High-quality assembly of the T2T genome for Isodon rubescens f. lushanensis reveals genomic structure variations between 2 typical forms of Isodon rubescens.

BACKGROUND: Rabdosiae rubescentis herba (Isodon rubescens) is widely used as a folk medicine to treat esophageal cancer and sore throat in China. Its germplasm resources are abundant in China, with I. rubescens (Hemsl.) Hara and I. rubescens f. lushanensis as 2 typical forms. I. rubescens (Hemsl.) Hara is featured by biosynthesis of the diterpenoid oridonin with strong anticancer activity, while I. rubescens f. lushanensis produces another diterpenoid with anticancer activity, lushanrubescensin. However, the biosynthetic pathways of both still need to be fully understood. In particular, little is known about the genetic background of I. rubescens f. lushanensis. FINDINGS: We used Pacific Biosciences (PacBio) single-molecule real-time and Nanopore Ultra-long sequencing platforms, respectively, and obtained 139.07 Gb of high-quality data, with a sequencing depth of about 328×. We also obtained a high-quality reference genome for I. rubescens f. lushanensis, with a genome size of 349 Mb and a contig N50 of 28.8 Mb. The heterozygosity of the genome is 1.7% and the repeatability is 83.43%. In total, 34,865 protein-coding genes were predicted. Moreover, we found that most of the variant or unique genes in the diterpenoid synthesis pathways of I. rubescens f. lushanensis and I. rubescens (Hemsl.) Hara were enriched in diterpene synthases. CONCLUSIONS: We provide the first genome sequence and gene annotation for the I. rubescens f. lushanensis, which provides molecular evidence for understanding the chemotypic differences of I. rubescens.

Comparative Study of the Anxiolytic Activity of Songorine in Elevated Plus Maze Test and by Recording Ultrasonic Vocalizations.

It was found that the diterpene alkaloid songorine administered per os to mice at a dose of 25 µg/kg provides a pronounced anxiolytic effect during elevated plus maze testing comparable to the effect of the benzodiazepine anxiolytic phenazepam. Recording of ultrasonic vocalizations of animals revealed an increase in the number of short high-frequency (50 kHz) signals under the action of songorine and the reference drug, which confirms their anti-anxiety properties.

Unprecedented nor-seco-diterpene lactones inhibited osteogenic differentiation of valve interstitial cells.

The first examples of ent-atisane and ent-isopimarane diterpene lactones with an unusual 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one nucleus, eufislactones A (1) and B (2), were isolated from the roots of Euphorbia fischeriana, together with a new (3) and fifteen known biosynthetic congeners (4-18). Their structures incorporating absolute configurations were elucidated via the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction analyses. Biogenetically, compounds 1 and 2 were constructed by the plausible monomeric precursors, ent-atis-16-ene-3,14-dione (6) and ent-isopimara-8(14),15-dien-3-one (17), respectively, via key Baeyer-Villiger oxidation, decarboxylation, and semi-acetalization reactions to create a unique 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one core. Our bioassays have revealed that eufislactone A (EFA, 1) displayed significant inhibitory effect on the osteogenic differentiation of human valvular interstitial cells (VICs), highlighting its potential as a preventive agent against the progression of human calcific aortic valve disease (CAVD).

Efficacy of Diterpene Polyalthic Acid Combined with Amphotericin B against Leishmania amazonensis In Vitro.

Background/Objectives: Leishmaniasis, a neglected disease caused by Leishmania spp. including L. amazonensis, urgently requires new treatments. Polyalthic acid (PA), a natural diterpene from Copaifera spp., has previously demonstrated significant antiparasitic potential. This study evaluated the leishmanicidal effects of polyalthic acid (PA), alone and with amphotericin B (AmpB), on L. amazonensis promastigote and amastigote forms. Results: PA showed significant activity against promastigotes, with 50% effective concentration (EC50) values of 2.01 µM at 24 h and an EC50 of 3.22 µM against amastigotes after 48 h. The PA and AmpB combination exhibited a synergistic effect on both forms without inducing cytotoxicity or hemolysis. Morphological changes in promastigotes, including vacuole formation and cell rounding, were more pronounced with the combination. Conclusions: These findings suggest that PA and AmpB together could form a promising new treatment strategy against Leishmania infections, offering enhanced efficacy without added toxicity.

Chemical constituents of Coccoloba peltata Schott leaves and their cytotoxic activities.

Chromatographic fractionation of CH2Cl2:MeOH (1:1) extract of Coccoloba peltata Schott cultivated in Egypt afforded four compounds, lupeol acetate (1), ent-13-epi-manoyl oxide (2), 5-methoxymethyl-7,8-dimethyltocol (3), and α-tocopherol quinone (4). The planar structures of the isolated compounds were concluded based on HRESIMS and NMR spectroscopy. X-ray crystallography of 2 is reported herein for the first time and its unambiguous absolute configuration was deduced from anomalous dispersion. To the best of our knowledge, this is the first known report on the isolation of compounds 1-4 from this species. Among the isolated compounds, only compound 4 showed a moderate level of cytotoxic activity against six cancer cell lines out of seven cell lines tested.

Impact of nitrogen rates on biosynthesis pathways: A comparative study of diterpene synthases in clerodane diterpenoids and enzymes in benzylisoquinoline alkaloids.

Tinospora sagittata is rich in secondary metabolites used in traditional medicine. However, environmental factors impact key enzymes in metabolite synthesis, highlighting the need for improved growth conditions. This study employs transcriptomics and metabolomics to assess nitrogen's impact on enzymes in secondary metabolites biosynthesis pathways. The gene expressions of berberine bridge enzymes (BBEs) like TsBBE2 had peak expression in low nitrogen treatments (A0 and A1) but were absent in higher nitrogen treatments (A2 and A3). Similar trends were observed for other enzymes such as (S)-scoulerine 9-O-methyltransferase (TsCMT3), Tetrahydroberberine oxidase (TsSTOX), and Columbamine O-methyltransferase (TsCoCOMT2-4) in response to nitrogen levels. In examining gene families related to diterpene synthases (diTPS), 1-deoxyxylulose 5-phosphate synthase (TsDXR1) expression increased with higher nitrogen fertilizer, while TsDXR2 peaked at maximal nitrogen levels. Geranylgeranyl diphosphate synthase (TsGGPP3 and TsGGPP5) decreased with nitrogen levels. (-)-kolavenyl diphosphate synthase (KPS) genes had higher expression in treatments, while ent-kaurene synthase (KSL) genes, especially TsKSL1 and TsKSL2, showed higher expression in control conditions with lower nitrogen fertilizer. Metabolite analysis confirmed more upregulated compounds in A3 compared to A0. These findings have practical implications for agriculture and pharmaceuticals, highlighting the link between nitrogen fertilization and specialized metabolism in medicinal plants.

Diterpene glycosides from Fructus Rubi ameliorates benign prostatic hyperplasia in rats through the androgen and TGF-ß/Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Rubi (FR), a food material with medicinal value, is used in traditional Chinese medicine (TCM) for treatment of various kidney-related problems, such as impotence, spermatorrhea, and frequent urination. It is also frequently used to produce diverse functional foods in China. AIM OF STUDY: The purpose of this research was to assess the therapeutic effects of FR diterpene glycosides on RWPE-1 epithelial cell (RWPE-1), a human normal prostatic epithelial cell, and benign prostate hyperplasia (BPH) rats, both of which had been exposed to dihydrotestosterone (DHT) and testosterone propionate (TP), respectively, and to investigate the mechanism of action. METHODS: Target proteins that could stably bind to certain diterpene glycosides were screened through drug affinity responsive target stability combined with mass spectrometry (DARTS/MS). DHT-induced RWPE-1 cells were used to detect drug activity. TP was subcutaneously injected to induce BPH in rats. The extract of diterpene glycosides from FR (FDS) was orally administered for 28 days. The DHT levels in the serum and prostate tissue of the rats were measured through enzyme-linked immunosorbent assay (ELISA), and to analyze cell proliferation and epithelial-mesenchymal transition (EMT), the protein expression of prostate-specific antigen (PSA), androgen receptor (AR), steroid 5α-reductase type 2 (SRD5A2), proliferating cell nuclear antigen (PCNA), S100 calcium-binding protein A2 (S100A2), transforming growth factor-ß1 (TGF-ß1), E-cadherin, vimentin, and Smad4 was determined through western blotting (WB), immunohistochemistry (IHC), or immunofluorescence (IF). RESULTS: FDS reduced the proliferation of DHT-induced RWPE-1 cells. It also significantly inhibited rat prostate enlargement; decreased DHT levels in the serum and prostate tissue; inhibited the protein expression of AR, PSA, PCNA, S100A2, TGF-ß1, E-cadherin, and Smad4; and increased the protein expression of E-cadherin. CONCLUSION: The present study is the first to report that diterpene glycosides isolated from FR inhibited BPH at the cellular level, regulated the proliferation of prostate cells through the androgen signaling pathway, and prevented EMT in the prostate through the S100A2-mediated TGF-ß/Smad signaling pathway. These results indicate that FDS is a promising multitarget therapy for BPH.

Pharmacological potential of Euphorbia tirucalliL. latex in gastric adenocarcinoma: from an ethnopharmacological perspective into new products.

Products derived from the latex of Euphorbia tirucalli were obtained through hydrolysis and column chromatography, resulting in products rich in triterpenes, ingenol 3-esters (I3E), and other derivatives from hydrolysed latex. These products underwent evaluation for their cytotoxic activity against gastric adenocarcinoma cells (AGS). Triterpene derivatives were synthesised, and the selectivity of each product was assessed. The results were compared with the previously described crude latex. Triterpenes and I3E were analysed in silico for their affinity with the active site of PKCδC1b. The hydrolysed latex (free of I3E) exhibited high cytotoxicity, albeit with reduced selectivity. Triterpenes and acetylated triterpenes were more cytotoxic than I3E, although the latter showed greater selectivity. Euphol benzoates and cinnamates showed no cytotoxicity. I3E demonstrated high affinity for the PKCδC1b. In summary, triterpenes exhibited higher cytotoxicity against AGS cells, while I3E displayed greater selectivity. Hydrolysed latex shows promise as a potential candidate for future gastric cancer treatment.

Double-barreled defense: dual ent-miltiradiene synthases in most rice cultivars.

Rice (Oryza sativa) produces numerous diterpenoid phytoalexins that are important in defense against pathogens. Surprisingly, despite extensive previous investigations, a major group of such phytoalexins, the abietoryzins, were only recently reported. These aromatic abietanes are presumably derived from ent-miltiradiene, but such biosynthetic capacity has not yet been reported in O. sativa. While wild rice has been reported to contain such an enzyme, specifically ent-kaurene synthase-like 10 (KSL10), the only characterized ortholog from O. sativa (OsKSL10), specifically from the well-studied cultivar (cv.) Nipponbare, instead has been shown to make ent-sandaracopimaradiene, precursor to the oryzalexins. Notably, in many other cultivars, OsKSL10 is accompanied by a tandem duplicate, termed here OsKSL14. Biochemical characterization of OsKLS14 from cv. Kitaake demonstrates that this produces the expected abietoryzin precursor ent-miltiradiene. Strikingly, phylogenetic analysis of OsKSL10 across the rice pan-genome reveals that from cv. Nipponbare is an outlier, whereas the alleles from most other cultivars group with those from wild rice, suggesting that these also might produce ent-miltiradiene. Indeed, OsKSL10 from cv. Kitaake exhibits such activity as well, consistent with its production of abietoryzins but not oryzalexins. Similarly consistent with these results is the lack of abietoryzin production by cv. Nipponbare. Although their equivalent product outcome might suggest redundancy, OsKSL10 and OsKSL14 were observed to exhibit distinct expression patterns, indicating such differences may underlie retention of these duplicated genes. Regardless, the results reported here clarify abietoryzin biosynthesis and provide insight into the evolution of rice diterpenoid phytoalexins. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00167-3.

In silico studies of bis-spiro- and Furano-Labdane diterpenoids from Rydingia persica Scheen (Otostegia persica) as α-glucosidase enzyme inhibitor.

The inhibition potential of α-glucosidase enzyme by crude- dichloromethane, methanol, and ethanol -extracts of Rydingia persica were evaluated using colorimetric method. We have isolated four labdane diterpenoids: 15, 16- epoxy-3α, 7ß, 9α -trihydroxylabdan-13- (16), 14-dien-6-one (1), 15, 16- epoxy-3α, 7α, 9α -trihydroxylabdan-13- (16), 14-dien-6-one (2), 9, 13, 15, 16-diepoxy- 3α, 7ß, 15α (ß)- trihydroxy-labdan- 6 one (3, 4) from the most potent enzyme inhibitor fraction; the ethyl acetate soluble part of ethanol extract of the aerial parts of R. persica. The structures of the compounds were elucidated by their 1H and13C NMR and ESIMS spectral data analyses. The enzyme inhibition potential of the compounds was evaluated against acetylcholine esterase (AChE) and α-glucosidase by simulation studies. The predicted binding energy of most diterpenes towards mouse AChE enzyme was low, while the binding energy of diterpenes towards α-glucosidase enzyme was moderate to potent.

Screening of ent-copalyl diphosphate synthase and metabolic engineering to achieve de novo biosynthesis of ent-copalol in Saccharomyces cerevisiae.

The diterpene ent-copalol is an important precursor to the synthesis of andrographolide and is found only in green chiretta (Andrographis paniculata). De novo biosynthesis of ent-copalol has not been reported, because the catalytic activity of ent-copalyl diphosphate synthase (CPS) is very low in microorganisms. In order to achieve the biosynthesis of ent-copalol, Saccharomyces cerevisiae was selected as the chassis strain, because its endogenous mevalonate pathway and dephosphorylases could provide natural promotion for the synthesis of ent-copalol. The strain capable of synthesizing diterpene geranylgeranyl pyrophosphate was constructed by strengthening the mevalonate pathway genes and weakening the competing pathway. Five full-length ApCPSs were screened by transcriptome sequencing of A. paniculata and ApCPS2 had the best activity and produced ent-CPP exclusively. The peak area of ent-copalol was increased after the ApCPS2 saturation mutation and its configuration was determined by NMR and ESI-MS detection. By appropriately optimizing acetyl-CoA supply and fusion-expressing key enzymes, 35.6 mg/L ent-copalol was generated. In this study, de novo biosynthesis and identification of ent-copalol were achieved and the highest titer ever reported. It provides a platform strain for the further pathway analysis of andrographolide and derivatives and provides a reference for the synthesis of other pharmaceutical intermediates.

Synthesized diterpene lactone derivative attenuated Freund's complete adjuvant-induced arthritis in Wistar rats.

Objectives: In this study, the SP-38 (Diterpene Lactone derivative) was designed, synthesized from clerodane diterpene (lactone) isolated from Polyanthia longifolia var. pendula, and tested for anti-arthritic activity using the FCA-induced arthritic rat model. Materials and Methods: This study examined the in vivo effects of SP-38 using three different doses (20, 10, and 5 mg/kg) by oral administration for 21 days from day 8 after 0.1 ml FCA sub-planter injection until day 28. Arthritis index, paw swelling, ankle diameter, body weight as well as biochemical, hematological, histopathological, and radiological parameters were examined. Results: Administered SP-38 reduced arthritis index, paw volume, and joint swelling compared to the arthritic control group. Accordingly, rats treated with SP-38 showed a remarkable increase in body weight and improved biochemical, hematological, histopathological, and radiological parameters. Furthermore, it reduced the increased production of CRP and RF while simultaneously decreasing ESR in all SP-38-treated rats. However, SP-38 showed promising liver protection by reducing elevated serum levels of liver and kidney function markers SGOT, SGPT, and ALP. Furthermore, splenic index, TNF-α, and IL-6 levels were significantly reduced compared to arthritic control rats at certain doses. Conclusion: The result of the present study concludes that SP-38 has significant anti-arthritic potential in FCA-induced arthritis in Wistar rats. SP-38 therefore showed promising anti-arthritic activity, as evidenced by attenuation of inflammation, inflammatory markers, and pro-inflammatory cytokine levels.

A novel diterpenic derivative produced by Streptomyces chrestomyceticus ADP4 is a potent inhibitor of biofilm and virulence factors in Candida albicans and C. auris.

AIM: Isolation, identification, structural and functional characterization of potent anti-Candida compound with specific antagonistic activities against significant human pathogens, Candida albicans and C. auris. METHODS AND RESULTS: The compound (55B3) was purified from the metabolites produced by Streptomyces chrestomyceticus ADP4 by employing column chromatography. The structure of 55B3 was determined from the analyses of spectral data that included LCMS, nuclear magnetic resonance, FTIR, and UV spectroscopies. It was identified as a novel derivative of diterpenic aromatic acid, 3-(dictyotin-11'-oate-15'α, 19'ß-olide)-4-(dictyotin-11'-oate-15″α, 19″ß-olide)-protocatechoic acid. The compound displayed potent antifungal and anti-biofilm activities against C. albicans ATCC 10231 (Minimum Inhibitory Concentration, MIC90:14.94 ± 0.17 µgmL-1 and MBIC90: 16.03 ± 1.1 µgmL-1) and against C. auris CBS 12372 (MIC90: 21.75 ± 1.5 µgmL-1 and Minimum Biofilm Inhibitory Concentration, MBIC90: 18.38 ± 1.78 µgmL-1). Further, pronounced inhibition of important virulence attributes of Candida spp., e.g. yeast-to-hyphae transition, secretory aspartyl proteinase and phospholipase B by 55B3 was noted at subinhibitory concentrations. A plausible mechanism of anti-Candida action of the compound appeared to be the inhibition of ergosterol biosynthesis, which was inhibited by 64 ± 3% at the MIC90 value. The non-cytotoxic attribute of the compound was noted in the liver cell line (HepG2 cells). CONCLUSION: The present work led to the discovery of a novel diterpenic derivative produced by S. chrestomyceticus ADP4. The compound displayed potent anti-Candida activity, particularly against the two most significant human pathogens, C. albicans and C. auris, which underlined its significance as a potential drug candidate for infections involving these pathogens.

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes.

Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.

Kallopterolides A-I, a New Subclass of seco-Diterpenes Isolated from the Southwestern Caribbean Sea Plume Antillogorgia kallos.

Kallopterolides A-I (1-9), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were isolated from the Caribbean Sea plume Antillogorgia kallos. The structures and relative configurations of 1-9 were characterized by analysis of HR-MS, IR, UV, and NMR spectroscopic data in addition to computational methods and side-by-side comparisons with published NMR data of related congeners. An investigation was conducted as to the potential of the kallopterolides as plausible in vitro anti-inflammatory, antiprotozoal, and antituberculosis agents.

New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling in cancer cells.

Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety. Several of these compounds triggered severe ER swelling associated with strong proteasomal inhibition and consequently cell death, a feature that was not observed with respect to mode of action of the natural product. Significantly, an analysis from the National Cancer Institute sixty cell line testing did not reveal any correlations between the most potent derivative and any other compound in the database, except at high concentrations (LC50). This study led to the discovery of a new set of sphaeropsidin derivatives that may be exploited as potential anti-cancer agents, notably due to their maintained activity towards multidrug resistant models.

Two undescribed constituents from Salvia castanea Diels and evaluation of their cytotoxic activity.

One previously undescribed abietane diterpene alkaloid containing an oxazole ring (1), one unreported abietane diterpene (2), and nine known abietane diterpenes (3-11) were isolated from the roots and rhizomes of Salvia castanea Diels. Their structures and absolute configurations were elucidated by a combination of HRESIMS, 1D and 2D NMR, and ECD. All compounds were evaluated for their cytotoxic activity against several human cancer cell lines (HepG2, A549, H460, MCF7, PC3, and Hela). The results showed that 1 exhibited a moderate cytotoxic effect on HepG2 cells (IC50: 14.22 ± 1.05 µM) and was able to inhibit the cell growth of MCF7 and Hela cells by 35.08% and 47.26% respectively, at a concentration of 20 µM, while other compounds showed low cytotoxic activity.

Gibberellin-biosynthetic ent-kaurene synthases in higher plants do not require their non-catalytic domains for the catalysis.

ent-Kaurene is a biosynthetic intermediate diterpene of phytohormone gibberellins, and is biosynthesized from geranylgeranyl diphosphate via ent-copalyl diphosphate (ent-CDP). The successive cyclization is catalyzed by two distinct diterpene synthases, ent-CDP synthase (ent-CPS) and ent-kaurene synthase (KS). Homologs of these diterpene synthase genes have been reported to be involved in the biosynthesis of specialized-metabolic diterpenoids for defense in several plant species, including rice (Oryza sativa). These diterpene synthases consist of three domains, αßγ domains. Active sites of ent-CPS exist at the interface of ß and γ domain, while those of KS are located within the α domain. We herein carried out domain-deletion experiments using several KSs and KS like enzymes (KSLs) to obtain insights into the roles of domains other than active-site domains. As previously reported in taxadiene synthase, deletion of γ or ßγ domains drastically decreased activities of specialized-metabolic OsKSL5, OsKSL8, OsKSL7 and OsKSL10 in O. sativa. However, unexpectedly, only α domains of several gibberellin-biosynthetic KSs, including OsKS1 in O. sativa, AtKS in Arabidopsis thaliana, TaKS in wheat (Triticum aestivum) and BdKS1 in Brachypodium distachyon, retained their original functions. Additionally, the specialized-metabolic OsKSL4, which is closely related to OsKS1, also functioned without its ßγ domains. Domain-swapping experiments showed that replacing ßγ domains in OsKSL7 with those from other KS/KSLs retained the OsKSL7 activity. Moreover, deletion of ßγ domains of bifunctional PpCPS/KS in moss (Physcomitrella patens) drastically impaired its KS-related activity. Thus, we demonstrate that monofunctional gibberellin-biosynthetic KSs are the unique diterpene synthases that retain their functions without ßγ domains.

Revealing Hidden Genes in Botrytis cinerea: New Insights into Genes Involved in the Biosynthesis of Secondary Metabolites.

Utilizing bioinformatics tools, this study expands our understanding of secondary metabolism in Botrytis cinerea, identifying novel genes within polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), sesquiterpene cyclase (STC), diterpene cyclase (DTC), and dimethylallyltryptophan synthase (DMATS) families. These findings enrich the genetic framework associated with B. cinerea's pathogenicity and ecological adaptation, offering insights into uncharted metabolic pathways. Significantly, the discovery of previously unannotated genes provides new molecular targets for developing targeted antifungal strategies, promising to enhance crop protection and advance our understanding of fungal biochemistry. This research not only broadens the scope of known secondary metabolites but also opens avenues for future exploration into B. cinerea's biosynthetic capabilities, potentially leading to novel antifungal compounds. Our work underscores the importance of integrating bioinformatics and genomics for fungal research, paving the way for sustainable agricultural practices by pinpointing precise molecular interventions against B. cinerea. This study sets a foundation for further investigations into the fungus's secondary metabolism, with implications for biotechnology and crop disease management.

Anticancer diterpenes of African natural products: Mechanistic pathways and preclinical developments.

BACKGROUND: The African continent is home to five biodiversity hotspots, boasting an immense wealth of medicinal flora, fungi and marine life. Diterpenes extracted from such natural products have compelling cytotoxic activities that warrant further exploration for the drug market, particularly in cancer therapy, where mortality rates remain elevated worldwide. PURPOSE: To demonstrate the potential of African natural products on the global stage for cancer therapy development and provide an in-depth analysis of the current literature on the activity of cancer cytotoxic diterpenes from African natural sources (to our knowledge, the first of its kind); not only to reveal the most promising candidates for clinical development, but to demonstrate the importance of preserving the threatened ecosystems of Africa. METHODS: A comprehensive search by means of the PRISMA strategy was conducted using electronic databases, namely Web of Science, PubMed, Google Scholar and ScienceDirect. The search terms employed were 'diterpene & mechanism & cancer' and 'diterpene & clinical & cancer'. The selection process involved assessing titles in English, Portuguese and Spanish, adhering to predefined eligibility criteria. The timeframe for inclusion spanned from 2010 to 2023, resulting in 218 relevant papers. Chemical structures were visualized using ChemDraw 21.0, PubChem was utilized to search for CID numbers. RESULTS: Despite being one of the richest biodiverse zones in the world, African natural products are proportionally underreported compared to Asian countries or otherwise. The diterpenes andrographolide (Andrographis paniculata), forskolin (Coleus forskohlii), ent-kauranes from Isodon spp., euphosorophane A (Euphorbia sororia), cafestol & kahweol (Coffea spp.), macrocylic jolkinol D derivatives (Euphorbia piscatoria) and cyathane erinacine A (Hericium erinaceus) illustrated the most encouraging data for further cancer therapy exploration and development. CONCLUSIONS: Diterpenes from African natural products have the potential to be economically significant active pharmaceutical and medicinal ingredients, specifically focussed on anticancer therapeutics.