the best way for preparation of β’-hydroxy-α,β-unsaturated ketones is reductive cleavage of α,β-unsaturated 2-isoxazolines by Mo(CO)6. Moreover, a fast, economical, and efficient protocol for the reduction of nonconjugated Δ2-isoxazolines to the corresponding β-hydroxy ketones using Al/CuCl2 as the reducing agent was developed. An alkyne-carbonyl metathesis reaction allowed production of a variety of E-α-substituted α,β-unsaturated ketones. The most intriguing discovery was found in reactions between 3-arylprop-2-ynyl esters and aldehydes leading to the formation of E and Z enones, 2:1 adducts and the Morita-Baylis-Hillman adducts. The reaction pathways were studied using 18O-labeling experiments. Thus, it was found that reactions proceeded either via classical alkyne-carbonyl metathesis route, or via an unprecedented nucleophilic addition-rearrangement cascade. Synthesized compounds were tested for their antiproliferative activity using different human cancer cell lines. The analysis of the GI50/IC50 values allowed us to establish several qualitative SARs, which results revealed a set of compounds valuable for further biological investigations. |
