Synthesis and SAR Studies of Novel Oxazolyl- and Thiazolyl-indoles and Their Intermediates as Selective Antiproliferative Agents Against HL-60 Leukemia and C6 Glioma Cell Lines.

in ChemMedChem by Patrik Pollák, Boglárka Szele, Máté Varga, Alexandra Paszternák, Kamilla Varga, András Dancsó, Gyula Simig, Balázs Volk, Tamás Tábi, Mátyás Milen

TLDR

  • Novel small molecules with selective antitumor effects were synthesized, demonstrating promising antiproliferative and cytotoxic properties. Sulfur-containing compounds and the presence of a chlorine substituent improved potency and cancer selectivity.

Abstract

1,3-Oxazole-2-carboxamides, -carbothioamides and their 1,3-thiazole analogues coupled with indoles were synthesized with promising selective antitumor effects. All compounds were prepared from tryptamine derivatives in 3-5 reaction steps including a Robinson-Gabriel cyclization to construct the oxazole or thiazole ring. The pharmacological activities of the intermediates and target compounds were assessed. Our findings revealed several novel small molecules with cancer cell-specific antiproliferative and/or cytotoxic properties, tested on HL-60 leukemia and C6 glioma cell lines. The 3-heteroarylindole target compounds demonstrated greater effectiveness compared to their acyclic intermediates. Notably, only the sulfur-containing compounds, such as thiazoles and the intermediates containing an acyclic side chain with a carbothioamide group showed significant antiproliferative properties. This activity was further enhanced by adding an extra sulfur atom, either by replacing oxazole heterocycles with thiazoles or by modifying carboxamides into carbothioamides. Additionally, the presence of a chlorine substituent at position 5 of the indole ring improved both the potency and cancer selectivity of the compounds. The synthesized novel compounds and the reported synthetic methodologies present valuable tools for drug discovery aiming at emerging pharmacological targets in the field of oncology.

Overview

  • The study focuses on the synthesis of novel small molecules with selective antitumor effects, comprising 1,3-oxazole-2-carboxamides, -carbothioamides, and their 1,3-thiazole analogues coupled with indoles.
  • The compounds were prepared from tryptamine derivatives in 3-5 reaction steps, including a Robinson-Gabriel cyclization to construct the oxazole or thiazole ring.
  • The primary objective is to identify novel small molecules with cancer cell-specific antiproliferative and/or cytotoxic properties, tested on HL-60 leukemia and C6 glioma cell lines.

Comparative Analysis & Findings

  • The study reveals several novel small molecules with cancer cell-specific antiproliferative and/or cytotoxic properties, with the 3-heteroarylindole target compounds demonstrating greater effectiveness compared to their acyclic intermediates.
  • Only the sulfur-containing compounds, such as thiazoles and carbothioamides, showed significant antiproliferative properties, with the presence of an extra sulfur atom enhancing these activities.
  • The presence of a chlorine substituent at position 5 of the indole ring improved both the potency and cancer selectivity of the compounds.

Implications and Future Directions

  • The synthesized novel compounds and reported synthetic methodologies present valuable tools for drug discovery aiming at emerging pharmacological targets in the field of oncology.
  • Future research directions could involve further optimization of the compounds, investigating their mechanisms of action, and testing their efficacy in animal models.
  • Developing these molecules into viable therapeutic agents could provide new hope for cancer treatment, particularly for pediatric and adult cancers with poor treatment options.
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