Synthesis of Tetrahydronaphthalene Lignan Esters by Intramolecular Cyclization of Ethyl p-Azidophenyl-2-phenylalkanoates and Evaluation of the Growth Inhibition of Human Tumor Cell Lines
Abstract
Intramolecular cyclization via nitrenium ion of 2-phenylpentanoic/2-phenylbutanoic acid esters with a terminal p-azidophenyl group gives direct access to tetrahydronaphthalene lignan esters. The p-azidophenyl-substituted butanoate led to an ethyl spirodienone carboxylate, while its homologue pentanoate gave ethyl 4-(4-aminophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylate in good yield. In contrast, the m-azidophenyl-substituted esters suffered aromatic nucleophilic addition of trifluoromethanesulfonate. X-ray crystallography established unequivocally the end products structure, and density functional theory studies were performed to rationalize the cyclization outcome. Reaction intermediates and end products were evaluated for their capacity to inhibit in vitro growth of the cell lines MCF-7 (breast cancer), NCI-H460 (lung cancer), SF-268 (CNS cancer), and UACC-62 (melanoma). Growth inhibition of breast, lung, and CNS cancer cell lines was observed with the spirodienone carboxylate, the m-nitrophenylalkyl iodides, and p-phenyl-substituted elongated ethyl esters, namely, the p-nitrophenylpentanoate and p-aminophenylbutanoate, with the latter being also effective on the melanoma cell line.
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THN-fused C3-spirooxindoles should possess good druglikeness because THN and spirooxindole derivatives are privileged drug-like architectures.
“We started with THN54, 55, 56, 57, 58, 59, 60, 61 and spirooxindole derivatives62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 because they are privileged drug-like architectures, so the resulting THN-fused C3-spirooxindoles should possess good druglikeness (Fig. 2C).”
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- Authors
- Pinto, O., Sardinha, J., Vaz, P. D., Piedade, F., Calhorda, M. J., Abramovitch, R., Nazareth, N., Pinto, M., Nascimento, M. S. J., & Rauter, A. P.
- Affiliations
- University of Lisbon (PT)
- Universidade de Lisboa, Faculdade de Ciências, Centro de Química e Bioquímica/Departamento de Química e Bioquímica (CQB/DQB), Ed. C8, Piso 5, 1749-016 Lisboa, Portugal
- Clemson University (US)
- Centro de Estudos de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Departamento de Ciências Químicas, Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha 164, 4050-047 Porto, Portugal
- Universidade do Porto (PT)
- Corresponding author
- Rauter, Amélia P.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-04-19
- Volume
- 54
- Issue
- 9
- Pages
- 3175-3187
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2323646647
- Cited by
- 27
- References
- 73
- Citations by year
- 2024: 6 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 2 · 2013: 2
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Science and Technology Facilities Council (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant-derived Lignans Synthesis and Bioactivity
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Chemical Reactions and Mechanisms
- Keywords
- intramolecular cyclization, nitrenium ions, structure-activity relationship, antiproliferative activity, MCF-7 cells, NCI-H460 lung cancer cells
- MeSH terms
- Antineoplastic Agents, Azides, Cyclization, Drug Screening Assays, Antitumor, Esters, Humans, Models, Molecular, Spiro Compounds, Structure-Activity Relationship, Tetrahydronaphthalenes, Lignans, Crystallography, X-Ray, Cell Line, Tumor, Cell Proliferation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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