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Thiophene analogues of the carcinogens benzidine and 4-aminobiphenyl: evaluation in vitro
Abstract:
A biologically active molecule with one or more aromatic rings often retains its activity when one of these rings is replaced by an isosteric and/or isoelectronic aromatic ring. Consideration has been given to whether this effect can be expected to apply to aromatic organic carcinogens. The literature relevant to this topic has been reviewed and the thiophene analogues of the carcinogens benzidine and 4-aminobiphenyl have been synthesized and evaluated for potential carcinogenicity. The compounds prepared were 5-p-acetamidophenyl-2-thiophenamine hydrochloride (XIII), 5-phenyl-2-thiophenamine hydrochloride (XIV), N-(5-p-acetamido-phenylthiophen-2-yl)acetamide (XV) and N-(5-phenylthiophen-2-yl)-acetamide (XVI) (see Chart for structures). Each compound was evaluated in the Salmonella reverse-mutation assay of Ames and the cell-transformation assay of Styles. The activity profiles observed for these compounds in vitro were consistent with their known chemistry, and indicate potential carcinogenicity. However, their overall chemical and biological behaviour casts doubt upon whether they would be capable of eliciting tumours in vivo. Because it is important to establish the degree of reliance which can be placed upon in vitro predictions of potential carcinogenicity generated for structurally new compounds, one of the thiophene derivatives, N-(5-phenylthiophen-2-yl)acetamide ((XVI), is currently being evaluated for carcinogenicity in mice.
Insights
Thiophene analogues of aromatic carcinogens were synthesized and tested for mutagenicity. While in vitro tests suggest potential carcinogenicity, their in vivo tumor-forming ability remains uncertain, prompting further mouse studies.
Area of Science:
- Medicinal Chemistry
- Toxicology
- Organic Chemistry
Background:
- Aromatic rings in biologically active molecules can often be replaced by isosteric/isoelectronic rings without losing activity.
- This principle's applicability to aromatic organic carcinogens requires investigation.
Purpose of the Study:
- To synthesize and evaluate thiophene analogues of benzidine and 4-aminobiphenyl for potential carcinogenicity.
- To assess the reliability of in vitro assays for predicting carcinogenicity of novel chemical structures.
Main Methods:
- Synthesis of four thiophene derivatives: 5-p-acetamidophenyl-2-thiophenamine hydrochloride (XIII), 5-phenyl-2-thiophenamine hydrochloride (XIV), N-(5-p-acetamido-phenylthiophen-2-yl)acetamide (XV), and N-(5-phenylthiophen-2-yl)-acetamide (XVI).
- Evaluation of synthesized compounds using the Salmonella reverse-mutation assay (Ames test) and the Styles cell-transformation assay.
- In vitro assessment of mutagenic and cell-transforming activities.
Main Results:
- The synthesized thiophene analogues exhibited activity profiles consistent with their chemical properties.
- In vitro assays indicated potential carcinogenicity for these compounds.
- Observed chemical and biological behavior raised doubts about their in vivo tumor-eliciting capabilities.
Conclusions:
- The in vitro potential carcinogenicity of thiophene analogues needs careful interpretation regarding in vivo effects.
- Further in vivo studies, such as the ongoing mouse carcinogenicity evaluation of N-(5-phenylthiophen-2-yl)acetamide (XVI), are crucial for validating in vitro predictions for novel compounds.