2. Academic Validation
  3. Diaryl disulfides and thiosulfonates as combretastatin A-4 analogues: Synthesis, cytotoxicity and antitubulin activity

Diaryl disulfides and thiosulfonates as combretastatin A-4 analogues: Synthesis, cytotoxicity and antitubulin activity

  • Bioorg Chem. 2020 Aug;101:104017. doi: 10.1016/j.bioorg.2020.104017.
Rejane Gonçalves Diniz Khodyuk 1,  Ruoli Bai 2,  Ernest Hamel 2,  Estela Mariana Guimarães Lourenço 1,  Euzébio Guimarães Barbosa 3,  Adilson Beatriz 1,  Edson Dos Anjos Dos Santos 4,  Dênis Pires de Lima 5
Affiliations

Affiliations

  • 1 Universidade Federal de Mato Grosso do Sul, Instituto de Química, Laboratório LP4, Av. Filinto Müller, 1555, 79074-460 Campo Grande (MS), Brazil.
  • 2 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research (FNLCR), National Cancer Institute (NCI), National Institutes of Health, Frederick, MD 21702, USA.
  • 3 Universidade Federal do Rio Grande do Norte, Departamento de Farmácia (DFAR), Grupo de Pesquisa em Química Computacional, Faculdade de Farmácia, 59012-570 Natal (RN), Brazil.
  • 4 Federal de Mato Grosso do Sul, Instituto de Biociências (INBIO), Laboratório de Bioquímica, Cidade Universitária, 79070-900 Campo Grande (MS), Brazil.
  • 5 Universidade Federal de Mato Grosso do Sul, Instituto de Química, Laboratório LP4, Av. Filinto Müller, 1555, 79074-460 Campo Grande (MS), Brazil. Electronic address: denis.lima@ufms.br.
PMID: 32629276 DOI: 10.1016/j.bioorg.2020.104017
Abstract

Diaryl disulfides and diaryl thiosulfonates were synthesized with the two phenyl rings of all compounds bearing identical halide substituents. Because of structural similarity to the potent antimitotic natural product combretastatin A-4 (CA-4), the compounds were examined for inhibition of tubulin polymerization, and the thiosulfonates were more active than the disulfides. The nine thiosulfonates had IC50 values ranging from 1.2 to 9.1 µM, as compared with 1.3 µM obtained with CA-4. The compounds thus ranged from equipotent with CA-4 to 7-fold less active. The nine disulfides had IC50 values ranging from 1.2 to 5.1 µM, as compared with 0.54 µM obtained with CA-4. The compounds thus ranged from less than half as active as CA-4 to over 9-fold less active. The most active members of each group, 2 g and 3c, in the assembly assay were modeled into the colchicine site. Compound 3c had significant hydrophobic interactions with β-tubulin residues CYS 241 and ALA 250, and its thiosulfonate bridge made a hydrogen bond with β-tubulin residue ASN 258. Compound 2 g had hydrophobic interactions with β-tubulin residues ALA 250, CYS 241 and ALA 254, but there was no significant interaction of the disulfide bridge with tubulin.

Keywords

Combretastatin A-4; Cytotoxicity; Diaryl disulfides; Diaryl thiosulfonates; Tubulin.

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