Natural products with varied functional attributes are available in large abundance in nature. Nature has been an infinite repository of resources leading to drug development, discovery of novel chemicals, pharmacophores, and several invaluable bioactive agents. Natural products play a critical role in modern drug development, especially for antibacterial and antitumor agents. Their varied chemical structure, composition, solubility, and synthetic pathways bestow upon them a high level of diversity. Prenylation is a covalent addition of hydrophobic moieties to proteins or any other chemical compounds. Generally, the hydrophobic moieties are farnesyl or geranylgeranyl isoprenyl groups. Prenylation of flavonoids, alkaloids, terpernoids, etc., leads to gain of varied functionalities to the natural products in addition to the already existing functions. The ever-increasing need for the discovery of new drugs finds a new avenue through the prenylation of natural products. Cell-free synthesis of the prenylated natural products can be seen as a new alternative for the natural synthesis, which warrants time-consuming isolation and purification techniques.
- natural products
Anything that is produced by life including biotic materials such as silk, hair, bio-based materials such as bioplastics, cornstarch, bodily fluids such as blood, milk, and other natural materials that were once found in living organisms such as shell, soil, coal, can all be called as natural products. They are products from various natural sources such as plants, microbes, and animals. The whole of the organism, a part of an organism, an extract from an organism, or pure compounds isolated from the organisms such as alkaloids, coumarins, flavonoids, steroids, lectins, lignans, terpenoids, nonribosomal polypeptides, and polyketides can all be termed as natural products. A limited scope of the definition of natural product can be any molecule synthesized by a living organism. Organic chemistry as we know today has its roots in the study of natural products. The semisynthetic chemistry is an offshoot of organic chemistry wherein the natural products are modified to alter/improve and enhance their activities.
The natural selection and evolutionary processes over millions of years have bestowed the natural products with high structural diversity and unique pharmacological or biological activities. Natural products exhibit structural diversity that is far exceeding the variety that could be synthesized in a laboratory. Classification of natural products is often based on their biological function, biosynthetic pathway, or their source. Primary metabolites and secondary metabolites are the two major classes of natural products. The substances required for an organism to survive are termed as primary metabolites, whereas the substances that are not required for an organism to survive are termed as secondary metabolites. Secondary metabolites confer the organism with advantage in growth and survival within its environment. In practice, the term natural products generally refers to the secondary metabolites and small molecules with molecular weight < 1500 amu.
Natural products have been used for medicinal purposes since ancient times as herbal remedies. Natural products and their structural analogues have a strong impact on human culture and have been used throughout human history as condiments, pigments, and pharmaceuticals. Many of the natural products are potential drug candidates due to the prevailing increased antibiotic resistance. In comparison to the standard combinatorial chemistry, the natural products provide distinct structural diversity and functions. Limited by the lack of cost-effective production methodologies, the study and therapeutic potential of natural products have not been optimally explored. The similarities in the structures and variation in the sources of isolation make it difficult to isolate the natural products. The challenges associated with isolation/production of natural products are circumvented by development of several semisynthetic chemical syntheses.
Due to the safety and efficacy of the natural products, they have been the drugs of choice in improving the human health despite facing a tough competition from compounds derived from computational and combinatorial chemistry. Their importance in drug discovery has been enhanced owing to their largely untapped structural diversity . Natural products containing prenyl side chains represent a rare class in themselves. For several decades now prenylated natural products are recognized as interesting and valuable biologically active phytochemicals . Simple modifications by biological or chemical approaches produce a variety of prenylated aromatic compounds with added structural diversity, altered biological activity, and enhanced therapeutic potential.
A covalent addition of any hydrophobic moiety to protein or any other chemical compound can be termed as prenylation. In case of proteins, generally it is the addition of farnesyl or geranylgeranyl moiety to the cysteine residue via a thioester linkage at the C-terminus. This addition of prenyl moiety bestows novel hydrophobic properties on proteins that leads to the localization of prenylated proteins to the plasma membrane or organellar membranes. It has been shown that well-characterized prenylated proteins are major players in most of the cell signal transduction pathways.
Prenylation of natural products enhances various biological activities as compared with the respective nonprenylated compounds. Due to their versatile and promising pharmacological properties and health benefits on multitarget tissues, the prenylated forms have gained prominence [3, 4]. The increased lipophilicity of prenylated natural products as compared with nonprenylated forms leads to high affinity with cell membranes and enhanced biological activities or significant pharmacological effects [4, 5]. A multitude of biological activities offered by these compounds justifies their enhanced pharmacological investigation. Recent in-depth investigation of prenylated natural compounds with the prenyl substituents playing a key role in the molecular activity has led to discovery of promising anticancer, anti-inflammatory, antioxidant, and neuroprotective compounds. The prenylation of natural compounds is catalyzed by the several enzyme groups of prenyltransferases (PTases), including membrane-embedded UbiA-type, bacterial and fungal ABBA-type, and fungal dimethylallyl tryptophan synthase (DMATS)-type PTases [6, 7, 8].
2. Different classes of natural products
Natural products belong to several different classes of molecules. On the basis of their biosynthetic origin, they can be classified as: alkaloids, phenylpropanoids, polyketides, and terpenoids. Prenyl groups appear in a wide variety of these natural products of microbial and plant origin, including amino acids, stilbenes, alkaloids, polyketides, and phenylpropanoids such as flavonoids, creating natural product hybrids with altered or enhanced bioactivities.
The term “alkaloid,” introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meißner, is derived from Latin root
Prenylated indole alkaloids are a large family of secondary metabolites containing indole/indoline and isoprenoid moieties or structures derived thereof. These alkaloids generally contain a diketopiperazine
Prenylated purine alkaloids isolated from the seeds of
Prenylated quinolinone alkaloids, aspoquinolones
Prenylated alkaloids isolated from plants and fungi are a good example of high structural diversity from only a limited array of structurally nondiverse starting materials. The assembly of complex carbon skeletons is mediated by enzyme catalyzed selective C▬H oxidation reactions. The ambivalent reactivity of the heteroatom is exploited in the diverse condensation chemistry during the prenylated alkaloid biogenesis .
A diverse family of secondary metabolites synthesized by plants, bacteria, and fungi from the amino acids phenylalanine and tyrosine are termed as phenylpropanoids. The term “phenylpropanoid” is generally used to refer to any compound bearing a 3-carbon propene chain attached to 6-carbon aromatic phenyl ring (C6-C3 compounds). Most of the phenylpropanoids are formed from cinnamic or
The prenylations of umbelliferone
Marianins are the prenylated phenylpropanoids, isolated from the fungus
Flavonoids are valuable natural phenylpropanoids products and widely distributed in the plant kingdom bestowing a self-defensive strategy to the plants. Flavonoids are categorized on the basis of their oxidative states and substituents, into chalcones
Prenylation at the two benzene rings, or α, β carbons in chalcones while enhancing the structural diversity, increases their bioactivities as well. The cytotoxic activity of the 3-hydroxylated derivative of xanthohumol
The success of cancer therapy is largely impeded by the development of multidrug resistance (MDR) by tumor cells. The MDR conferred to the cancer cells by the overexpression of the P-glycoprotein (Pgp) . In comparison to the flavanones, isoflavones, and glycosyl derivatives, chalcones, flavones, and flavonols bind more strongly to Pgp cytosolic site. For the ability of these modulators to mimic the adenine moiety of ATP, the hydroxylation at position 5 is essential, in addition to the presence of a ketone at position 4 . Interestingly, the modulating effects of C-prenylated derivatives produced by nontoxic concentrations suggest that these compounds should be investigated in vivo as potential Pgp modulator in tumor cells.
Polyketides are produced by bacteria, fungi, plants, and few marine organisms. These secondary metabolites exhibit a high degree of structural diversity, even though they are synthesized from simple acyl building blocks. They form a chain of either alternating ketones or reduced ketones and methylene groups. Polyketides, owing to their structural diversity and acute toxicity, find applications in medicine, agriculture, and industry. The substitution with prenyl moieties either at a carbon atom of the polyketide nucleus or connection via an ether linkage is a prominent feature in most of these metabolites.
Epoxyphomalin A and B
Prenylated phenyl polyketides named peplidiforones A–D
Three novel and unusual prenylated polyketides, namely oumarone
The organic compounds derived from the 5-carbon compound isoprene
About 1000 prenylated phenolic composite-type terpenoid compounds have been identified to date in plants. The prenylated flavonoids constitute the active components of various medicinal plants. They show sustained biological activities in humans and therefore have been actively investigated as pharmaceuticals . Coumarin derivatives are a group of lactonized phenylpropanoids. The isoprenoid units are not seen in the basic structure of the Furanocoumarins (FCs); therefore the FCs, which are a subgroup of coumarin core with an attached furan ring, are not generally recognized as terpenoid derivatives. However, their furan rings are derived from prenyl chains, followed by the cleavage of a C3 unit to yield the atypical terpenoid derivatives .
Two rare antioxidative prenylated terpenoids from loop-root Asiatic mangrove
3. Prenyltransferases (PTs)
All those enzymes that catalyze the transfer of prenyl groups to a wide variety of acceptors such as proteins, isoprenoid groups, aromatic compounds, etc., are termed as prenyltransferase (PT). PTs are distributed widely in all the living kingdoms and participate in a variety of the metabolic routes . Of late, with increased interest in isoprenoid chemistry, PTs have gained more recognition. The importance of prenylation for the regulation and targeting of bioactive compounds in the cell has been recognized. Among these, the farnesylation of proteins in signal transduction cascades involved in carcinogenesis has been very prominent instance .
PTs are unique enzymes in that, apart from creating new C▬C bonds, they are also successful in introducing a double bond in the end product. The activation as well as enhancement of the biological activity is generally associated with such features. PTs are peculiar enzymes because they not only create a new C▬C bond, a reaction that only some aldolases and lyases have been previously used for , but also introduce a double bond in the framework of the final product, a feature that is often associated with the activation or the enhancement of biological properties .
The regiospecific/stereoselective chemical synthesis of prenylated aromatic compounds is an arduous task to achieve in good yield, besides the usage of protective groups. But the essential feature in a molecule to exhibit biological activity is its regiospecificity/stereoselectivity. Therefore, an interesting tool for the organic synthesis of biologically active compounds is by the possibility of manipulating enzymatic catalysts such as PTs.
Generally, depending upon the stereochemistry of the resulting products, PTs are divided into two classes, namely cis (or Z) and trans (or E). Dimethylallyltranstransferase is an example of trans-prenyltranferase, whereas dehydrodolichol diphosphate synthase is an example of cis-prenyltransferase.
The transfer of a C5 (dimethylallyl), C10 (geranyl), or C15 (farnesyl) prenyl group derived from the corresponding isoprenyl diphosphate metabolites onto a variety of electron-rich aromatic acceptors is catalyzed by aromatic prenyltransferases. By increasing the affinity for biological membranes and interactions with cellular targets, prenylation provides a higher level of bioactivity compared with the nonprenylated precursor . In a Friedel-Crafts-like reaction, aromatic compounds such as hydroxybenzoic acids and hydroxyphenylketones are prenylated by phenol-oligoprenyldiphosphatase . The role of regiospecific catalysts in widening the horizon of diversity and biological activities of many classes of natural products both
The prenylated natural compounds exhibit a broad spectrum of interesting molecular, biological, and pharmacological activities. There is a definite consonance between the structure-activity relationship and bioactivities of prenylated natural compounds. The prenyl-moiety increases the chemical diversity and makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation enhances the antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities of several natural compounds. Therefore, to fully explore the health-promoting potential, more research is required in the future. Especially the prenyl groups seem to be crucial for the anticancer activity of the natural compounds, possibly leading to enhanced cell membrane targeting and thus increased intracellular activity. Today, cancer prevention is an increasingly important social issue, and the identification and characterization of dietary components or natural products with distinct cancer-preventive qualities and possibly even therapeutic properties, while bearing only low toxicity, are a promising research approach.
|DMATS||dimethylallyl tryptophan synthase|
|cAMP||cyclic adenosine monophosphate|
|cGMP||cyclic guanosine monophosphate|
|CNS||central nervous system|
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