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Regio- and Diastereoselective Arylation of rosin acids: A practical strategy for bioactive compounds discovery
Farked S Wahoodi1, Antonio Fernández1, Juan Sainz2
1Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain.
Abstract:
A mild, sustainable, and cost-effective arylation of rosin-acids is reported. This new approach, based on a regio- and diastereoselective Friedel-crafts alkylation, enabled the synthesis of fourteen new resin acid derivatives. Selected compounds were screened for cytotoxic activity against three human tumor cell lines. Remarkably, quinone 14 exhibited significant activity: Against HL-60 cells (IC₅₀ = 5.94 μM) cell, and phenol 11f displayed selective cytotoxic activity against HT-29 cells (IC₅₀ = 8.90 μM) cells. Flow cytometry confirmed apoptosis as the primary mechanism of cell death, reaching 78% in HL-60 (14) and 72.6% in HT-29 (11 g), with minimal necrosis. Cell-cycle analysis showed S-phase arrest in HL-60 (14) and G0/G1 arrest in HT-29 (11f/11 g). Consistently, ΔΨm assays showed near-complete collapse in HL-60 (14) and significant depolarization in HT-29 (11 g). In addition, the anti-inflammatory activity of some synthesized compounds was assessed in LPS-stimulated RAW 264.7 macrophages. All tested compounds achieved 70-100% NO inhibition at subcytotoxic concentrations. Derivatives 13 and 14 showed the highest activity (IC50 NO = 0.85 μM and 5.43 μM, respectively). Overall, this green arylation approach enables rapid access to 7-aryl methyl ester dehydroabietic acid libraries with significant cytotoxic and anti-inflammatory activities.
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