An IMDAF approach to annellated 1,4:5,8-diepoxynaphthalenes and their metathesis reaction leading to novel scaffolds displaying an antiproliferative activity toward cancer cells

A series of 1,4:5,8-diepoxynaphthalenes, annellated with six-membered carbo- A nd heterocycles, was obtained via the intramolecular Diels-Alder furan (IMDAF) cycloaddition approach from bis-furyl dienes and acetylenic dienophiles (dialkyl acetylenedicarboxylates and hexafluoro-2-butyne). To achieve a wide variety of different products for subsequent biotesting, ethylene-promoted ring-opening cross-metathesis (ROCM) reactions, Prilezhaev epoxidation, catalytic hydrogenation, and N-or O-deprotection reactions of pentacycles were performed. The polyfunctional scaffolds of the resulting diverse heterocycles were tested on cancer lines (PC3, DU-145, MDA-MB-231, HT-1080, and HCT116) and normal lung fibroblasts (WI-26 VA4), and it was found that some of the obtained compounds exerted a concentration-dependent antiproliferative action toward MDA-MB-231 human triple-negative breast cancer and especially PC3 human prostate cancer cell lines. It was demonstrated that compound 16f (hydrogenated 7-(tert-butyl)-4,5-dimethyl-2,8a-divinyl-3,5a-epoxyfuro[2,3,4-de]isoquinoline-4,5,7-tricarboxylate) possessed a time-dependent apoptosis induction activity associated with caspase 3/7 activation in prostate cancer cells, which clearly represents a viable lead for the further development of new-generation anticancer agents. © 2021 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Authors
Kvyatkovskaya E.A. 1 , Borisova K.K. 1 , Epifanova P.P. 1 , Senin A.A. 1 , Khrustalev V.N. 1, 2 , Grigoriev M.S.3 , Bunev A.S.4 , Gasanov R.E.4 , Polyanskii K.B. 1 , Zubkov F.I. 1
Publisher
Royal Society of Chemistry
Number of issue
41
Language
English
Pages
19497-19505
Status
Published
Volume
45
Year
2021
Organizations
  • 1 Organic Chemistry Department, Faculty of Science, Peoples' Friendship University of Russia, RUDN University, 6 Miklukho-Maklaya St., Moscow, 117198, Russian Federation
  • 2 N. D. Zelinsky Institute of Organic Chemistry, RAS, 47 Leninsky Prospect, Moscow, 119991, Russian Federation
  • 3 A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences Leninsky, pr. 31 bld. 4, Moscow, 119071, Russian Federation
  • 4 Medicinal Chemistry Center, Togliatti State University, 14 Belorusskaya St., Togliatti, 445020, Russian Federation
Keywords
Cell culture; Cell death; Cycloaddition; Diseases; Ethylene; Scaffolds; Scaffolds (biology); Urology; 2-Butyne; Antiproliferative activities; Cancer cells; Cycloadditions; Dialkyl acetylenedicarboxylates; Diels-Alder; Dienophiles; Heterocycles; MDA-MB-231; Metathesis reactions; Hydrogenation
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