The 1,2,4-triazole nucleus is recognized as a key pharmacophore being present in a wide variety of biologically active compounds, including anticancer agents. In the previous years, we synthesized a series of imidazo[1,2-b]pyrazole derivatives, which exhibited notable anti-cancer, anti-angiogenic, and anti-inflammatory activities, with anti-proliferative effects in the low micromolar IC₅₀ range against selected tumor cell lines. Among these, compound Ia showed significant cytotoxicity against both patient-derived melanoma cells (MEOV NT) and Vemurafenib-resistant melanoma cells (MEOV PLX-R), highlighting its potential as a lead compound for melanoma therapy. Additionally, compound Ib displayed low micromolar IC₅₀ values against the SKMEL-28 melanoma cell line, and proteomic analyses revealed its ability to downregulate Ras-responsive element-binding protein 1 (RREB1), a key regulator in melanoma pathogenesis. To further explore the structure-activity relationships of this scaffold and improve anti-proliferative activity, we designed and synthesized a novel series of compounds, incorporating a 1,2,4-triazole moiety at position 7 of the imidazo[1,2-b]pyrazole core. These molecules were further functionalized with a substituted phenyl ring at position 4 of the triazole (structurally related to the catechol moiety of I), and either a thiomethyl (compounds 1a–g) or a hydroxy group (compound 1h) at position 3. Preliminary screening performed by the National Cancer Institute on a panel of 60 cancer cell lines identified compound 1h as the most promising candidate. Subsequent investigations assessed the cytotoxic and pro-oxidant effects of the compound in MeOV and MeTRAV human metastatic melanoma cell lines as well as its mom-mutagenic activity in normal HaCAT keratinocytes, thus enhancing its selectivity toward cancer cells. Additionally, in silico predictions of drug-like and pharmacokinetic properties, along with micellar solubilization studies, were conducted to further support the development of imidazo[1,2-b]pyrazole-based as interesting lead structures to counteract melanoma.
Novel Triazol-imidazo[1,2-b]pyrazoles Selectively Impair Melanoma Cell Survival While Preserving Healthy Keratinocyte Viability
Matteo Lusardi;Chiara Brullo;Barbara Marengo;Cinzia Domenicotti;Elena Cichero;Annalisa Salis;Debora Caviglia;Eleonora Russo;Andrea Spallarossa
2025-01-01
Abstract
The 1,2,4-triazole nucleus is recognized as a key pharmacophore being present in a wide variety of biologically active compounds, including anticancer agents. In the previous years, we synthesized a series of imidazo[1,2-b]pyrazole derivatives, which exhibited notable anti-cancer, anti-angiogenic, and anti-inflammatory activities, with anti-proliferative effects in the low micromolar IC₅₀ range against selected tumor cell lines. Among these, compound Ia showed significant cytotoxicity against both patient-derived melanoma cells (MEOV NT) and Vemurafenib-resistant melanoma cells (MEOV PLX-R), highlighting its potential as a lead compound for melanoma therapy. Additionally, compound Ib displayed low micromolar IC₅₀ values against the SKMEL-28 melanoma cell line, and proteomic analyses revealed its ability to downregulate Ras-responsive element-binding protein 1 (RREB1), a key regulator in melanoma pathogenesis. To further explore the structure-activity relationships of this scaffold and improve anti-proliferative activity, we designed and synthesized a novel series of compounds, incorporating a 1,2,4-triazole moiety at position 7 of the imidazo[1,2-b]pyrazole core. These molecules were further functionalized with a substituted phenyl ring at position 4 of the triazole (structurally related to the catechol moiety of I), and either a thiomethyl (compounds 1a–g) or a hydroxy group (compound 1h) at position 3. Preliminary screening performed by the National Cancer Institute on a panel of 60 cancer cell lines identified compound 1h as the most promising candidate. Subsequent investigations assessed the cytotoxic and pro-oxidant effects of the compound in MeOV and MeTRAV human metastatic melanoma cell lines as well as its mom-mutagenic activity in normal HaCAT keratinocytes, thus enhancing its selectivity toward cancer cells. Additionally, in silico predictions of drug-like and pharmacokinetic properties, along with micellar solubilization studies, were conducted to further support the development of imidazo[1,2-b]pyrazole-based as interesting lead structures to counteract melanoma.
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