What are Diterpenoids?

The terpenoid class includes diterpenoids, which are chemical compounds with 20 carbon atoms. They are made up of four isoprene units and are derived from geranylgeraniol, a C₂₀ precursor. They have a C₂₀H₃₂ basic structure. These characteristics distinguish diterpenoids from simple terpenes, which have just 10 carbon atoms.

Characteristics of Diterpenoids

Alcohol, phenol, aldehyde, chiton, and acidic functional groups can all be found in diterpenoid molecules. These compounds have high lipophilicity, are odorless, and can have strong flavors. As standard products of plant metabolism, they're often found in fungi and resins of higher-order plants.

Diterpenes are chemical compounds that are made up of four isoprene units and have the molecular formula C₂₀H₃₂. Plants, animals, and fungi biosynthesize them through the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate as a primary intermediate. Diterpenes are the building blocks for bioactive compounds like retinol, retinal, and phytol. They have antimicrobial and anti-inflammatory properties.

Structure of Diterpenoids

As with most terpenes, there are a plethora of possible configurations, which can be classified based on the number of rings present. Diterpenes are hydrocarbons, which means they don't contain any heteroatoms. Although the two terms are often used interchangeably in scientific literature, functionalized structures should be called diterpenoids. While there are many different terpene structures, only a few are biologically significant; on the other hand, diterpenoids have a diverse pharmacology and include essential compounds including retinol and phytol.

Synthesis

The addition of one IPP unit to FPP to form geranylgeranyl-pyrophosphate yields diterpenes (GGPP). Two groups of enzymes, diterpene synthases and cytochromes P450, are primarily responsible for structural diversity in GGPP. Plants and cyanobacteria contain a variety of diterpenes. By the action of the enzyme geranylgeranyl reductase, GGPP is also a precursor for the synthesis of phytane. The phytol functional group is used in the formation of chlorophyll a, ubiquinone’s, plastoquinone, and phylloquinone, and it is used in the biosynthesis of tocopherols.

Natural diterpenoid products cover a wide range of chemical diversity and contain a variety of medicinal and industrially important compounds. Both diterpenoids are made from (E, E, E)-geranylgeranyl diphosphate, which is cyclized into one of many scaffolds by a diterpene synthase (DTS). Although diterpene biosynthesis in plants and fungi has been extensively studied, bacteria are now known for producing specific diterpenoids and are likely to harbor an untapped reservoir of new DTSs. Bacterial diterpenoid biosynthesis can be used to discover new natural products, gain a deeper understanding of how DTSs function, and rationally engineer entire metabolic pathways. Based on our recent work with the DTSs involved in platensimycin and platencin biosynthesis, this chapter describes methods and protocols for identifying and characterization of bacterial DTSs.

Features of Diterpenoids

Antitubercular activity has been discovered in diterpenoids from the abietane and pimarane sequence, as well as aromatized nor abietane diterpenoids. A fused, angular, three six-membered carbocyclic ring structure was found in all of the compounds studied. Several ring oxygenations (e.g., phenolic at $\text{C-12 or ketonic at C-11, C-12, and/or C-14)}$ have ready oxidation sites that can produce radicals, which may explain their antitubercular properties.

Seco-abietanes have antitubercular activity as well, and their molecular architecture is identical to that of their tricyclic relatives. Furthermore, labdanes were found to have only mediocre antitubercular activity. Although the polyacrylate jatrophane diterpenoids found in Thai medicinal plants have mild-to-moderate activity, their structures are very different, with a bicyclic architecture (cyclopentane fused with a do decadiene or modified moiety). Their architecture resembles that of rifamycin’s at first glance.

The Importance of Diterpenoids

Diterpenoids are secondary metabolites that contain 20 carbon atoms and are made up of four isoprenyl units. They are found in the plant kingdom, and the majority of them are biosynthetically derived from geranylgeranyl diphosphate, which forms acyclic (phytanes), bicyclic (labdanes, halimanes, clerodanes), tricyclic (pimaranes, abietanes, cassanes, rosanes, vouacapanes, podocarpanes), tetracyclic (trachylobanes, kauranes, aphidicolanes, stemodanes, stemaranes, atisanes, gibberellanes), and macrocyclic diterpenes (taxanes, cembranes, daphnanes, tiglianes, ingenanes) according to the cyclization that occurs. Diterpenoids are classified into over 45 groups and are found in marine animals, where they provide fascinating skeletons like elisapterane.

Secondary metabolites are produced by plants in response to environmental factors in their biotope. To combat these, the host plant releases diterpenes, which can pose a problem in the species' living environment due to the allelopathic activity of some of these terpenoids against nearby flora. Furthermore, diterpenoid quinones derived from the roots of Salvia officinalis were previously documented to cause DNA damage in colonic and hepatic human cells cultured in vitro, despite cytotoxic activity. Despite this, these structures are created in plant cells using a well-established process.

Diterpenoid Alkaloids

Diterpenoid alkaloids are found in Aconitum and Delphinium and are known to have anticancer activity). Lappaconitine, for example, induces G0/G1 cell cycle arrest, apoptosis, and cyclin E1 gene expression downregulation in NSCLC. Taipeinine A, a $\text{C19}$-diterpenoid alkaloid derived from the roots of Aconitum taipeicum, increases Bax and caspase-3 protein expression while suppressing $\text{Bcl-2 and CCND1}$. The MTT approach was used to assess the cytotoxic activities of the Delphinium diterpenoid alkaloids and the IC50 values against A549 cancer cells ranged from 12.03 to 52.79 M. Their anticancer pathways are still being investigated.

Diterpenoids are a chemically diverse group of compounds, all of which have a C20 carbon skeleton made up of four isoprene units. Depending on their skeletal center, diterpenes may be categorized as linear, bicyclic, tricyclic, tetracyclic, pentacyclic, or macrocyclic. They are often found in nature in a polyoxygenated form with keto and hydroxyl groups, which are frequently esterified by small aliphatic or aromatic acids. Ginkgolides are rare Ginkgo biloba constituents that can only be found in this tree.

The cage skeleton of ginkgolides is made up of six five-membered rings: a spiro [4.4]-nonane carbocyclic ring, three lactones, and a tetrahydrofuran ring. Cembrane-class diterpenoids are common metabolites in several gorgonian genera, especially Eunicea and Lophogorgia. This is also valid for Pseudopterogorgia gorgonians, though only in a much more limited way. While cembrane-based diterpenoids are found in only three of the known Pseudopterogorgia species, P. Bipinnata is by far the most prolific producer of cembrane derivatives. The high degree of oxygenation and complex pharmacological properties of Pseudopterogorgia cembranolides are the most notable features.

Context and Applications

This topic is significant in the professional exams for both undergraduate and graduate courses, especially for,

 B.Sc. in Chemistry, Biotechnology, Biochemistry and Biology

M.Sc. in Chemistry, Biotechnology, Biochemistry and Biology   

Related Concepts

Triterpene, Sesquiterpene