2. Academic Validation
  3. Structural hybridization as a tool for developing novel biologically active analogues of protulactone A

Structural hybridization as a tool for developing novel biologically active analogues of protulactone A

  • Bioorg Chem. 2026 Feb:169:109416. doi: 10.1016/j.bioorg.2025.109416.
Sanja Djokić 1,  Mirjana Popsavin 1,  Slađana Stanisavljević 1,  Marko V Rodić 1,  Biljana Krüger 2,  Brankica Filipić 3,  Dimitar Jakimov 4,  Marija Hefer 5,  Ana Petrović 5,  Srdjan Bjedov 1,  Martina Smolić 5,  Velimir Popsavin 6,  Jovana Francuz 7
Affiliations

Affiliations

  • 1 University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
  • 2 University of Innsbruck, Institute of Mineralogy and Petrography, Innrain 52, 6020 Innsbruck, Austria.
  • 3 University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia.
  • 4 University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Put doktora Goldmana 4, 21204 Sremska Kamenica, Serbia.
  • 5 J. J. Strossmayer University of Osijek, Faculty of Dental Medicine and Health, Crkvena 21, 31000 Osijek, Croatia.
  • 6 University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia; Serbian Academy of Sciences and Arts, Kneza Mihaila 35, 11000 Belgrade, Serbia.
  • 7 University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: jovana.francuz@dh.uns.ac.rs.
PMID: 41435775 DOI: 10.1016/j.bioorg.2025.109416
Abstract

The study described in the manuscript includes the synthesis of twelve novel hybrid analogues of protulactone A and the evaluation of their antiproliferative activity against a panel of ten tumour and one normal human cell line (foetal lung fibroblasts, MRC-5). The key step in the synthesis was the Grignard addition of PhMgBr to the aldehyde derived from d-galactose, followed by removal of the 1,2-O-isopropylidene protecting group and cyclocondensation of the resulting lactols with Meldrum's acid to build the [3.3.0]furofuranone core. After routine manipulation with present functional groups, the natural product protulactone A and several new hybrid analogues were obtained, ready for biological testing. Several analogues, particularly compounds 9, 13, and 16, showed IC₅₀ values below 10 μM against leukaemia (K562, HL-60), breast (MCF-7, MDA-MB-231), and cervical (HeLa) Cancer cells. Selected derivatives (3, 8, 11) further reduced MRP1 levels and induced Apoptosis through Caspase-3 activation in K562 cells, indicating their potential as modulators of multidrug resistance. Structure-activity relationship analysis revealed that the introduction of a phenyl group at the C-7 position and specific stereochemical configurations significantly enhanced cytotoxic potency. Importantly, none of the analogues displayed Antibacterial or Antifungal activity, underscoring their selectivity for tumour cells. Cellular LC-MS/MS profiling revealed that compound 11 achieves uniform high uptake but remains non-toxic to normal cells, demonstrating true pharmacodynamic Cancer selectivity. These findings highlight the structural hybridization of protulactone A and styryl lactone as a rational strategy for designing novel Anticancer agents with selectivity and relevance in drug resistance contexts.

Keywords

Antimicrobial activity; Antiproliferative activity; Goniofufurone; Hybrid molecules; Natural products; Protulactone a; Structural hybridization.

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