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  3. Photochemical Metal-Free synthesis and biological Assessment of isocryptolepine analogues targeting estrogen receptor Alpha in breast cancer cells

Photochemical Metal-Free synthesis and biological Assessment of isocryptolepine analogues targeting estrogen receptor Alpha in breast cancer cells

  • Bioorg Chem. 2024 Dec:153:107942. doi: 10.1016/j.bioorg.2024.107942.
F B Bogdanov 1,  R Yu Balakhonov 2,  E S Volkov 3,  I V Sonin 4,  O E Andreeva 5,  D V Sorokin 6,  Yu A Piven 7,  A M Scherbakov 8,  V Z Shirinian 9
Affiliations

Affiliations

  • 1 Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24 bldg.15, 115522 Moscow, Russia; Faculty of Medicine, Moscow State University, Lomonosov prospect 27 bldg.1, 119991 Moscow, Russia. Electronic address: f.bogdanov.f@yandex.ru.
  • 2 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow, Russia. Electronic address: balakhnvrman3@gmail.com.
  • 3 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow, Russia. Electronic address: esvolkov@inbox.ru.
  • 4 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow, Russia. Electronic address: igors3112@list.ru.
  • 5 Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24 bldg.15, 115522 Moscow, Russia. Electronic address: o.andreeva@ronc.ru.
  • 6 Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24 bldg.15, 115522 Moscow, Russia. Electronic address: d.sorokin@ronc.ru.
  • 7 Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Akad. Kuprevicha st. 5/2, Minsk 220084, Belarus. Electronic address: piven.ya@gmail.com.
  • 8 Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24 bldg.15, 115522 Moscow, Russia; Gause Institute of New Antibiotics, Bol'shaya Pirogovskaya ulitsa 11, 119021 Moscow, Russia. Electronic address: alex.scherbakov@gmail.com.
  • 9 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow, Russia. Electronic address: svbegunt@mail.ru.
PMID: 39515131 DOI: 10.1016/j.bioorg.2024.107942
Abstract

The aim of this study was to develop a new series of isocryptolepines and evaluate their antiproliferative and antiestrogenic activities on Cancer cells. A series of isocryptolepine derivatives were synthesized using developed one-pot photochemical, metal-free protocol, employing readily available 2-arylindoles as starting compounds. The resulting isocryptolepines demonstrated (sub)micromolar inhibitory activity against selected breast Cancer cell lines. The IC50 values ​​of lead compound 3c against hormone-dependent breast Cancer types (MCF7 and T47D) were 0.3 μM and 0.12 μM, respectively, and significantly greater than 3 μM against Estrogen Receptor α (ERα)-deficient cell lines, MDA-MB-231 and HCC1954, respectively. To assess the antiestrogenic potency of compound 3c, MCF7 cells were transfected with a plasmid containing a luciferase reporter gene under the control of an estrogen-responsive element (ERE), creating the MCF7/ERE-LUC cell subline. In these cells, luciferase activity was induced by the natural ERα ligand, 17β-estradiol (E2). Compound 3c inhibited luciferase activity by 50 % at a concentration of 0.12 μM, highlighting its potent inhibitory effect on ERα. Molecular modeling further indicated that compound 3c could directly bind to ERα. Compound 3c induced Apoptosis, as evidenced by PARP cleavage and downregulation of p-Bcl-2 and Bcl-2, and demonstrated synergistic effects in combination with the chemotherapeutic agent 5-fluorouracil. Compound 3c also showed selectivity towards hormone-dependent breast Cancer cells, likely targeting ERα - a key driver in this Cancer subtype. In summary, we report the development of a first-in-class antiestrogenic isocryptolepine with notable pro-apoptotic efficacy.

Keywords

2-c]quinolines; Antiestrogenic potency; Antiproliferative activity; Breast cancer; Indolo[3; Isocryptolepines.

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