Open AccessAntitumor Potential of the Isoflavonoids (+)- and (−)-2,3,9-Trimethoxypterocarpan: Mechanism-of-Action Studies
Author(s) -
Kaio Moraes de Farias,
Roner F. da Costa,
Assuero Silva Meira,
Jairo Diniz-Filho,
Eveline M. Bezerra,
V. N. Freire,
P. G. Guest,
Maryam Nikahd,
Xinghua Ma,
Michael G. Gardiner,
Martin G. Banwell,
Maria da Conceição Ferreira de Oliveira,
Manoel O. de Moraes,
Cláudia Pessoa
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00097
Subject(s) - mechanism of action , apoptosis , chemistry , mitosis , enantiomer , cytotoxic t cell , stereochemistry , mechanism (biology) , cell culture , cytotoxicity , drug , cell , receptor , pharmacology , in vitro , biochemistry , computational biology , combinatorial chemistry , biology , microbiology and biotechnology , genetics , philosophy , epistemology
Synthetically derived samples of (+)-(6a S ,11a S )-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.