Abstract
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.
Highlights
The last 15–20 years have seen considerable interest in cyclophanes, which are bridged aromatic macrocyclic compounds composed of aromatic or heteroaromatic rings connected by aliphatic chains
The strategy towards the target macrodiolides includes the successive synthesis of the above-mentioned α,ω-alka-nZ,(n+4)Z-dienediols by the Ti-catalyzed intermolecular homo-cyclomagnesiation of O-containing 1,2-dienes with Grignard reagents, which we developed previously, and intermolecular esterification of the products with aromatic dicarboxylic acids
We developed an original method for stereoselective synthesis of previously unreported cyclophanes containing a 1Z,5Z-diene moiety in their structure with good yields and high stereoselectivity
Summary
The last 15–20 years have seen considerable interest in cyclophanes, which are bridged aromatic macrocyclic compounds composed of aromatic or heteroaromatic rings connected by aliphatic chains. This type of macrolide is widely used in various fields, including supramolecular chemistry, materials science, catalysis, and pharmaceutics. Macrocyclic natural bis-dibenzyl compounds, for example, riccardins C, D, and H, marchantins A and B, cavicularin, etc., are used as potent antifungal and antibacterial agents and exhibit cytotoxic activity against P-388 lymphocytic leukemia and nasopharyngeal carcinoma cells [11,12,13]. The macrocycles containing an aromatic ring in the molecule exhibited selective cytotoxic activity against the Jurkat and U937 cell lines (IC50 = 0.02–0.06 μM) [17,18]. It was of interest to find out how the cytotoxicity of 1Z,5Z-diene compounds changes in the presence of several aromatic moieties
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