Search Results (8)

We synthesized 16 representatives of a new class of tetraene macrodiolides with two pharmacophore cis,cis-1,5-diene fragments of the molecule in their structure in rather high yields (from 67 to 84%), which, in turn, were synthesized by a catalytic intermolecular cyclocondensation reaction of α,ω-alka-nZ,(n+4)Z-diendiols with α,ω-alka-nZ,(n+4)Z-diendioic acids using Hf(OTf)₄. The synthesis of starting substrates with 1Z,5Z-diene moieties with a high degree of stereoselectivity was carried out using the authors’ original reaction of catalytic homo-cyclomagnesiation of O-containing allenes. The cytotoxic potential of the examined compounds was assessed using the following cell lines: Jurkat, K562, U937, HL60, HEK293, and Wi-38 (fibroblasts). Biological tests of the synthesized compounds showed a direct effect on mitochondrial biogenesis by the dissociation of oxidation and phosphorylation and the release of cytochrome P450 into the cell cytosol, as well as the induction of mitochondrial apoptosis. The selectivity index demonstrates significant variability, ranging from approximately 2.5 to 5.3 for Jurkat cells and from 3.0 to 5.8 for the other cell lines. Full article

Macrocyclic compounds, including macrolactones and macrodiolides, play a significant role in the development of supramolecular chemistry, materials science, the perfume industry, and pharmaceuticals. In previous studies conducted by our group over several years, previously undescribed macrocyclic compounds containing pharmacophoric 1Z,5Z- diene fragments in their structure were synthesized for the first time, which showed high potential in studies on cytotoxicity, apoptosis-inducing activity, effects on the cell cycle, and mitochondria in tumor cell lines (Jurkat, K562, U937). As part of the continuing research on the development of methods for synthesizing new unsaturated macrodiolides and studying their antitumor properties, this work presents, for the first time, the stereoselective synthesis of macrocyclic compounds based on 1,14 -tetradeca-5Z,9Z-dienoic acid and α,ω-alka-nZ, (n + 4)Z-dienediols (1,12-dodeca-4Z,8Z-dienediol, 1,14-tetradeca-5Z,9Z-dienediol, 1,16-octadeca-6Z,10Z-dienediol) in good yields. The method for the synthesis of new macrodiolides is based on the previously well-proven reaction of direct intermolecular cyclocondensation of dienedioic acid with diene diols in the presence of 5 mol.% hafnium(IV) triflate. As a result of the experiments, it was shown that the reaction between 1,14-tetradeca-5Z,9Z-dienedioic acid and 1,16-octadeca-6Z,10Z-dienediol in toluene proceeded within 18 h with the highest yield of 76%, with the formation of previously undescribed tetraenoic macrodiolides containing two 1Z,5Z-diene fragments in their structure. Full article

Macrocycles represent an important class of compounds that are widespread in nature. Of particular interest to researchers are aromatic macrocyclic compounds, which, due to their rigid structure and unique physicochemical properties, can find application in many areas of science, industry and medicine. Previously, we synthesized polyether aromatic macrodiolides, which showed intriguing antitumor properties. In the work, Peyrottes S. and co-authors showed that the introduction of biphenyl or naphthyl rings, as well as triple bonds, into the structure of the compounds they synthesized, not only helps to reduce the molecular flexibility of the molecule, but also increases the bioavailability after oral administration of the corresponding neutral prodrugs. Studies in mice have shown that the presence of two aromatic groups is well tolerated and has resulted in compounds with valuable properties in vitro and in vivo. Based on these results, in continuation of our research on the synthesis of biologically active macrodiolides, in the framework of this work, new aromatic macrocycles were synthesized, the structure of which, along with the 1Z,5Z-diene fragment, contains phenyl or naphthyl rings. The target polyester macrodiolides were obtained by Hf-catalyzed intermolecular cyclocondensation of 1,14-tetradeca-5Z,9Z-dienedioic acid with diols synthesized from dihydroxybenzenes and naphthalenediols. Full article

For the first time, a synthetic analogue of natural (5Z,9Z)-dienoic acid has been synthesized in the form of a hybrid molecule containing a fragment of oleanolic acid and (5Z,9Z)-tetradeca-5.9-dienedicarboxylic acid, synthesized using a new reaction of Ti-catalyzed homo-cyclomagnesiation 1,2-dienes. The high cytotoxic activity of (5Z,9Z)-14-[(3,28-dioxoolean-12-en-28-yl)oxy]tetradeca-5,9-dienoic acid against tumor cells Jurkat, K562, U937 and HL60 was established. This compound is also an inducer of apoptosis, affects the cell cycle and inhibits human topoisomerase I. Full article

Stereoselective synthesis of (7Z,11Z)-octadeca-7,11-diene-1,18-dioic acid was carried out using a homo-cyclomagnesiation reaction of 2-(nona-7,8-dien-1-yloxy)tetrahydro-2H-pyran. After Steglisch esterification of the synthesized acid and polyester acetylenes in the presence of DCC and DMAP, the corresponding diesters were synthesized in good yields (67–75%). Based on symmetric diesters with terminal triple bonds, polyether macrodiolides containing conjugated triple bonds and pharmacophoric cis,cis-1,5-diene fragments in their structure were synthesized for the first time. Full article

Based on (5Z,9Z)-tetradeca-5,9-diene-1,14-dioic acid, previously undescribed polyether aromatic macrodiolides were synthesized in good yields (53–67%). The cytotoxicity of the resulting macrocyclic compounds in vitro against tumor Jurkat cells, K562 cells, conditionally normal Hek293 cell lines and normal fibroblasts was the assessment carried out. The ability of the most active macrodiolide to induce apoptosis toward Jurkat cells and influence the cell cycle was studied. Full article

An original synthetic route was developed for the preparation of previously unknown unsaturated polyaromatic macrolactones containing a 1Z,5Z-diene moiety in 48–71% yields and with >98% stereoselectivity. The method is based on intermolecular cyclocondensation of aromatic dicarboxylic acids with α,ω-alka-nZ,(n+4)Z-dienediols (1,12-dodeca-4Z,8Z-dienediol, 1,14-tetradeca-5Z,9Z-dienediol, 1,18-octadeca-7Z,11Z-dienediol) mediated by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)/4-dimethylaminopyridine (DMAP). The unsaturated diols were prepared by successive homo-cyclomagnesiation of tetrahydropyran ethers of O-containing 1,2-dienes with EtMgBr in the presence of Mg metal and the Cp₂TiCl₂ catalyst (10 mol.%) and subsequent treatment with 0.1 equiv. of para-toluenesulfonic acid of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes. The resulting cyclophanes exhibited high cytotoxic activity in vitro against Jurkat, K562, U937, and HL60 cancer lines. Additionally, the synthesized products were studied for their effect on mitochondria, ability to induce apoptosis, and influence on the cell cycle using modern flow cytometry methods. Full article

For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5Z,9Z)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5Z,9Z-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2–4 times higher than that of camptothecin, a known topoisomerase I inhibitor. Using flow cytometry and fluorescence microscopy, it was first shown that these new molecules are efficient apoptosis inducers in HeLa, U937, Jurkat, K562, and Hek293 cell cultures. In addition, the results of investigations into the effect of the synthesized acids on mitochondria and studies of possible DNA damage in Jurkat tumor cells are also presented. Full article