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

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.

The Isoflavanoid (+)‐PTC Regulates Cell‐Cycle Progression and Mitotic Spindle Assembly in a Prostate Cancer Cell Line

“…In particular, they display cytotoxic effects against, inter alia, hematological, breast, colon, glioblastoma, and ovarian malignancies while being non-cytotoxic toward, for example, PBMCs. [7,11,[13][14][15] The anti-proliferative effects of the isoflavonoid (+)-PTC are manifest in its capacity to increase apoptosis in the target cells. This occurs due to a disruption of mitosis, in silico studies of which suggest are a consequence of the compound's interaction with Eg5, a kinesin-related motor protein.…”

“…Thus, while the so‐treated cells achieve bipolarity (without affecting centriole duplication), the compound promotes collapse of bipolar spindles [19] . This is likely the result of (+)‐PTC inhibiting the function of Eg5 [7] …”

“…monoasters. [4,5] Certain pterocarpans display anti-proliferative, [6,7] anti-estrogenic [8] anti-oxidant and anti-inflammatory activities. [9,10] As such they constitute potential regulators of mitosis.…”

“…[19] This is likely the result of (+)-PTC inhibiting the function of Eg5. [7] Prostate cancer (PC) is the second most common malignancy in men and the fifth leading cause of cancer death in several parts of the world. [20] Although presenting favorable outcomes when confined to the prostate, some 20 % of patients confront a poor prognosis when afflicted by metastatic forms of the disease.…”

Asymmetric hydrogenation and transfer hydrogenation in the enantioselective synthesis of flavonoids

“…20 Finally, the antiproliferative activity of both enantiomers of 2,3,9-trimethoxypterocarpan was recently evaluated; the (+)-( S , S )-enantiomer, isolated from Platymiscium floribundum , showed in vitro cytotoxicity 400-fold more potent in comparison with the (−)-( R , R )-enantiomer, isolated from Pisium sativum infected with Fusarium solani . 21…”