Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies.

Abstract

Simple SummaryCurrently, the whole world is acutely concerned with the selection of effective treatment regimens for oncological diseases. This problem is becoming more and more catastrophic every year due to the phenomenon of multidrug resistance, the consequence of which is the loss of the effectiveness of drugs against tumor cells. One of the solutions to the problem described above is the synthesis of new low molecular weight compounds that can effectively affect molecular cellular targets, for example, enzymes of the cell cycle, and, as a consequence, interrupt DNA synthesis, contributing to tumor death. Within the framework of this article, we carried out the Z-stereoselective synthesis of natural unsaturated acids containing a 1Z,5Z,9Z-triene moiety, for which it was shown that they are effective inhibitors of human topoisomerase I, and also affect mitochondria. At the same time, using multiplex analysis, the activation of signaling pathways was studied and a probable mechanism of the antitumor action of the synthesized trienoic acids was proposed.The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway. A probable mechanism of topoisomerase I inhibition was also hypothesized on the basis of in silico studies resorting to docking. The activation and inhibition of the most versatile intracellular signaling pathways (CREB, JNK, NFkB, p38, ERK1/2, Akt, p70S6K, STAT3 and STAT5 tyrosine kinases) responsible for cell proliferation and for initiation of apoptosis were studied by multiplex assay technology (Luminex xMAP).