Jolkinolide B inhibits the progression of hepatocellular carcinoma by regulating Musashi-2 protein.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. However, the HCC treatment is still challenging. Herein, we aimed to reveal the anti-tumor effect of Jolkinolide B in HCC cell lines Huh-7 and SK-Hep-1. The results showed that Jolkinolide B inhibited the migration, invasion, and epithelial-to-mesenchymal transition(EMT) of HCC cells. In addition, Jolkinolide B induced HCC cell apoptosis by upregulating Bax and downregulating BCL-2 expressions. Furthermore, we demonstrated that Jolkinolide B inactivated the ß-catenin signaling and reduced Musashi-2 expression. Finally, we revealed that Musashi-2 overexpression reversed the Jolkinolide B-induced anti-HCC effect. Overall, we proved that Jolkinolide B is a potential candidate for treating HCC.

Recent Advances in Grayanane Diterpenes: Isolation, Structural Diversity, and Bioactivities from Ericaceae Family (2018-2024).

Diterpenes represent one of the most diverse and structurally complex families of natural products. Among the myriad of diterpenoids, grayanane diterpenes are particularly notable. These terpenes are characterized by their unique 5/7/6/5 tetracyclic system and are exclusive to the Ericaceae family of plants. Renowned for their complex structures and broad spectrum of bioactivities, grayanane diterpenes have become a primary focus in extensive phytochemical and pharmacological research. Recent studies, spanning from 2018 to January 2024, have reported a series of new grayanane diterpenes with unprecedented carbon skeletons. These compounds exhibit various biological properties, including analgesic, antifeedant, anti-inflammatory, and inhibition of protein tyrosine phosphatase 1B (PTP1B). This paper delves into the discovery of 193 newly identified grayanoids, representing 15 distinct carbon skeletons within the Ericaceae family. The study of grayanane diterpenes is not only a deep dive into the complexities of natural product chemistry but also an investigation into potential therapeutic applications. Their unique structures and diverse biological actions make them promising candidates for drug discovery and medicinal applications. The review encompasses their occurrence, distribution, structural features, and biological activities, providing invaluable insights for future pharmacological explorations and research.

New pimarane diterpenoids with antibacterial activity from fungus Arthrinium sp. ZS03.

A comprehensive chemical study of the endophytic fungus Arthrinium sp. ZS03, associated with Acorus tatarinowii Schott, yielded eleven pimarane diterpenoids (compounds 1-11), including seven novel compounds designated arthrinoids A-G (1-7). The determination of their structures and absolute configurations was achieved through extensive spectroscopic techniques, quantum chemical calculations of electronic circular dichroism (ECD), and single-crystal X-ray diffraction analysis. Furthermore, 7 demonstrated inhibitory activity against Klebsiella pneumoniae, comparable to the reference antibiotic amikacin, with a minimum inhibitory concentration (MIC) of 8 µg·mL-1.

13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents.

Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.

Recent advances in developing modified C14 side chain pleuromutilins as novel antibacterial agents.

Owing to the increasing resistance to most existing antimicrobial drugs, research has shifted towards developing novel antimicrobial agents with mechanisms of action distinct from those of current clinical options. Pleuromutilins are antibiotics known for their distinct mechanism of action, inhibiting bacterial protein synthesis by binding to the peptidyl transferase center of the ribosome. Recent studies have revealed that pleuromutilin derivatives can disrupt bacterial cell membranes, thereby enhancing antibacterial efficacy. Both marketed pleuromutilin derivatives and those in clinical trials have been developed by structurally modifying the pleuromutilin C14 side chain to improve their antimicrobial activity. Therefore, this review aims to review advancement in the chemical structural characteristics, antibacterial activities, and structure-activity relationship studies of pleuromutilins, specifically focusing on modifications made to the C14 side chain in recent years. These findings provide a valuable reference for future research and development of pleuromutilins.

Structure, Absolute Configuration, Antiproliferative and Phytotoxic Activities of Icetexane and Abietane Diterpenoids from Salvia carranzae and Chemotaxonomic Implications.

From the aerial parts of Salvia carranzae Zamudio and Bedolla, three new icetexane-type diterpenoids were isolated. Their structures were established through spectroscopic methods and named the following: salvicarranzanolide (1), 19-deoxo-salvicarranzanolide (2) and 19-deoxo-20-deoxy-salvicarranzanolide (3). In addition, the known icetexane-type diterpenoids, 6,7,11,14-tetrahydro-7-oxo-icetexone (4), iso-icetexone (5), 19-deoxo-iso-icetexone (6), icetexone (7), 19-deoxo-icetexone (8) and 7α-acetoxy-6,7-dihydroicetexone (9), were also isolated, along with the abietanes sessein (10) and ferruginol (11). α-Tocopherol was also identified. Compounds 5, 6 and 8 were tested for their antiproliferative activity using the sulforhodamine B assay on six cancer and one normal human cell lines. Diterpenoids 5 and 6 showed noteworthy antiproliferative activity, exhibiting an IC50 (µM) = 0.43 ± 0.01 and 1.34 ± 0.04, respectively, for U251 (glioblastoma), an IC50 (µM) = 0.45 ± 0.01 and 1.29 ± 0.06 for K5621 (myelogenous leukemia), 0.84 ± 0.07 and 1.03 ± 0.10 for HCT-15 (colon cancer), and 0.73 ± 0.06 and 0.95 ± 0.09 for SKLU-1 (lung adenocarcinoma) cell lines. On the other hand, the phytotoxicity of compounds 5-7 and 9-10 was evaluated on seed germination and root growth in some weeds such as Medicago sativa, Panicum miliaceum, Amaranthus hypochondriacus and Trifolium pratense as models. While compounds 5 and 10 exhibited a moderate inhibitory effect on the root growth of A. hypochondriacus and T. pratense at 100 ppm, the diterpenoids 6, 7 and 9 were ineffective in all the plant models. Taxonomic positions based on the chemical profiles found are also discussed.

The molecular mechanism of action for the potent antitumor component extracted using supercritical fluid extraction from Croton crassifolius root.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. AIM OF THE STUDY: At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. MATERIALS AND METHODS: Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. RESULTS: Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC50 = 8.58 µM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. CONCLUSIONS: Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo.

Identification and structural modification of ent-rosane diterpenoids from Euphorbia milii inhibiting RANKL-induced osteoclastogenesis.

Phytochemical study on Euphorbia milii, a common ornamental plant, resulted in the identification of thirteen new ent-rosane diterpenoids (1-13), three new ent-atisane diterpenoids (14-16), and a known ent-rosane (17). Their structures were delineated using spectroscopic data, quantum chemical calculations, and X-ray diffraction experiments. Euphomilone F (1) represented a rare ent-rosane-type diterpenoid with a 5/7/6 skeleton. Euphoainoid G (8) was a rare rosane diterpenic acid. Compounds 9 and 10 carried infrequent tetrahydrofuran rings, and compounds 11-13 was 18-nor-ent-rosane diterpenoids. All isolates were evaluated for their inhibitory effects on RANKL-induced osteoclasts. Notably, compounds with aromatic ester groups (2-7) showed promising activities (IC50 < 10 µM), underscoring the significance of acylated A-ring moieties in the ent-rosane skeleton for anti-osteoclastogenesis. Thirteen synthetic derivatives were obtained through esterification of 17. Of these, compound 27 exhibited remarkable improvement, with an IC50 of 0.8 µM, more than a 12-fold increase in potency compared to the parent compound 17 (IC50 > 10 µM). This work presents a series of new ent-rosane diterpenoids with potential antiosteoporosis agents.

In vitro antimetastatic potential of pseudolaric acid B in HSC-3 human tongue squamous carcinoma cell line.

OBJECTIVE: Pseudolaric acid B (PAB) is a novel diterpenoid derived from the traditional Chinese medicinal herb Cortex pseudolaricis that exerts anticancer, anti-inflammatory, and immunomodulatory properties. While the anticancer potential of PAB has been studied, its effects on metastasis have not been well-studied. This study aims to determine the inhibitory effects of PAB on HSC-3 human tongue squamous cell carcinoma (TSCC) cell line. DESIGN: Cell viability and soft agar colony formation assays were conducted to assess cellular proliferation and in vitro tumorigenic capacity of TSCC cells, respectively. Additionally, wound healing, transwell migration, and invasion assays were conducted to monitor the aggressive behavior of TSCC cells. Furthermore, Western blotting analysis was conducted to reveal the signaling pathways involved in the modulation of epithelial-mesenchymal transition (EMT). RESULTS: The migratory and invasive capacities of HSC-3 cells were suppressed by PAB irrespective of their proliferation states. PAB's effects on EMT involved upregulation of E-cadherin expression and downregulation of Twist; these were concomitantly accompanied by downregulated phosphorylation of epidermal growth factor receptor (EGFR). CONCLUSIONS: PAB suppresses human TSCC in vitro by regulating Twist/E-cadherin through the EGFR signaling pathway. PAB may have potential as a candidate antimetastatic drug for TSCC treatment.

Discovery of Pesticide Candidates from Natural Plant Products: Semisynthesis and Characterization of Andrographolide-Based Esters and Study of Their Pesticidal Properties and Toxicology.

To explore the use of nonfood plant-derived secondary metabolites for plant protection, a series of ester derivatives for controlling the major migratory agricultural pests were obtained by structural modification of andrographolide, a labdane diterpenoid isolated from Andrographis paniculata. Compound Id showed good insecticidal activity against the fall armyworm Spodoptera frugiperda Smith. Compounds IIa (LC50: 0.382 mg/mL) and IIIc (LC50: 0.563 mg/mL), the acaricidal activities of which were, respectively, 13.1 and 8.9 times that of andrographolide (LC50: 4.996 mg/mL), exhibited strong acaricidal and control effects against Tetranychus cinnabarinus Boisduval. Against Aphis citricola Van der Goot, compounds IIIc and IVb displayed 3.9- and 3.7-fold pronounced aphicidal activity of andrographolide. Effects of compound Id on three protective enzymes (superoxide dismutase, peroxidase, and catalase) of S. frugiperda were also observed. The obvious differences of epidermal cuticle structures of mites treated with compound IIa were determined by scanning electron microscopy. Structure-activity relationships indicated that 14-ester derivatives of andrographolide showed potential insecticidal/acaricidal activities and can be further utilized as lead compounds.

Isolation of New Diterpenoids from the Halophyte, Vitex rotundifolia, and their Antioxidant and Anti-inflammatory Activities.

In this study, three diterpenoids (1-3), including one known compound (1), were isolated from the fruits of Vitex rotundifolia and their structures were determined via spectroscopic analysis. In lipopolysaccharide-stimulated RAW264.7 cells, these compounds dose-dependently decreased the intracellular reactive oxygen species levels and nitric oxide production compared to those in the control cells. At 25 µM/mL, these compounds also diminished the protein expression of the pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-6, with compound 3 exhibiting the most potent inhibitory effect.

Enhancing lathyrane structural diversity and MDR activity by combinatorial modification of lathyrane nucleus and ester side chain: A case study of Euphorbia Factor L1 and Euphorbia Factor L3.

The chemical transformation of lathyrane nucleus through reduction and oxidation reactions using Euphorbia Factor L1 (EFL1) and Euphorbia Factor L1 (EFL3) as examples were investigated, along with a co-modification strategy of lathyrane nucleus and its side ester chain. A total of 38 lathyrane derivatives (5-42) including 34 new compounds were obtained, which greatly enriched the structural diversity of the lathyrane-type diterpenoids. Cytotoxicity against drug-sensitive and drug (adriamycin, ADM) resistant MCF-7 cells showed that 23 out of 38 transformed derivatives possessed obvious cytotoxic activity with IC50 values ranging from 7.0 to 41.1 µM and 3.2 to 45.5 µM, respectively, against both cells, compared to the noncytotoxic EFL1 and EFL3. The multidrug resistance (MDR) reversing activities of these lathyrane derivatives were further evaluated in MCF-7/ADM. Three transformed compounds (reversal fold, RF = 151.33, 62.94 and 47.3 for 27, 37 and 42) showed markedly higher activity than EFL1 (RF = 32.92) and EFL3 (RF = 39.68). Structure-activity relationship study revealed an essential role of C-6/17 and C-12/13 double bonds on lathyrane nucleus for exerting MDR reversal activity. Western blotting analysis showed that 42 could reduce the expression level of P-glycoprotein (P-gp) in MCF-7/ADM cells; however, the most active compound 27 with an unnatural 5/7/7/4 fused-ring diterpenoid skeleton, had no inhibitory effect on P-gp expression.

Diterpenoids from Torreya grandis and their cytotoxic activities.

Eight previously undescribed diterpenoids, along with eleven previously reported analogues, were obtained from the supercritical CO2 extracts of Torreya grandis aril. The structures of these compounds were elucidated based on HRESIMS, NMR, ECD, and single-crystal X-ray diffraction data. In the MTT assay, compound 18 exhibited significant inhibitory effects on two human colon cancer cell lines, HT-29 and HCT 116 cells, with IC50 values of 7.37 µM and 6.55 µM, respectively. It was found that compound 18 induced apoptosis and significantly inhibited the migration of HCT 116 colon cancer cells in a concentration-dependent manner.

Highly modified cephalotane-type diterpenoids from Cephalotaxus fortunei var. alpina and C. sinensis.

Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis, leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A-F (1-6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13-p-hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents.

Structurally intriguing diterpenoids from Euphorbia wallichii Hook. f. with potential antioxidant activity.

Chemical investigation of Euphorbia wallichii Hook. f. led to the isolation of four undescribed rearranged diterpenoids, euphwanoids I-IV (1-4), and six unreported tigliane diterpenoids walliglianes A-F (5-10). Euphwanoids I-III (1-3) possess a rare 6/6/7/3 ring scaffold, euphwanoid IV (4) is the first spiro[tricyclo[5.4.0.02,4]undecane-8,1'-cyclopentane] skeleton to be found in the tigliane family. The structures of compounds 1-10 were established by utilizing spectroscopic data analysis, experimental electronic circular dichroism measurements, 13C NMR calculations, and single-crystal X-ray diffraction. In the preliminary bioassay, compounds 3, 4, and 7 were found to protect BV-2 cells against H2O2-induced cell injury in a dose-dependent manner by the CCK8 assay.

New clerodane diterpenoids from Callicarpa pseudorubella and their antitumor proliferative activity.

Six previously undescribed clerodane diterpenes, cardorubellas A-F (1-6), along with seven known ones (7-13), were isolated from the aerial parts of Callicarpa pseudorubella. Their chemical structures were established by analysis of 1D and 2D NMR, HR-ESI-MS, X-ray diffraction, and electronic circular dichroism (ECD) data. Notably, cardorubella B (2) represented the first examples of naturally occurring succinic anhydride-containing clerodane diterpenes derivatives. The anti-proliferative activities of these compounds were assessed. Remarkably, compound 2 exhibited comparable inhibitory activity against HEL cell lines, surpassing the positive control with an IC50 value of 14.01 ± 0.77 µM, compared to 17.02 ± 4.70 µM for 5-fluorouracil.

New daphnane diterpenoidal 1,3,4-oxdiazole derivatives as potential anti-hepatoma agents: Synthesis, biological evaluation and molecular modeling studies.

Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction.

Diterpenoid tanshinones inhibit gastric cancer angiogenesis through the PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge is a kind of Chinese herbal medicine known for activating blood circulation and removing blood stasis, with the effect of cooling blood and eliminating carbuncles, and has been proven to have the effect of treating tumors. However, the inhibitory effect of Salvia miltiorrhiza Bunge extracts (Diterpenoid tanshinones) on tumors by inhibiting angiogenesis has not been studied in detail. AIM OF THE STUDY: This study aimed to investigate the anti-gastric cancer effect of diterpenoid tanshinones (DT) on angiogenesis, including the therapeutic effects and pathways. MATERIALS AND METHODS: This experiment utilized network pharmacology was used to identify relevant targets and pathways of Salvia miltiorrhiza Bunge-related components in the treatment of gastric cancer. The effects of DT on the proliferation and migration of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line HUVECs were evaluated, and changes in the expression of angiogenesis-related factors were measured. In vivo, experiments were conducted on nude mice to determine tumor activity, size, immunohistochemistry, and related proteins. RESULTS: The findings showed that DT could inhibit the development of gastric cancer by suppressing the proliferation of gastric cancer cells, inducing apoptosis, and inhibiting invasion and metastasis. In addition, the content of angiogenesis-related factors and proteins was significantly altered in DT-affected cells and animals. CONCLUSIONS: Results suggest that DT has potential as a therapeutic agent for the treatment of gastric cancer, as it can inhibit tumor growth and angiogenesis. It was also found that DT may affect the expression of the angiogenic factor VEGF through the PI3K/Akt/mTOR pathway, leading to the regulation of tumor angiogenesis. This study provides a new approach to the development of anti-tumor agents and has significant theoretical and clinical implications for the treatment of gastric cancer.

Abietane diterpenoids with anti-neuroinflammation activity from Rosmarinus officinalis.

A total of 12 abietane diterpenoids were isolated and identified from Rosmarinus officinalis in which 6 ones were undescribed compounds. Their structures were illuminated by the HRESIMS, NMR, and ECD methods and named as rosmarinusin Q-V (1-6). It worthy mentioned that rosmarinusin Q was a novel abietane diterpenoid with 6/6/5 skeleton whose C ring was an α,ß-unsaturated five-element ketone. All the compounds and four compounds (13-16) reported in our previous paper were evaluated their anti-neuroinflammatory activities on the LPS-induced BV2 cells. Compounds 5, 8, 9, 11, and 15 displayed significant anti-neuroinflammatory activity at the concentration of 10, 20, and 40 µM respectively. These results confirmed that R. officinalis contained abundant abietane diterpenoids and these compounds showed potential values of anti-neuroinflammation which could be developed as neuroprotective agents for the treatment of nerve damage caused by inflammation.

Disparate Effects of Two Clerodane Diterpenes of Giant Goldenrod (Solidago gigantea Ait.) on Bacillus spizizenii.

New substances with antimicrobial properties are needed to successfully treat emerging human, animal, or plant pathogens. Seven clerodane diterpenes, previously isolated from giant goldenrod (Solidago gigantea) root, were tested against Gram-positive Bacillus subtilis, Bacillus spizizenii and Rhodococcus fascians by measuring minimal bactericidal concentration (MBC), minimal inhibitory concentration (MIC) and half-maximal inhibitory concentration (IC50). Two of them, Sg3a (a dialdehyde) and Sg6 (solidagoic acid B), were proved to be the most effective and were selected for further study. Bacillus spizizenii was incubated with the two diterpenes for shorter (1 h) or longer (5 h) periods and then subjected to genome-wide transcriptional analyses. Only a limited number of common genes (28 genes) were differentially regulated after each treatment, and these were mainly related to the restoration of cell membrane integrity and to membrane-related transports. Changes in gene activity indicated that, among other things, K+ and Na+ homeostasis, pH and membrane electron transport processes may have been affected. Activated export systems can be involved in the removal of harmful molecules from the bacterial cells. Inhibition of bacterial chemotaxis and flagellar assembly, as well as activation of genes for the biosynthesis of secondary metabolites, were observed as a general response. Depending on the diterpenes and the duration of the treatments, down-regulation of the protein synthesis-related, oxidative phosphorylation, signal transduction and transcription factor genes was found. In other cases, up-regulation of the genes of oxidation-reduction processes, sporulation and cell wall modification could be detected. Comparison of the effect of diterpenes with the changes induced by different environmental and nutritional conditions revealed several overlapping processes with stress responses. For example, the Sg6 treatment seems to have caused a starvation-like condition. In summary, there were both common and diterpene-specific changes in the transcriptome, and these changes were also dependent on the length of treatments. The results also indicated that Sg6 exerted its effect more slowly than Sg3a, but ultimately its effect was greater.