**Mai Khater 1,2, Francesca Greco <sup>1</sup> and Helen M. I. Osborn 1,\***


Academic Editor: H.P. Vasantha Rupasinghe Received: 18 August 2020; Accepted: 10 October 2020; Published: 14 October 2020

**Abstract:** An imbalance of angiogenesis contributes to many pathologies such as cancer, arthritis and retinopathy, hence molecules that can modulate angiogenesis are of considerable therapeutic importance. Despite many reports on the promising antiangiogenic properties of naturally occurring flavonoids, no flavonoids have progressed to the clinic for this application. This systematic review and meta-analysis therefore evaluates the antiangiogenic activities of a wide range of flavonoids and is presented in two sections. The first part of the study (Systematic overview) included 402 articles identified by searching articles published before May 2020 using ScienceDirect, PubMed and Web of Science databases. From this initial search, different classes of flavonoids with antiangiogenic activities, related pathologies and use of in vitro and/or in/ex vivo angiogenesis assays were identified. In the second part (Meta-analysis), 25 studies concerning the antiangiogenic evaluation of flavonoids using the in vivo chick chorioallantoic membrane (CAM) assay were included, following a targeted search on articles published prior to June 2020. Meta-analysis of 15 out of the 25 eligible studies showed concentration dependent antiangiogenic activity of six compared subclasses of flavonoids with isoflavones, flavonols and flavones being the most active (64 to 80% reduction of blood vessels at 100 μM). Furthermore, the key structural features required for the antiangiogenic activity of flavonoids were derived from the pooled data in a structure activity relationship (SAR) study. All in all, flavonoids are promising candidates for the development of antiangiogenic agents, however further investigations are needed to determine the key structural features responsible for their activity.

**Keywords:** flavonoids; angiogenesis; inflammation; cancer; in-vivo angiogenesis; CAM assay; SAR
