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Figure 1. Principal categories of natural flavonoids

[31]
be included in a vitamin category) greatly enhanced the antiscorbutic activity of L-ascorbic acid , which
commenced lasting interest in their pharmacological activity. Flavonoids constitute a class of ubiquitous
plant metabolites, which stem from common biogenetic transformation, combining shikimic acid -
phenylalanine, and acetyl CoA pathways, resulting in the assembly of a phenylpropanoid scaffold ending
up as 2- or 3-phenylchromane derivatives, categorized as: flavones, flavanones, catechins, anthocyanidins,
and isoflavones [26,27] . These structures tend to be further diversified biocatalytically by oxidation, hydroxyl
group alkylation (methylation, isoprenylation), and/or glycosylation, but also by C-C coupling reactions,
which lead to oligomerization and polymerization, producing in turn a wide array of structural variety,
and consequently a very complex matrix of biological activity (Figure 1 shows low-molecular-weight
flavonoids only). Presently, it is clear that the biogenesis of flavonoids, which is common throughout the
plant kingdom, can be considered one of the most significant evolutionary developments, occurring first as
[32]
a protective environmental adaptation and further adopted for many other functions .
In the last decades, hundreds of new papers devoted to the biological activity of plant flavonoids
(including review papers) have appeared in the scientific literature. The majority have dealt with preclinical
pharmacology, studied using molecular and subcellular models, as well as cell lines and experimental
animals [33-40] . Antioxidant activity and anti-inflammatory pathways were among the favorite study
subjects . Cancer prevention and anticancer activity evoked continuous interest [20,30] and the proportion
[28]
of papers heralding the intimate connection between flavonoids and cancer is remarkably high [37-41] .
Comments on flavonoid systemic activity point out their limited bioavailability [42,43] , which offers poor
prognosis for clinical efficacy. Despite encouraging results in many preclinical studies, no flavonoid drug
candidate could be seen advancing beyond early stages of clinical trials until very recently. A breakthrough
came from the side of dihydrochalcone - phloretin glycoside, (phlorizin, known since the mid-XIXth