Natural product protulactone A: Total synthesis from D-galactose, X-ray analysis and biological evaluation

Bioorg Chem. 2022 Oct:127:105980. doi: 10.1016/j.bioorg.2022.105980. Epub 2022 Jun 23.

Abstract

Synthesis of protulactone A (PLA, 1) and twelve of its analogues have been achieved starting from d-galactose. PLA was isolated in the crystalline state, and its crystal structure was determined utilizing X-ray crystallography, which confirmed the assumed stereochemistry at all stereocenters. All tested compounds displayed antiproliferative activity against a panel of tumour cell lines, and all of them were non-cytotoxic toward the normal cells (MRC-5). Natural product PLA (1) was the most active against the K562 and MCF-7 cell lines (IC50 6.52 and 2.20 μM, respectively). Some of the synthesized derivatives showed very potent cytotoxicity, especially analogues 11, 13 and 15 (IC50 1.08-1.14 μM against MCF-7), and 9 and 14 (IC50 1.29 and 1.64 μM against K562). SAR analysis indicated important structural motifs for antiproliferative activity. Unfortunately, PLA (1), its C-7 epimer (2) and demethylated analogue (3) did not display a significant antimicrobial activity (two Gram-positive and two Gram-negative bacteria and one fungal strain) and they also cannot affect the ability to modulate bacterial communication.

Keywords: Antimicrobial activity; Antiproliferative activity; Bicyclic lactone; Natural product; Protulactone A; X-ray analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Biological Products* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Screening Assays, Antitumor
  • Galactose
  • Humans
  • Molecular Structure
  • Polyesters / pharmacology
  • Polyketides
  • Structure-Activity Relationship
  • X-Rays

Substances

  • Antineoplastic Agents
  • Biological Products
  • Polyesters
  • Polyketides
  • protulactone A
  • Galactose