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. 2023 Apr 17;22(1):e133868.
doi: 10.5812/ijpr-133868. eCollection 2023 Jan-Dec.

Design, Synthesis, and Investigation of Cytotoxic Effects of 5-Hydroxyindole-3-Carboxylic Acid and Ester Derivatives as Potential Anti-breast Cancer Agents

Arezo Teymori  1 , Shaya Mokhtari  2   3 , Anna Sedaghat  1 , Arash Mahboubi  4 , Farzad Kobarfard  1   2   3
Affiliations

Design, Synthesis, and Investigation of Cytotoxic Effects of 5-Hydroxyindole-3-Carboxylic Acid and Ester Derivatives as Potential Anti-breast Cancer Agents

Arezo Teymori et al. Iran J Pharm Res. .

Abstract

Breast cancer is a deadly disease with a high prevalence rate among females. Despite several treatments, scientists are still engaged in finding less invasive treatments for this disease. The cellular proliferation rate and cell viability survey are critical to assess the drug's effect on both normal and malignant cell populations. Indole derivatives are promising candidates for their cytotoxic effect causing on breast cancer cells; however, they are less toxic on normal cells. This study synthesized 23 novel 5-hydroxyindole-3-carboxylic acids and related esters featuring various linear, cyclic, and primary aromatic amines. The MTT assay indicated the cytotoxicity of all acid and ester derivatives against the MCF-7 cells with no significant cytotoxicity on normal human dermal fibroblasts cells. Compound 5d, an ester derivative possessing a 4-methoxy group, was the most potent compound, with a half-maximal effective concentration of 4.7 µM. Compounds 5a, 5d, and 5l bearing ester group in their structure demonstrated cytotoxicity values < 10 µM against the MCF-7 cell line and were safe for advanced screening.

Keywords: 5-Hydroxy Indole; Human Breast Cancer Cell Line (MCF-7); MTT Assay; Survivin.

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Conflict of interest statement

No financial or research support has been used in this article, and the authors of this article are students and faculty members of Shahid Beheshti University and are not employed by any particular organization. This article has no personal financial interest for any of the authors. The authors of this article do not have any kind of shares in any particular company and have not received or given any fees for consulting. This article is not and will not be patented anywhere. There are no personal relationships in this article. Membership without dues in a governmental or non-governmental organization. None of the authors of this article is a member of the editorial board or reviewer of this journal.

Figures

Figure 1.
Figure 1.. Natural and medicinal compounds bearing indole scaffold
Figure 2.
Figure 2.. Structure of lead compounds (1-4) and the present study’s designed structures (6a-k)
Figure 3.
Figure 3.. Synthesis of 5-hydroxyindole-carboxylic acid derivatives
Figure 4.
Figure 4.. Half-maximal effective concentration in MCF-7 and human dermal fibroblasts for target indole esters (5) and acids (6). HDF, human dermal fibroblasts; EC50, half-maximal effective concentration; SI, selectivity index.
Figure 5.
Figure 5.. Binding modes of ethyl 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1h-indole-3-carboxylate (5d) in the active site of survivin protein (PDB entry: 3UIH)
Figure 6.
Figure 6.. Comparison of log P for ester and acid derivatives of 5-hydroxyindole derivatives
See this image and copyright information in PMC

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