TY - JOUR

T1 - Synthesis and exploration of anticancer potential of spirocyclic 1,2,3-triazoline and aziridine derivatives of natural eudesmanolide isoalantolactone

AU - Patrushev, Sergey S.

AU - Kichkina, Daria O.

AU - Moralev, Arseny D.

AU - Rybalova, Tatyana V.

AU - Krasnov, Vyacheslav I.

AU - Chernyak, Elena I.

AU - Zenkova, Marina A.

AU - Markov, Andrey V.

AU - Shults, Elvira E.

N1 - This research was supported by the Russian Science Foundation: grant No. 23-73-00077 (synthesis and spectroscopic studies) and grant No. 23-14-00374 (biological experiments).

PY - 2025/2

Y1 - 2025/2

N2 - Eudesmane-type sesquiterpene lactone isoalantolactone 1 is of great interest due to its availability, biological activity and synthetic application. Respective series of original spirocyclic (11S,5ʹ) (1,2,3-triazoline-eudesma-4,15-enolides) and (11S)-aziridine-eudesma-4,15-enolides were efficiently synthesized via a chemoselective 1,3-dipolar cycloaddition reaction of organic azides to the exocyclic double bond of the lactone ring of isoalantolactone or 13E-(aryl)isoalantolactones by heating in DMF or toluene. The thermal reactions of isoalantolactone with benzyl azide, 2-azidoethanol, or n-butyl azide in 2-methoxyethanol afforded 13-(alkyamino)isoalantolactones formed as a mixture of (Z) and (E)-isomers. The results of in vitro biological assays showed that novel spirocyclic isoalantolactone derivatives exhibited cytotoxicity against human breast cancer and glioblastoma cells at low micromolar concentrations. The most cytotoxic and selective (11S,5ʹ)-spiro-1,2,3-triazoline from 13E-(fluorophenyl)isoalantolactone 20 (IC50(MCF-7) = 8 ± 0.1 µM, SI(MCF-7) > 12.5) was found to induce ROS-dependent death of MCF-7 human breast cancer cells via mitochondrial apoptosis. The corresponding (11S)-spiroaziridine derivatives 21 at non-toxic concentrations (10 and 20 µM) effectively suppressed motility, clonogenicity and adhesion of glioblastoma cells and exhibited synergistic cytotoxicity in combination with temozolomide. In silico analysis revealed the potential ability of the 13-aryl (11S)-spiroaziridine derivative 21 to bypass the blood–brain barrier and exhibit anti-glioblastoma activity probably based on the direct interaction with Hsp90α.

AB - Eudesmane-type sesquiterpene lactone isoalantolactone 1 is of great interest due to its availability, biological activity and synthetic application. Respective series of original spirocyclic (11S,5ʹ) (1,2,3-triazoline-eudesma-4,15-enolides) and (11S)-aziridine-eudesma-4,15-enolides were efficiently synthesized via a chemoselective 1,3-dipolar cycloaddition reaction of organic azides to the exocyclic double bond of the lactone ring of isoalantolactone or 13E-(aryl)isoalantolactones by heating in DMF or toluene. The thermal reactions of isoalantolactone with benzyl azide, 2-azidoethanol, or n-butyl azide in 2-methoxyethanol afforded 13-(alkyamino)isoalantolactones formed as a mixture of (Z) and (E)-isomers. The results of in vitro biological assays showed that novel spirocyclic isoalantolactone derivatives exhibited cytotoxicity against human breast cancer and glioblastoma cells at low micromolar concentrations. The most cytotoxic and selective (11S,5ʹ)-spiro-1,2,3-triazoline from 13E-(fluorophenyl)isoalantolactone 20 (IC50(MCF-7) = 8 ± 0.1 µM, SI(MCF-7) > 12.5) was found to induce ROS-dependent death of MCF-7 human breast cancer cells via mitochondrial apoptosis. The corresponding (11S)-spiroaziridine derivatives 21 at non-toxic concentrations (10 and 20 µM) effectively suppressed motility, clonogenicity and adhesion of glioblastoma cells and exhibited synergistic cytotoxicity in combination with temozolomide. In silico analysis revealed the potential ability of the 13-aryl (11S)-spiroaziridine derivative 21 to bypass the blood–brain barrier and exhibit anti-glioblastoma activity probably based on the direct interaction with Hsp90α.

KW - 1,3-Dipolar cycloaddition

KW - 2,3-triazolines

KW - Azides

KW - Isoalatolactone

KW - Selectivity

KW - Sesquiterpene lactones

KW - Spiroaziridines

KW - Spirocyclic 1

KW - Humans

KW - Antineoplastic Agents/pharmacology

KW - Drug Screening Assays, Antitumor

KW - Structure-Activity Relationship

KW - Aziridines/chemistry

KW - Spiro Compounds/chemistry

KW - Molecular Structure

KW - Cell Proliferation/drug effects

KW - Sesquiterpenes/pharmacology

KW - Triazoles/chemistry

KW - Cell Line, Tumor

KW - Dose-Response Relationship, Drug

KW - Apoptosis/drug effects

KW - Sesquiterpenes, Eudesmane/pharmacology

KW - Biological Products/pharmacology

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85214455254&origin=inward&txGid=a258be625b484762c47cee74b3d6e1b2

UR - https://www.mendeley.com/catalogue/5b48ebee-2090-33a9-ade6-6830dfd1499d/

U2 - 10.1016/j.bioorg.2025.108124

DO - 10.1016/j.bioorg.2025.108124

M3 - Article

C2 - 39798454

VL - 155

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

M1 - 108124

ER -