In Search of Bioactivity – Phyllobilins, an Unexplored Class of Abundant Heterocyclic Plant Metabolites from Breakdown of Chlorophyll

Abstract

The fate of the green plant pigment chlorophyll (Chl) in de‐greening leaves has long been a fascinating biological puzzle. In the course of the last three decades, various bilin‐type products of Chl breakdown have been identified, named phyllobilins (PBs). Considered ‘mere’ leftovers of a controlled biological Chl detoxification originally, the quest for finding relevant bioactivities of the PBs has become a new paradigm. Indeed, the PBs are abundant in senescent leaves, in ripe fruit and in some vegetables, and they display an exciting array of diverse heterocyclic structures. This review outlines briefly which types of Chl breakdown products occur in higher plants, describes basics of their bio‐relevant structural and chemical properties and gives suggestions as to ‘why’ the plants produce vast amounts of uniquely ‘decorated’ heterocyclic compounds. Clearly, it is worthwhile to consider crucial metabolic roles of PBs in plants, which may have practical consequences in agriculture and horticulture. However, PBs are also part of our plant‐based nutrition and their physiological and pharmacological effects in humans are of interest, as well.

An evergreen mind and a heart for the colors of fall

“…Among these are yellow phyllobilins (YCCs and DYCCs), first described in 2008 ( Moser et al , 2008b ) and 2019 ( Li et al , 2019 ), respectively, and now classified as phylloxanthobilins, which are readily oxidized further to the corresponding pink products (PiCCs and DPiCCs, classified as phylloroseobilins) ( Kräutler, 2016 ). The phyllochromobilins promise to have interesting biological properties, contrasting with the earlier characterization of the chlorophyll breakdown pathway as a mere detoxification mechanism ( Moser and Kräutler, 2019 ; Karg et al , 2020 ).…”

Facile retro-Dieckmann cleavage of a pink phyllobilin: new type of potential downstream steps of natural chlorophyll breakdown

“…Thus, the discovery of the natural yellow-and pink-coloured PBs induced a first, decisive, consideration of their possible biological function as coloured pigments [11,31]. In more recent years, a number of biological roles have been suggested for the natural PBs [4,32], e.g., in signalling [33,34], as highly effective polar antioxidants [32,35], as metal chelators [21,28], as potential chromophores, and as inhibitors of the biosynthetic assembly of photoreceptors [4]. The striking blue luminescence of the colourless fluorescent Chl-catabolites [36], specifically of their persistent 'hypermodified' type (discovered in bananas [33,37]), may serve the communication between plants and (frugivorous) animals [4,36].…”

“…The degradation of the Chls in higher plants involves, roughly, 1000 million tons each year [1]. Thus, the natural Chl-breakdown via the PaO/phyllobilin pathway generates massive amounts of diverse PBs [7,8], polar natural products with remarkable heterocyclic structures [4,5,31], whose potential for a range of interesting biological roles should not be overlooked [23,32,38]. At various developmental stages, especially during leaf senescence [39] and fruit ripening [35,40], plant cells are 'flooded' with Chl-catabolites.…”

Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives

“…However, these properties do not fully illustrate/predict their biological effects in the cell; therefore, it is necessary to evaluate different heterocycle subtypes and consider their impact on biological systems. Heterocyclic compounds also occur in the environment as part of plant secondary metabolites [ 3 , 4 ] and show various effects, including in vitro cytotoxicity towards some cancer cell lines [ 5 ]. Many other heterocyclic compounds with high biological importance, such as serotonin, histidine, etc., are spread in the human organism.…”

“…It was reported that rel - N -(2,4-dichlorophenyl)-2-[(5aR,11bR)-2-oxo-5a,11b-dihydro-2 H ,5 H -chromeno[4′,3′:4,5]thiopyrano[2,3- d ][ 1 , 3 ]thiazol-3(6 H )-yl]acetamide (Les-2194), 5,10-dihydro-2 H -benzo[ 6 , 7 ]thiochromeno[2,3- d ][ 1 , 3 ]thiazole-2,5,10-trione (Les-3377), and 3-{2-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene}-2,3-dihydro-1 H -indol-2-one (Les-3640) exerted a high toxic effect on human squamous carcinoma cells (SCC-15). They were found to act mainly in a PPARγ-dependent manner [ 25 , 26 ].…”