In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: Identifying sinensetin as a novel antiangiogenesis agent

Abstract

The in vivo structure-activity relationship (SAR) analysis indicated that a flavonoid with a methoxylated group at the C3' position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity. This study provides new insight into how modification of the chemical structure of polymethoxylated flavonoids affects this newly identified antiangiogenesis activity.

Anticancer Activities of Citrus Peel Polymethoxyflavones Related to Angiogenesis and Others

“…Nobiletin differs from sinensetin by having methylation at the C8 position. Together with previous research of nobiletin [55], structure-activity relationship analysis indicated that the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity via observing intersegmental vessel development in zebrafish embryos [54]. …”

“…Sinensetin, which showed the most potent antiangiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes flt1 , kdrl , and hras in zebrafish [54]. Nobiletin differs from sinensetin by having methylation at the C8 position.…”

Antivascular and anti-parasite activities of natural and hemisynthetic flavonoids from New Caledonian Gardenia species (Rubiaceae)

“…Noticeable anti-parasitic activity has been reported for flavones and related secondary metabolites such as flavanones, chalcones or catechins [22,24] and for semisynthetic analogs [28]. Nevertheless, with the exception of santin (8) [12], 5,7-dihydroxy-3,6-dimethoxyflavones have never been screened against this type of target.…”

<i>Citrus</i> Flavonoids and Human Cancers

“…In this regard, Citrus flavonoids have been shown to target tumor angiogenesis. Lam et al [127] reported that hydroxylated PMFs suppressed the expression of VEGF and MMP-9 in colonic tumors. Sinensetin, a common PMFs found in Citrus fruits, which showed the most potent anti-angiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes fl1, kdrl, and hras in zebrafish.…”