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

Kaio Farias; Roner F da Costa; Assuero S Meira; Jairo Diniz-Filho; Eveline M Bezerra; Valder N Freire; Prue Guest; Maryam Nikahd; Xinghua Ma; Michael G Gardiner; Martin G Banwell; Maria da C F de Oliveira; Manoel O de Moraes; Claudia do Ó Pessoa

doi:10.1021/acsmedchemlett.0c00097

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. eCollection 2020 Jun 11.

Authors

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.

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.