Antileishmanial Activity of Lignans, Neolignans …
127
responsible for the last step of the shikimate pathway, using flavin that serves as an
electron donor for 19 [79, 80].
The shikimic pathway is an important active carbon transport machinery, and,
since it is exclusively located in fungi, bacteria and plants, it could be an appropriate
target for novel antibiotic or herbicide development (an ideal and “safe” target for
novel drug candidates) [69, 79, 81–83]. By chorismate (20) generation, the shikimate
pathway enters a crossroad from which three aromatic acids, tryptophan (21), and
especially tyrosine (24) and phenylalanine (25) (via prephenate (22) and arogenate
(23), catalyzed by chorismate mutase and prephenate aminotransferase), are derived.
Phenylalanine (25), as one of the key final products of the shikimate pathway, is then
transformed to the key phenylpropanoid group member, (E)-cinnamic acid (26). This
transformation is catalyzed by one of the most well-studied plant enzymes, phenylalanine ammonia-lyase (PAL). The key function of this enzyme is the deamination
of phenylalanine to yield (E)-cinnamic acid (26). Further transformation of 26 mediated by cinnamate-4-hydroxylase (C4H) and 4-coumarate/coenzyme A ligase (4CL)
yields (E)-4-coumaric acid (28) and (E)-4-coumaroyl-CoA (30), respectively. All
additional phenylpropanoid-based structures, regardless of their complexity, originate from these compounds. Such complexity can be either introduced via “oxidative”
modification of the original structure (phenylpropanoid acids, coumarins), dimerization and subsequent modification of dimers (lignans and neolignans), or via condensation of the phenylpropanoid unit with malonyl coenzyme A (e.g. flavonoids). Overall,
these transformations rely on the vast variety of enzymes such as chalcone synthase
(CHS), chalcone flavanone isomerase (CFI), flavone 3-hydroxylase (F3H), or dihydroflavonol reductase (DFR), to name just a few, and yield important groups of
secondary metabolites such as lignans, sinapate esters, coumarins, isoflavonoids,
stilbenes, aurones, flavones, flavonols, and anthocyanins. The regulation of these
processes is maintained by transcription factors that are closely linked to the biotic
and abiotic factors that surround the plant [84, 85]. The overall process is then carried
out in the outer membrane of the endoplasmic reticulum [84].
3.1 Phenolics
During their long evolution, plants have had to adapt to various and dramatically
changing biotic and abiotic conditions. As previously mentioned, their answer to
such challenges was the development of a massive arsenal of secondary metabolites
(SM). The “move” of plants from aquatic conditions to the point where they were
fully adapted to life on land, was accompanied with a huge burst in the biosynthesis
of phenolic compounds. A main driving force for this is that phenolics can protect
plants against deadly UV irradiation [86, 87].
This might also be the reason why phenolics became one of the most widely
distributed groups of secondary metabolites in plants (these are uncommon in
bacteria, fungi, and algae) [88–90]. To be classified as “a phenolic compound,” it must
contain at least one phenolic unit, and these vary from simple compounds to complex
127
responsible for the last step of the shikimate pathway, using flavin that serves as an
electron donor for 19 [79, 80].
The shikimic pathway is an important active carbon transport machinery, and,
since it is exclusively located in fungi, bacteria and plants, it could be an appropriate
target for novel antibiotic or herbicide development (an ideal and “safe” target for
novel drug candidates) [69, 79, 81–83]. By chorismate (20) generation, the shikimate
pathway enters a crossroad from which three aromatic acids, tryptophan (21), and
especially tyrosine (24) and phenylalanine (25) (via prephenate (22) and arogenate
(23), catalyzed by chorismate mutase and prephenate aminotransferase), are derived.
Phenylalanine (25), as one of the key final products of the shikimate pathway, is then
transformed to the key phenylpropanoid group member, (E)-cinnamic acid (26). This
transformation is catalyzed by one of the most well-studied plant enzymes, phenylalanine ammonia-lyase (PAL). The key function of this enzyme is the deamination
of phenylalanine to yield (E)-cinnamic acid (26). Further transformation of 26 mediated by cinnamate-4-hydroxylase (C4H) and 4-coumarate/coenzyme A ligase (4CL)
yields (E)-4-coumaric acid (28) and (E)-4-coumaroyl-CoA (30), respectively. All
additional phenylpropanoid-based structures, regardless of their complexity, originate from these compounds. Such complexity can be either introduced via “oxidative”
modification of the original structure (phenylpropanoid acids, coumarins), dimerization and subsequent modification of dimers (lignans and neolignans), or via condensation of the phenylpropanoid unit with malonyl coenzyme A (e.g. flavonoids). Overall,
these transformations rely on the vast variety of enzymes such as chalcone synthase
(CHS), chalcone flavanone isomerase (CFI), flavone 3-hydroxylase (F3H), or dihydroflavonol reductase (DFR), to name just a few, and yield important groups of
secondary metabolites such as lignans, sinapate esters, coumarins, isoflavonoids,
stilbenes, aurones, flavones, flavonols, and anthocyanins. The regulation of these
processes is maintained by transcription factors that are closely linked to the biotic
and abiotic factors that surround the plant [84, 85]. The overall process is then carried
out in the outer membrane of the endoplasmic reticulum [84].
3.1 Phenolics
During their long evolution, plants have had to adapt to various and dramatically
changing biotic and abiotic conditions. As previously mentioned, their answer to
such challenges was the development of a massive arsenal of secondary metabolites
(SM). The “move” of plants from aquatic conditions to the point where they were
fully adapted to life on land, was accompanied with a huge burst in the biosynthesis
of phenolic compounds. A main driving force for this is that phenolics can protect
plants against deadly UV irradiation [86, 87].
This might also be the reason why phenolics became one of the most widely
distributed groups of secondary metabolites in plants (these are uncommon in
bacteria, fungi, and algae) [88–90]. To be classified as “a phenolic compound,” it must
contain at least one phenolic unit, and these vary from simple compounds to complex