Direct Synthesis of Polyaromatic Cyclophanes Containing Bis-Methylene-Interrupted <i>Z</i>-Double Bonds and Study of Their Antitumor Activity In Vitro

• Main Authors: Vladimir A. D’yakonov, Ilgiz I. Islamov, Lilya U. Dzhemileva, Elina Kh. Makarova, Usein M. Dzhemilev
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: International Journal of Molecular Sciences
• Subjects: cyclophanes; 1,5-dienoic compounds; 1,2-dienes; cyclomagnesiation; homogeneous catalysis
• Online Access: https://www.mdpi.com/1422-0067/22/16/8787

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 <i>N</i>-(3-dimethylaminopropyl)-<i>N</i>′-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.