2. Academic Validation
  3. Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency

Discovery of derivatives of 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: novel, hypoxia-selective HIF-1α inhibitors with strong antiestrogenic potency

  • Bioorg Chem. 2020 Nov;104:104324. doi: 10.1016/j.bioorg.2020.104324.
Galina I Buravchenko 1,  Alexander M Scherbakov 2,  Lyubov G Dezhenkova 3,  Evgeny E Bykov 4,  Svetlana E Solovieva 4,  Alexander A Korlukov 5,  Danila V Sorokin 6,  Lianet Monzote Fidalgo 7,  Andrey E Shchekotikhin 8
Affiliations

Affiliations

  • 1 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia. Electronic address: buravchenkogi@gmail.com.
  • 2 Blokhin National Medical Research Center of Oncology, 24 Kashirskoye sh., Moscow 115522, Russia. Electronic address: alex.scherbakov@gmail.com.
  • 3 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia. Electronic address: dezhenkovalg@yahoo.com.
  • 4 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
  • 5 Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St., Moscow 119991, Russia.
  • 6 Blokhin National Medical Research Center of Oncology, 24 Kashirskoye sh., Moscow 115522, Russia. Electronic address: dsorokin2018@gmail.com.
  • 7 Department of Parasitology, Pedro Kouri Tropical Medicine Institute, Havana, Cuba. Electronic address: monzote@ipk.sld.cu.
  • 8 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia. Electronic address: shchekotikhin@mail.ru.
PMID: 33142432 DOI: 10.1016/j.bioorg.2020.104324
Abstract

In this article, we describe the synthesis of 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides bearing cyclic diamine residues at positions 6 or 7; the synthesis is based on the nucleophilic substitution of halogens. All synthesized 6(7)-aminoquinoxaline-2-carbonitrile 1,4-dioxides 3-6 demonstrated higher cytotoxicity and hypoxia selectivity compared to the reference agent tirapazamine against breast adenocarcinoma cell lines (MCF7, MDA-MB-231). The structure and position of the diamine residue considerably affects the antiproliferative properties of the quinoxaline-2-carbonitrile 1,4-dioxides. The introduction of a halogen atom at position 7 in the quinoxaline ring of 4a considerably increases the cytotoxicity of compounds 5a and 6a under both normoxic and hypoxic conditions. However, the most hypoxia-selective derivatives were non-halogenated 7-aminosubstituted 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides 3a-j. Of the 32 novel synthesized derivatives, approximately 20 of the 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides demonstrated high antiproliferative potency against wild type leukemia cells K562 and drug-resistant subline K562/4 with the expression of P-glycoprotein (p-gp) compared to the reference agent doxorubicin, which exhibited one order of magnitude lower activity towards K562/4 cells than towards K562 cells. Lead compounds 5a and 3f inhibited HIF-1α expression and activity and induced Apoptosis in hypoxic tumor cells, which was confirmed by poly(ADP-ribose)polymerase (PARP) cleavage. Moreover, 5a and 3f showed strong antiestrogenic potencies in MCF7 breast Cancer cells. Thus, the described series of quinoxaline 1,4-dioxides has high Anticancer potential and good aqueous solubility. Therefore, these compounds are promising for further drug development of hypoxia-targeted Anticancer agents.

Keywords

Antiestrogenic potency; Antiproliferative activity; ERK 1/2 signaling pathway; HIF-1α; Hypoxia selectivity; Quinoxaline-2-carbonitrile 1,4-dioxide.

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