Naturally Occurring Plant-Based Anticancerous Candidates as Potential ERK2 Inhibitors: In-Silico Database Mining and Molecular Dynamics Simulations.

The evolutionarily conserved extracellular signal-regulated kinase 2 (ERK2) is involved in regulating cellular signaling in both normal and pathological conditions. ERK2 expression is critical for human development, while hyperactivation is a major factor in tumor progression. Up to now, there have been no approved inhibitors that target ERK2, and as such, here we report on screening of a naturally occurring plant-based anticancerous compound-activity-target (NPACT) database for prospective ERK2 inhibitors. More than 1,500 phytochemicals were screened using in-silico molecular docking and molecular dynamics (MD) approaches. NPACT compounds with a docking score lower than a co-crystallized LHZ inhibitor (calc.-10.5 kcal/mol) were subjected to MD simulations. Binding energies (ΔGbinding) of inhibitor-ERK2 complexes over the MD course were estimated using an MM-GBSA approach. Based on MM-GBSA//100 ns MD simulations, the steroid zhankuic acid C (NPACT01034) demonstrated greater binding affinity against ERK2 protein than LHZ, with ΔGbinding values of -50.0 and -47.7 kcal/mol, respectively. Structural and energetical analyses throughout the MD course demonstrated stabilization of zhankuic acid C complexed with ERK2 protein. The anticipated ADMET properties of zhankuic acid C indicated minimal toxicity. Moreover, in-silico evaluation of fourteen ERK2 inhibitors in clinical trials demonstrated the higher binding affinity of zhankuic acid C towards ERK2 protein.

Secondary Metabolites Generated from Saussurea lappa and Ligusticum sinensis Essential Oils by Microwave-Assisted Hydrodistillation: in Silico Molecular Docking and in Vitro Antibacterial Efficacy.

In the current study, both the essential oil composition and biological activity of Saussurea lappa and Ligusticum sinensis were investigated by means of microwave-assisted hydrodistillation (MAHD) and characterized by Gas chromatography/mass spectrometry (GC/MS), whereas the antimicrobial efficiency of MAHD essential oils was examined against four pathogens: Staphylococcus aureus, Escherichia coli, Aspergillus niger, and Candida albicans responsible for microbial infections. The goal was to spot synergy and a favorable method that gives essential oils to possibly use as alternatives to common antimicrobial agents for the treatment of bacterial infections using a microdilution assay. S. lappa's 21 compounds were characterized by MAHD extraction. Sesquiterpene lactones (39.7 % MAHD) represented the major components, followed by sesquiterpene dialdehyde (25.50 % MAHD), while L. sinensis's 14 compounds were identified by MAHD extraction. Tetrahydroisobenzofurans (72.94 % MAHD) was the predominant compound class. S. lappa essential oil collection showed the strongest antimicrobial activity with MIC values of 16 µg/ml against all pathogens tested, while L. sinensis showed strong antibacterial activity and moderate antifungal activity with MIC values of 32 µg/ml and 500 µg/ml, respectively. The principal components of both oils, (velleral, eremanthin and neocnidilide), were docked into the bacterial histidine kinase (HK) and the fungal heat shock protein 90 (Hsp90).

Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation.

BRD4 (bromodomain-containing protein 4) is an epigenetic reader that realizes histone proteins and promotes the transcription of genes linked to cancer progression and non-cancer diseases such as acute heart failure and severe inflammation. The highly conserved N-terminal bromodomain (BD1) recognizes acylated lysine residues to organize the expression of genes. As such, BD1 is essential for disrupting BRD4 interactions and is a promising target for cancer treatment. To identify new BD1 inhibitors, a SuperDRUG2 database that contains more than 4600 pharmaceutical compounds was screened using in silico techniques. The efficiency of the AutoDock Vina1.1.2 software to anticipate inhibitor-BRD4-BD1 binding poses was first evaluated based on the co-crystallized R6S ligand in complex with BRD4-BD1. From database screening, the most promising BRD4-BD1 inhibitors were subsequently submitted to molecular dynamics (MD) simulations integrated with an MM-GBSA approach. MM-GBSA computations indicated promising BD1 binding with a benzonaphthyridine derivative, pyronaridine (SD003509), with an energy prediction (ΔGbinding) of -42.7 kcal/mol in comparison with -41.5 kcal/mol for a positive control inhibitor (R6S). Pharmacokinetic properties predicted oral bioavailability for both ligands, while post-dynamic analyses of the BRD4-BD1 binding pocket demonstrated greater stability for pyronaridine. These results confirm that in silico studies can provide insight into novel protein-ligand regulators, specifically that pyronaridine is a potential cancer drug candidate.

Feature-Based Molecular Networking for the Exploration of the Metabolome Diversity of Common Egyptian Centaurea Species in Relation to Their Cytotoxic Activity.

Centaurea is a genus compromising over 250 herbaceous flowering species and is used traditionally to treat several ailments. Among the Egyptian Centaurea species, C. lipii was reported to be cytotoxic against multidrug-resistant cancer cells. In this context, we aimed to explore the metabolome of C. lipii and compare it to other members of the genus in pursuance of identifying its bioactive principles. An LC-MS/MS analysis approach synchronized with feature-based molecular networks was adopted to offer a holistic overview of the metabolome diversity of the Egyptian Centaurea species. The studied plants included C. alexandrina, C. calcitrapa, C. eryngioides, C. glomerata, C. lipii, C. pallescens, C. pumilio, and C. scoparia. Their constitutive metabolome showed diverse chemical classes such as cinnamic acids, sesquiterpene lactones, flavonoids, and lignans. Linking the recorded metabolome to the previously reported cytotoxicity identified sesquiterpene lactones as the major contributors to this activity. To confirm our findings, bioassay-guided fractionation of C. lipii was adopted and led to the isolation of the sesquiterpene lactone cynaropicrin with an IC50 of 1.817 µM against the CCRF-CEM leukemia cell line. The adopted methodology highlighted the uniqueness of the constitutive metabolome of C. lipii and determined the sesquiterpene lactones to be the responsible cytotoxic metabolites.

Naphthoquinone derivatives as P-glycoprotein inducers in inflammatory bowel disease: 2D monolayers, 3D spheroids, and in vivo models.

Inflammatory bowel disease (IBD) represents a chronic inflammation of the gastrointestinal tract characterized by an overreaction of immune responses and damage at the intestinal mucosal barrier. P-glycoprotein (P-gp) plays a key role to protect the intestinal barrier from xenobiotic accumulation and suppressing excessive immune responses. Therefore, induction/activation of P-gp function could serve as a novel therapeutic target to treat IBD. This study aimed to evaluate the potential therapeutic values of naphthoquinone derivatives (NQ-1 - NQ-8) as P-gp modulators to counterbalance intestinal inflammation. The data indicate that NQ-2, NQ-3, and NQ-4 act as P-gp inducers/activators and are recognized as substrates for P-gp. The three derivatives possess anti-inflammatory effects mediated by suppression of NF-κB and HDAC6 activity in Caco2 monolayer cells. Besides, they reversed LPS-induced intestinal barrier dysfunction by enhancing the expression of P-gp and ZO-1 tight junction proteins in a Caco-2 spheroid model. NQ-2, NQ-3, and NQ-4 showed a robust inhibitory effect on IL-1ß maturation in LPS-primed THP-1 cells. This effect may contribute to alleviate the inflammatory cascades associated with IBD. Distinctively, NQ-2 and NQ-3 exerted anti-NLRP3 inflammasome activity evidenced by the inhibition of CASP-1 activity and the promotion of autophagy. Both compounds induced disruptions of the microtubule network in transfected U2OS-GFP-α-tubulin cells. Treatment with NQ-2 remarkably attenuated dextran sulfate sodium (DSS)-induced colitis in rats by suppressing changes in colon length, colon mass index, and intestinal histopathology scores. Thus, 1,4-naphthoquinone derivatives such as NQ-2 may provide potential therapeutic anti-inflammatory effects for IBD patients and for other NLRP3-associated inflammatory diseases.

Molecular Network Guided Cataloging of the Secondary Metabolome of Selected Egyptian Red Sea Soft Corals.

Soft corals are recognized as an abundant source of diverse secondary metabolites with unique chemical features and physiologic capabilities. However, the discovery of these metabolites is usually hindered by the traditional protocol which requires a large quantity of living tissue for isolation and spectroscopic investigations. In order to overcome this problem, untargeted metabolomics protocols have been developed. The latter have been applied here to study the chemodiversity of common Egyptian soft coral species, using only minute amounts of coral biomass. Spectral similarity networks, based on high-resolution tandem mass spectrometry data, were employed to explore and highlight the metabolic biodiversity of nine Egyptian soft coral species. Species-specific metabolites were highlighted for future prioritization of soft coral species for MS-guided chemical investigation. Overall, 79 metabolites were tentatively assigned, encompassing diterpenes, sesquiterpenes, and sterols. Simultaneously, the methodology assisted in shedding light on newly-overlooked chemical diversity with potential undescribed scaffolds. For instance, glycosylated fatty acids, nitrogenated aromatic compounds, and polyketides were proposed in Sinularia leptoclados, while alkaloidal terpenes and N-acyl amino acids were proposed in both Sarcophyton roseum and Sarcophyton acutum.

In Silico and In Vitro Screening of 50 Curcumin Compounds as EGFR and NF-κB Inhibitors.

The improvement of cancer chemotherapy remains a major challenge, and thus new drugs are urgently required to develop new treatment regimes. Curcumin, a polyphenolic antioxidant derived from the rhizome of turmeric (Curcuma longa L.), has undergone extensive preclinical investigations and, thereby, displayed remarkable efficacy in vitro and in vivo against cancer and other disorders. However, pharmacological limitations of curcumin stimulated the synthesis of numerous novel curcumin analogs, which need to be evaluated for their therapeutic potential. In the present study, we calculated the binding affinities of 50 curcumin derivatives to known cancer-related target proteins of curcumin, i.e., epidermal growth factor receptor (EGFR) and nuclear factor κB (NF-κB) by using a molecular docking approach. The binding energies for EGFR were in a range of −12.12 (±0.21) to −7.34 (±0.07) kcal/mol and those for NF-κB ranged from −12.97 (±0.47) to −6.24 (±0.06) kcal/mol, indicating similar binding affinities of the curcumin compounds for both target proteins. The predicted receptor-ligand binding constants for EGFR and curcumin derivatives were in a range of 0.00013 (±0.00006) to 3.45 (±0.10) µM and for NF-κB in a range of 0.0004 (±0.0003) to 10.05 (±4.03) µM, indicating that the receptor-ligand binding was more stable for EGFR than for NF-κB. Twenty out of 50 curcumin compounds showed binding energies to NF-κB smaller than −10 kcal/mol, while curcumin as a lead compound revealed free binding energies of >−10 kcal/mol. Comparable data were obtained for EGFR: 15 out of 50 curcumin compounds were bound to EGFR with free binding energies of <−10 kcal/mol, while the binding affinity of curcumin itself was >−10 kcal/mol. This indicates that the derivatization of curcumin may indeed be a promising strategy to improve targe specificity and to obtain more effective anticancer drug candidates. The in silico results have been exemplarily validated using microscale thermophoresis. The bioactivity has been further investigated by using resazurin cell viability assay, lactate dehydrogenase assay, flow cytometric measurement of reactive oxygen species, and annexin V/propidium iodide assay. In conclusion, molecular docking represents a valuable approach to facilitate and speed up the identification of novel targeted curcumin-based drugs to treat cancer.

Sarcoconvolutums F and G: Polyoxygenated Cembrane-Type Diterpenoids from Sarcophyton convolutum, a Red Sea Soft Coral.

Natural products and chemical analogues are widely used in drug discovery, notably in cancer and infectious disease pharmacotherapy. Sarcophyton convolutum (Alcyoniidae) a Red Sea-derived soft coral has been shown to be a rich source of macrocyclic diterpenes and cyclized derivatives. Two previously undescribed polyoxygenated cembrane-type diterpenoids, sarcoconvolutums F (1) and G (2), as well as four identified analogues (3-6) together with a furan derivate (7) were isolated from a solvent extract. Compounds were identified by spectroscopic techniques, including NMR, HREIMS, and CD, together with close spectral comparisons of previously published data. Sarcoconvolutum F (1) contains a rare 1-peroxid-15-hydroxy-10-ene functionality. Isolated metabolites (1-7) were screened against lung adenocarcinoma (A549), cervical cancer (HeLa) and oral cavity carcinoma (HSC-2) lines. Compound 4 exhibited an IC50 56 µM and 55 µM against A549 and HSC-2 cells, respectively.

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study.

The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.

Oxygenated Cembrene Diterpenes from Sarcophyton convolutum: Cytotoxic Sarcoconvolutum A-E.

The soft coral genus Sarcophyton contains the enzymatic machinery to synthesize a multitude of cembrene-type diterpenes. Herein, highly oxygenated cembrenoids, sarcoconvolutum A-E (1-5) were purified and characterized from an ethyl acetate extract of the red sea soft coral, Sarcophyton convolutum. Compounds were assemblies according to spectroscopic methods including FTIR, 1D- and 2D-NMR as well as HRMS. Metabolite cytotoxicity was tested against lung adenocarcinoma, cervical cancer, and oral-cavity carcinoma (A549, HeLa and HSC-2, respectively). The most cytotoxic compound, (4) was observed to be active against cell lines A549 and HSC-2 with IC50 values of 49.70 and 53.17 µM, respectively.

Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition.

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

Guaianolide Sesquiterpene Lactones from Centaurothamnus maximus.

Centaurothamnus maximus (family Asteraceae), is a leafy shrub indigenous to the southwestern Arabian Peninsula. With a paucity of phytochemical data on this species, we set out to chemically characterize the plant. From the aerial parts, two newly identified guaianolides were isolated: 3ß-hydroxy-4α(acetoxy)-4ß(hydroxymethyl)-8α-(4-hydroxy methacrylate)-1αH,5αH, 6αH-gual-10(14),11(13)-dien-6,12-olide (1) and 15-descarboxy picrolide A (2). Seven previously reported compounds were also isolated: 3ß, 4α, 8α-trihydroxy-4-(hydroxymethyl)-lαH, 5αH, 6ßH, 7αH-guai-10(14),11(13)-dien-6,12-olide (3), chlorohyssopifolin B (4), cynaropikrin (5), hydroxyjanerin (6), chlorojanerin (7), isorhamnetin (8), and quercetagetin-3,6-dimethyl ether-4'-O-ß-d-pyranoglucoside (9). Chemical structures were elucidated using spectroscopic techniques, including High Resolution Fast Atom Bombardment Mass Spectrometry (HR-FAB-MS), 1D NMR; 1H, 13C NMR, Distortionless Enhancement by Polarization Transfer (DEPT), and 2D NMR (1H-1H COSY, HMQC, HMBC) analyses. In addition, a biosynthetic pathway for compounds 1-9 is proposed. The chemotaxonomic significance of the reported sesquiterpenoids and flavonoids considering reports from other Centaurea species is examined.

In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (Mpro) Inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ -40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of -51.9 vs. -33.6 kcal/mol, respectively. Protein-protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target-function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.

Vitamin K3 thio-derivative: a novel specific apoptotic inducer in the doxorubicin-sensitive and -resistant cancer cells.

Vitamin K3, also known as menadione, is a synthetic lipid-soluble 2-methyl-1,4- naphthoquinone analogs of vitamin K. The vitamin K derivatives exhibit potent cytotoxicity against several cancer cell lines through ROS induction and mitochondrial dysfunction. We investigated vitamin K3-inspired derivatives as potential apoptotic inducers and analyzed their mechanisms beyond apoptosis. The cytotoxicity of a panel of vitamin K3 analogs was screened against 10 doxorubicin-sensitive and -resistant cancer cell lines overexpressing ATP-binding cassette transporters (P-glycoprotein, ABCB5, BCRP) or oncogenes (ΔEGFR) or with knockout of tumor suppressors (p53), Cell cycle arrest, apoptosis, cell migration, and microtubule formation were further investigated. The online tool SwissTargetPrediction was utilized for target prediction. Among the screened compounds, one vitamin K3 thio-derivative (No. 45, VKT-1) exhibited the most potent cytotoxicity specifically against both drug-sensitive and -resistant cancer cell lines. In addition, VKT-1 arrested the cells at the G2/M phase and induced apoptosis as detected by flow cytometry. As predicted by SwissTargetPrediction, VKT-1 targeted microtubule-associated tau protein. Indeed, VKT-1 dramatically inhibited cell migration and microtubule formation in vitro. In conclusion, the synthetic vitamin K3 thio-derivative (VKT-1) inhibited doxorubicin-sensitive and -resistant tumor cells by cell arrest, apoptosis induction, as well as, migration inhibition, and microtubule deterioration of U2OS-GFP-α-tubulin cells.

Terpenoid bio-transformations and applications via cell/organ cultures: a systematic review.

Structurally diverse natural products are valued for their targeted biological activity. The challenge of working with such metabolites is their low natural abundance and complex structure, often with multiple stereocenters, precludes large-scale or unsophisticated chemical synthesis. Since select plants contain the enzymatic machinery necessary to produce specialized compounds, tissue cultures can be used to achieve key transformations for large-scale chemical and/or pharmaceutical applications. In this context, plant tissue-culture bio-transformations have demonstrated great promise in the preparation of pharmaceutical products. This review describes the capacity of cultured plant cells to transform terpenoid natural products and the specific application of such transformations over the past three decades (1988-2019).

New Rare Ent-Clerodane Diterpene Peroxides from Egyptian Mountain Tea (Qourtom) and Its Chemosystem as Herbal Remedies and Phytonutrients Agents.

Genus Stachys, the largest genera of the family Lamiaceae, and its species are frequently used as herbal teas due to their essential oils. Tubers of some Stachys species are also consumed as important nutrients for humans and animals due to their carbohydrate contents. Three new neo-clerodane diterpene peroxides, named stachaegyptin F-H (1, 2, and 4), together with two known compounds, stachysperoxide (3) and stachaegyptin A (5), were isolated from Stachys aegyptiaca aerial parts. Their structures were determined using a combination of spectroscopic techniques, including HR-FAB-MS and extensive 1D and 2D NMR (1H, 13C NMR, DEPT, 1H-1H COSY, HMQC, HMBC and NOESY) analyses. Additionally, a biosynthetic pathway for the isolated compounds (1-5) was discussed. The chemotaxonomic significance of the isolated diterpenoids of S. aegyptiaca in comparison to the previous reported ones from other Stachys species was also studied.

Cardenolides: Insights from chemical structure and pharmacological utility.

Cardiac glycosides (CGs) are a class of naturally occurring steroid-like compounds, and members of this class have been in clinical use for more than 1500 years. They have been used in folk medicine as arrow poisons, abortifacients, heart tonics, emetics, and diuretics as well as in other applications. The major use of CGs today is based on their ability to inhibit the membrane-bound Na+/K+-ATPase enzyme, and they are regarded as an effective treatment for congestive heart failure (CHF), cardiac arrhythmia and atrial fibrillation. Furthermore, increasing evidence has indicated the potential cytotoxic effects of CGs against various types of cancer. In this review, we highlight some of the structural features of this class of natural products that are crucial for their efficacy, some methods of isolating these compounds from natural resources, and the structural elucidation tools that have been used. We also describe their physicochemical properties and several modern biotechnological approaches for preparing CGs that do not require plant sources.

Marine Natural Products: A Source of Novel Anticancer Drugs.

Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.

Euphosantianane E-G: Three New Premyrsinane Type Diterpenoids from Euphorbia sanctae-catharinae with Contribution to Chemotaxonomy.

Euphorbia species were widely used in traditional medicines for the treatment of several diseases. From the aerial parts of Egyptian endemic plant, Euphorbia sanctae-catharinae, three new premyrsinane diterpenoids, namely, euphosantianane E-G (1-3), alongside four known triterpenes, 9,19-cyclolanostane-3ß,24S-diol (4), 25-methoxycycloartane-3ß,24S-diol (5), 25-methylenecycloartan-3ß,24R-diol (6), and 25-methylenecycloartan-3ß,24S-diol (7), were isolated and identified. The chemical structures were proven depending upon spectroscopic analysis, including FTIR, HRFABMS, and 1D/2D-NMR. The chemotaxonomic significance of the isolated compounds, especially diterpenes from E. sanctae-catharinae compared to those documented from different Euphorbia species was also studied via agglomerative hierarchical clustering (AHC). The Egyptian endemic Euphorbia sanctae-catharina was grouped with E. bupleuroides, E. fidjiana, E. fischeriana, E. pithyusa subsp. cupanii, E. prolifera, and E. seguieriana, where myrsinol diterpenoids were the characteristic compounds.

Euphosantianane A⁻D: Antiproliferative Premyrsinane Diterpenoids from the Endemic Egyptian Plant Euphorbia Sanctae-Catharinae.

Euphorbia species are rich in diterpenes. A solvent extraction of Euphorbia sanctae-catharinae, a species indigenous to the Southern Sinai of Egypt, afforded several premyrsinane diterpenoids (1⁻4) as well as previously reported metabolites (5⁻13) that included three flavonoids. Isolated compounds were chemically characterized by spectroscopic analysis. Identified compounds were bioassayed for anti-proliferative activity in vitro against colon (Caco-2) and lung (A549) tumor cell lines. Compound 9 exhibited robust anti-proliferative activity against A549 cells (IC50 = 3.3 µM). Absolute configurations for 8 versus 9 were determined by experimental and TDDFT-calculated electronic circular dichorism (ECD) spectra.