Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca 2+ or Mg 2+ Cross-Linked Alginate.

Autor: Sedenkova KN; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Leschukov DN; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Grishin YK; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Zefirov NA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Gracheva YA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Skvortsov DA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Hrytseniuk YS; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Vasilyeva LA; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia., Spirkova EA; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), 142432 Chernogolovka, Russia., Shevtsov PN; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), 142432 Chernogolovka, Russia., Shevtsova EF; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), 142432 Chernogolovka, Russia., Lukmanova AR; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Spiridonov VV; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Markova AA; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia., Nguyen MT; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia., Shtil AA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.; Institute of Cyber Intelligence Systems, National Research Nuclear University MEPhI, 115409 Moscow, Russia., Zefirova ON; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Yaroslavov AA; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Milaeva ER; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Averina EB; Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
Jazyk: angličtina
Zdroj: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2023 Oct 21; Vol. 16 (10). Date of Electronic Publication: 2023 Oct 21.
DOI: 10.3390/ph16101499
Abstrakt: Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC 50 down to 1-4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound ( N -(4-methoxyphenyl)- N ,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca 2+ or Mg 2+ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation.
Databáze: MEDLINE
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