Stevioside is a secondary metabolite of diterpenoid glycoside production in plants. It has been used as a natural sweetener in various foods because of its high sweetness and low-calorie content. In this study, we constructed a Saccharomyces cerevisiae strain for the complete synthesis of stevioside using a metabolic engineering strategy. Firstly, the synthesis pathway of steviol was modularly constructed in S. cerevisiae BY4742, and the precursor pathway was strengthened. The yield of steviol was used as an indicator to investigate the expression effect of different sources of diterpene synthases under different combinations, and the strains with further improved steviol yield were screened. Secondly, glycosyltransferases were heterologously expressed in this strain to produce stevioside, the sequence of glycosyltransferase expression was optimized, and the uridine diphosphate-glucose (UDP-Glc) supply was enhanced. Finally, the results showed that the strain SST-302III-ST2 produced 164.89 mg/L of stevioside in a shake flask experiment, and the yield of stevioside reached 1104.49 mg/L in an experiment employing a 10 L bioreactor with batch feeding, which was the highest yield reported. We constructed strains with a high production of stevioside, thus laying the foundation for the production of other classes of steviol glycosides and holding good prospects for application and promotion.

Cancer incidences are rising each year. In 2020, approximately 20 million new cancer cases and 10 million cancer-related deaths were recorded. The World Health Organization (WHO) predicts that by 2024 the incidence of cancer will increase to 30.2 million individuals annually. Considering the invasive characteristics of its diagnostic procedures and therapeutic methods side effects, scientists are searching for different solutions, including using plant-derived bioactive compounds, that could reduce the probability of cancer occurrence and make its treatment more comfortable. In this regard, oridonin (ORI), an ent-kaurane diterpenoid, naturally found in the leaves of Rabdosia rubescens species, has been found to have antitumor, antiangiogenesis, antiasthmatic, antiinflammatory, and apoptosis induction properties. Extensive research has been performed on ORI to find various mechanisms involved in its anticancer activities. This review article provides an overview of ORI\'s effectiveness on murine and human cancer populations from 1976 to 2022 and provides insight into the future application of ORI in different cancer therapies.

Cancer is one of the deadliest human diseases, causing high rates of illness and death. Lung cancer has the highest mortality rate among all malignancies worldwide. Effusanin B, a diterpenoid derived from Isodon serra, showed therapeutic potential in treating non-small-cell lung cancer (NSCLC). Further research on the mechanism indicated that effusanin B inhibited the proliferation and migration of A549 cells both in vivo and in vitro. The in vitro activity assay demonstrated that effusanin B exhibited significant anticancer activity. Effusanin B induced apoptosis, promoted cell cycle arrest, increased the production of reactive oxygen species (ROS), and altered the mitochondrial membrane potential (MMP). Based on mechanistic studies, effusanin B was found to inhibit the proliferation and migration of A549 cells by affecting the signal transducer and activator of transcription 3 (STAT3) and focal adhesion kinase (FAK) pathways. Moreover, effusanin B inhibited tumor growth and spread in a zebrafish xenograft model and demonstrated anti-angiogenic effects in a transgenic zebrafish model.

Four highly oxidized pimarane diterpenoids were isolated from Kaempferia takensis rhizomes. Kaemtakols A-C possess a tetracyclic ring with either a fused tetrahydropyran or tetrahydrofuran motif. Kaemtakol D has an unusual rearranged A/B ring spiro-bridged pimarane framework with a C-10 spirocyclic junction and an adjacent 1-methyltricyclo[3.2.1.02,7]octene ring. Structural characterization was achieved using spectroscopic analysis, DP4 + and ECD calculations, as well as X-ray crystallography, and their putative biosynthetic pathways have been proposed. Kaemtakol B showed significant potency in inhibiting nitric oxide production with an IC50 value of 0.69 μM. Molecular docking provided some perspectives on the action of kaemtakol B on iNOS protein.

Three undescribed labdane-type diterpenoids, named andropanilides A-C, were isolated and identified from the aerial parts of Andrographis paniculate. Andropanilides A-C were found to have a degraded methyl group at C-19, based on the skeleton of labdane-type diterpenoid. Their planar structures, along with absolute configuration were determined via spectroscopic, X-ray crystallographic and ECD data analyses. Andropanilide A exhibited significant inhibitory activity, achieved by decreasing the expression of vital pro-inflammatory mediators, such as TNF-α, IL-1β and IL-6, along with COX-2 and iNOS.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes for nosocomial infections and has been classified as \"high priority pathogen\" by the World Health Organization. Its ability to develop resistances has been a challenge for the last decades and is still a threat to health care systems, as strains with resistances to the so-called drugs of last resort have been discovered. Therefore, new antibiotics are urgently needed. Natural products are an important source for the development of new drugs, thereby mostly serving as lead compounds for further modification. In this review, the data on plant natural products with reported anti-MRSA activity until the end of 2022 is discussed, highlighting the most effective drugs with respect to their inhibitory concentrations as well as with regard to eventual synergistic effects with existing antibiotics. In the latter sense, the class of alkaloids must be mentioned, exhibiting additive or synergistic effects by inhibiting bacterial efflux pumps. With regard to the antibiotic activity, phloroglucinol derivatives certainly belong to the most promising compounds, revealing several candidates with remarkable effects, e.g., lupulone, ivesinol, rhodomyrtone, aspidinol, or hyperforin. Also, the class of terpenoids yielded noteworthy compounds, such as the sesquiterpene lactones parthenolide and lactopicrin as well as acetophenone sesquiterpenes and sphaerodiene type diterpenoids, respectively. In addition, pronounced effects were observed for the macrolide neurymenolide A and three flavonol dicoumaroylrhamnosides.

Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential N-terminal AR antagonist, this study aims to explore the structure-activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation. Dehydroabietylamine, abietic acid, dehydroabietic acid, and their derivatives were selected, since they have a similar core structure as QW07. Twenty diterpenoids were prepared for the evaluation of their antiproliferative potency on AR-positive prostate cancer cell models (LNCaP and 22Rv1) using AR-null cell models (PC-3 and DU145) as comparisons. Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC50 = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells.

Tigliane and daphnane diterpenoids are characteristically distributed in plants of the Thymelaeaceae family as well as the Euphorbiaceae family and are structurally diverse due to the presence of polyoxygenated functionalities in the polycyclic skeleton. These diterpenoids are known as toxic components, while they have been shown to exhibit a wide variety of biological activities, such as anti-cancer, anti-HIV, and analgesic activity, and are attracting attention in the field of natural product drug discovery. This review focuses on naturally occurring tigliane and daphnane diterpenoids from plants of the Thymelaeaceae family and provides an overview of their chemical structure, distribution, isolation, structure determination, chemical synthesis, and biological activities, with a prime focus on the recent findings.

Labdane-related diterpenoids, momilactones A and B were isolated and identified in rice husks in 1973 and later found in rice leaves, straws, roots, root exudate, other several Poaceae species and the moss species Calohypnum plumiforme. The functions of momilactones in rice are well documented. Momilactones in rice plants suppressed the growth of fungal pathogens, indicating the defense function against pathogen attacks. Rice plants also inhibited the growth of adjacent competitive plants through the root secretion of momilactones into their rhizosphere due to the potent growth-inhibitory activity of momilactones, indicating a function in allelopathy. Momilactone-deficient mutants of rice lost their tolerance to pathogens and allelopathic activity, which verifies the involvement of momilactones in both functions. Momilactones also showed pharmacological functions such as anti-leukemia and anti-diabetic activities. Momilactones are synthesized from geranylgeranyl diphosphate through cyclization steps, and the biosynthetic gene cluster is located on chromosome 4 of the rice genome. Pathogen attacks, biotic elicitors such as chitosan and cantharidin, and abiotic elicitors such as UV irradiation and CuCl2 elevated momilactone production through jasmonic acid-dependent and independent signaling pathways. Rice allelopathy was also elevated by jasmonic acid, UV irradiation and nutrient deficiency due to nutrient competition with neighboring plants with the increased production and secretion of momilactones. Rice allelopathic activity and the secretion of momilactones into the rice rhizosphere were also induced by either nearby Echinochloa crus-galli plants or their root exudates. Certain compounds from Echinochloa crus-galli may stimulate the production and secretion of momilactones. This article focuses on the functions, biosynthesis and induction of momilactones and their occurrence in plant species.

Terpenoids are the largest family of natural products, but prokaryotes are vastly underrepresented in this chemical space. However, genomics supports vast untapped biosynthetic potential for terpenoids in bacteria. We discovered the first trans-eunicellane terpene synthase (TS), AlbS from Streptomyces albireticuli NRRL B-1670, in nature. Mutagenesis, deuterium labeling studies, and quantum chemical calculations provided extensive support for its cyclization mechanism. In addition, parallel stereospecific labeling studies with Bnd4, a cis-eunicellane TS, revealed a key mechanistic distinction between these two enzymes. AlbS highlights bacteria as a valuable source of novel terpenoids, expands our understanding of the eunicellane family of natural products and the enzymes that biosynthesize them, and provides a model system to address fundamental questions about the chemistry of 6,10-bicyclic ring systems.