Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca2+ or Mg2+ Cross-Linked Alginate

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 cyclohepta...

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Published inPharmaceuticals (Basel, Switzerland) Vol. 16; no. 10; p. 1499
Main Authors Sedenkova, Kseniya N., Leschukov, Denis N., Grishin, Yuri K., Zefirov, Nikolay A., Gracheva, Yulia A., Skvortsov, Dmitry A., Hrytseniuk, Yanislav S., Vasilyeva, Lilja A., Spirkova, Elena A., Shevtsov, Pavel N., Shevtsova, Elena F., Lukmanova, Alina R., Spiridonov, Vasily V., Markova, Alina A., Nguyen, Minh T., Shtil, Alexander A., Zefirova, Olga N., Yaroslavov, Alexander A., Milaeva, Elena R., Averina, Elena B.
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 21.10.2023
MDPI
Subjects
apoptosis inducer
aromatic nucleophilic substitution
Binding sites
Bioavailability
Biocompatibility
Cancer
Cell division
Chemotherapy
Cytotoxicity
FDA approval
Hydrocarbons
Ligands
pyrimidine
tetrahydroquinazoline
Toxicity
tubulin polymerization inhibitor
verubulin
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Summary: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 IC50 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 Ca2+ or Mg2+ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation.
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ISSN:1424-8247
1424-8247
DOI:10.3390/ph16101499