Antitumor Potential of the Isoflavonoids (+)- and (-)-2,3,9-Trimethoxypterocarpan: Mechanism-of-Action Studies

  • ACS Med Chem Lett. 2020 May 20;11(6):1274-1280. doi: 10.1021/acsmedchemlett.0c00097.
Kaio Farias  1 ,  Roner F da Costa  2 ,  Assuero S Meira  1 ,  Jairo Diniz-Filho  1 ,  Eveline M Bezerra  2 ,  Valder N Freire  3 ,  Prue Guest  4 ,  Maryam Nikahd  4 ,  Xinghua Ma  4 ,  Michael G Gardiner  4 ,  Martin G Banwell  4  5 ,  Maria da C F de Oliveira  6 ,  Manoel O de Moraes  1 ,  Claudia do Ó Pessoa  1
Affiliations
  • 1. Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil.
  • 2. Department of Natural Sciences, Mathematics and Statistics, Federal Rural University of the Semi-Arid Region - UFERSA, Mossoró - RN 59625-900, Brazil.
  • 3. Department of Physics, Science Center, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil.
  • 4. Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia.
  • 5. Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou 510632, China.
  • 6. Department of Organic and Inorganic Chemistry, Science Center, Federal University of Ceará, Fortaleza, CE 60430-275, Brazil.
PMID: 32551011 DOI: 10.1021/acsmedchemlett.0c00097
Abstract

Synthetically derived samples of (+)-(6aS,11aS)-2,3,9-trimethoxypterocarpan [(+)-1] and its enantiomer [(-)-1], both of which are examples of naturally occurring isoflavonoids, were evaluated, together with the corresponding racemate, as cytotoxic agents against the HL-60, HCT-116, OVCAR-8, and SF-295 tumor cell lines. As a result it was established that compound (+)-1 was particularly active with OVCAR-8 cells being the most sensitive and responding in a dose-dependent manner. A study of cell viability and drug-induced morphological changes revealed the compound causes cell death through a mechanism characteristic of Apoptosis. Finally, a computational study of the interactions of compound (+)-1 and (S)-monastrol, an established, synthetically derived, potent, and cell-permeant inhibitor of Mitosis, with the kinesin-type protein Eg5 revealed that both bind to this receptor in a similar manner. Significantly, compound (+)-1 binds with greater affinity, an effect attributed to the presence of the associated methoxy groups.