Exploring the cytotoxic potential of biflavones of Araucaria cunninghamii: Precise identification combined by LC-HRMS-metabolomics and database mining, targeted isolation, network pharmacology, in vitro cytotoxicity, and docking studies.

The leaves of Araucaria cunninghamii are known to be nonedible and toxic. Previous studies have identified biflavones in various Araucaria species. This study aimed to investigate the in vitro cytotoxicity of the isolated compounds from Araucaria cunninghamii after metabolomics and network pharmacological analysis. Methanol extract of Araucaria cunninghamii leaves was subjected to bioassay-guided fractionation. The active fraction was analyzed using LC-HRMS, through strategic database mining, by comparing the data to the Dictionary of Natural Products to identify 12 biflavones, along with abietic acid, beta-sitosterol, and phthalate. Eight compounds were screened for network pharmacology study, where in silico ADME analysis, prediction of gene targets, compound-gene-pathway network and hierarchical network analysis, protein-protein interaction, KEGG pathway, and Gene Ontology analyses were done, that showed PI3KR1, EGFR, GSK3B, and ABCB1 as the common targets for all the compounds that may act in the gastric cancer pathway. Simultaneously, four biflavones were isolated via chromatography and identified through NMR as dimeric apigenin with varying methoxy substitutions. Cytotoxicity study against the AGS cell line for gastric cancer showed that AC1 biflavone (IC50 90.58 µM) exhibits the highest cytotoxicity and monomeric apigenin (IC50 174.5 µM) the lowest. Besides, the biflavones were docked to the previously identified targets to analyze their binding affinities, and all the ligands were found to bind with energy ≤-7 Kcal/mol.

Phytochemical and pharmacological aspects of genus Amaranthus.

The variety of bioactive compounds found in different species of Amaranthus, an herb that is a staple food in many parts of India. The plethora of herb Amaranthus has been a rich source of bioactive compounds like essential oils, sesquiterpenes, diterpenes, triterpenes, phenolic acids, flavonoids, etc. The traditional uses of Amaranthus, spp. have been established scientifically and were shown due to the presence of different phytochemicals. Although the pharmacological activities of Amaranthus genus have been well-documented, further studies are needed to fully understand their mechanisms of action and clinical applications. In conclusion, the phytochemistry and pharmacological activity of genus Amaranthus make it a promising source of natural products for drug discovery and development. The present is review mainly concise to the ethnopharmacological relevance and pharmacological studies of Amaranthus species. This conclusive review work may on Amaranthus species provided the interconnection of bioactive molecules with its ethno pharmacological utility of plant species.

Unveiling the healing properties of 2,3-dehydrosilychristin: a potential silymarin-derived flavonolignan from Vitex negundo.

The compound 2,3-dehydrosilychristin, a flavonolignan linked to silychristin and silymarin, remains intriguing due to its challenging isolation from silymarin. While silymarin has been the exclusive source of flavonolignans - silybin, silychristin and silydianin - 2,3-dehydrosilychristin is reported in this study from Vitex negundo Linn. leaves. 2,3-Dehydrosilychristin (7) and 14 other compounds were isolated through focused extraction. Its subsequent pharmacological evaluation demonstrated potent antioxidant and in-vitro anti-inflammatory effects, notably inhibiting cytokines TNF-α, IL-6, IL-8 and VEGF. In in-vivo assessments, 2,3-dehydrosilychristin (7) revealed remarkable hepatoprotective potential by reducing liver enzyme levels AST and ALT. These findings expand the potential of 2,3-dehydrosilychristin and suggest bioprospecting Vitex species as alternate sources of bioactive flavonolignans.

New cycloartane triterpenoids from Dysoxylum malabaricum and their cytotoxic evaluation.

The cytotoxic dichloromethane-methanol bark extract of Dysoxylum malabaricum was subjected to bioassay-guided fractionation, followed by systematic dereplication to focus on the identification of new compounds. From the bark of Dysoxylum malabaricum, two new cycloartane-type triterpenoids were isolated in addition to two previously known triterpenoids. The structures and absolute configurations of the isolated compounds were elucidated unambiguously via NMR, HRESIMS data, and electronic circular dichroism calculations. The isolated compounds were tested for their cytotoxic potential against the panel of breast, lung, and hypopharynx cancer cell lines and displayed notable cytotoxicity against breast cancer cell lines. Compound 3 exhibited the most potent cytotoxic effect with an IC50 14 µM against MCF-7 cell lines and induced cell cycle arrest. Through western blot and cell cycle analysis, it was revealed that compound 3 halts the G0/G1 phase of the cell cycle by inhibiting CDC20 and CDC25 enzymes.

Indole derivatives targeting colchicine binding site as potential anticancer agents.

Microtubules are appealing as intracellular targets for anticancer activity due to their importance in cell division. Three important binding sites are present on the tubulin protein: taxane, vinca, and colchicine binding sites (CBS). Many USFDA-approved drugs such as paclitaxel, ixabepilone, vinblastine, and combretastatin act by altering the dynamics of the microtubules. Additionally, a large number of compounds have been synthesized by medicinal chemists around the globe that target different tubulin binding sites. Although CBS inhibitors have proved their cytotoxic potential, no CBS-targeting drug had been able to reach the market. Several studies have reported design, synthesis, and biological evaluation of indole derivatives as potential anticancer agents. These compounds have been shown to inhibit cancer cell proliferation, induce apoptosis, and disrupt microtubule formation. Moreover, the binding affinity of these compounds to the CBS has been demonstrated using molecular docking studies and competitive binding assays. The present work has reviewed indole derivatives as potential colchicine-binding site inhibitors. The structure-activity relationship studies have revealed the crucial pharmacophoric features required for the potent and selective binding of indole derivatives to the CBS. The development of these compounds with improved efficacy and reduced toxicity could potentially lead to the development of novel and effective cancer therapies.

The genus Leucas: A review on phytochemistry and pharmacological activities.

Genus Leucas (family Lamiaceae) has been used as the traditional medicine for the treatment of a variety of disorders like skin diseases, diabetes, rheumatic pain, wounds, snake bites, etc. Several species of genus Leucas have been explored for their pharmacological activities and found to possess diverse properties like antimicrobial, antioxidant, anti-inflammatory, cytotoxic and anticancer, antinociceptive, antidiabetic, antitussive, wound healing, phytotoxic, etc. Phytochemical investigations of the different plant parts of Genus Leucas have revealed the presence of phytochemicals including terpenoids, flavonoids, lignans, phenolic glycosides, sterols, and essential oils. Terpenoids have been obtained as the major components of the isolated compounds and could be used as the marker compounds for the genus Leucas. The traditional uses of Leucas spp. have been established scientifically and were shown due to the presence of different phytochemicals. Although the pharmacological activities of Leucas plants have been well-documented, further studies are needed to fully understand their mechanisms of action and clinical applications. In conclusion, the phytochemistry and pharmacological activity of genus Leucas make it a promising source of natural products for drug discovery and development. The present review aims to provide a comprehensive note on the phytochemistry and pharmacological properties of the genus Leucas.

Iodine-mediated one-step synthesis of ipomone from gibberellic acid.

A fast and efficient method for synthesising ipomone (4), a bicyclo[3.2.1]octanone containing aromatised derivative, from gibberellic acid (1) has been developed using molecular iodine as a mild and effective mediator under heating conditions in a single step. Evidence was obtained that the reaction simultaneously proceeds through aromatisation and pinacol-pinacolone type 1,2-alkyl shift. Use of excess iodine afforded iodomethyl derivative (5) that could serve as starting material for the synthesis of additional analogs.

Isolation of a new cytotoxic colchinoid from Gloriosa superba roots.

A new colchinoid compound, identified as N-deacetyl-N-formylcornigerine (1), named glorigerine was isolated from the roots of Gloriosa superba, along with two known compounds. The structures of isolated compounds were elucidated by 1 D and 2 D NMR and HRMS experiments. Glorigerine (1) differed from cornigerine (6) by the presence of an N-formyl group instead of the N-acetyl group. Glorigerine (1) was found to have moderate cytotoxicity when tested against four human cancer cell lines.

Natural products as a source of cytotoxic warheads in antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are one of the most rapidly expanding classes of oncology therapeutics. Till now, 11 ADCs have been approved by USFDA, with the first ADC approval of gemtuzumab ozogamicin (Mylotarg) in 2000. A large number of ADCs are being evaluated in different stages of clinical trials and pre-clinical studies. Interestingly, the cytotoxic warheads of the all approved ADCs, as well as clinical and preclinical candidates, belong to different classes of natural products viz. calicheamicins, auristatins, maytansinoids, camptothecin derivatives, pyrolidobenzodiazepines (PBDs), and duocarmycins, etc. Herein, a review of the natural product-based cytotoxic warheads, briefly discussing their source, modifications, and mechanism of action, has been conducted.

LCMS-DNP based dereplication of Araucaria cunninghamii Mudie gum-resin: identification of new cytotoxic labdane diterpene.

As a part of natural defense, plants initiate the secretion of gum containing numerous pharmacologically active essential metabolites. A fraction of such gum-resin from Araucaria cunninghamii Mudie, when screened against human cancer cell lines, was found to be active. Further, it was subjected to an LCMS-DNP (Dictionary of Natural Products) based dereplication study followed by a detailed phytochemical investigation to obtain pure metabolites. Also, the gum resin of A. cunninghamii was found to be a rich source of abietanes and labdanes. The LCMS-DNP-based dereplication study identified many known metabolites, which were isolated for the first time from this plant as well as a new labdane diterpenoid (9). The compounds were characterized via spectroscopic techniques, which were subsequently compared with the already existing literature data. The metabolites were screened against seven human cancer cell lines. The anticancer activity was further supported by molecular docking studies.

Exploring the Potential of Chemical Inhibitors for Targeting Post-translational Glycosylation of Coronavirus (SARS-CoV-2).

The Spike (S) protein of SARS-CoV-2 expressed on the viral cell surface is of particular importance as it facilitates viral entry into the host cells. The S protein is heavily glycosylated with 22 N-glycosylation sites and a few N-glycosylation sites. During the viral surface protein synthesis via the host ribosomal machinery, glycosylation is an essential step in post-translational modifications (PTMs) and consequently vital for its life cycle, structure, immune evasion, and cell infection. Interestingly, the S protein of SARS-CoV-2 and the host receptor protein, ACE2, are also extensively glycosylated and these surface glycans are critical for the viral-host cell interaction for viral entry. The glycosylation pathway of both virus (hijacked from the host biosynthetic machinery) and target cells crucially affect SARS-CoV-2 infection at different levels. For example, the glycosaminoglycans (GAGs) of host cells serve as a cofactor as they interact with the receptor-binding domain (RBD) of S-glycoprotein and play a protective role in host immune evasion via masking the viral peptide epitopes. Hence, the post-translational glycan biosynthesis, processing, and transport events could be potential targets for developing therapeutic drugs and vaccines. Especially, inhibition of the N-glycan biosynthesis pathway amplifies S protein proteolysis and, thus, blocks viral entry. The chemical inhibitors of SARS-CoV-2 glycosylation could be evaluated for Covid-19. In this review, we discuss the current status of the chemical inhibitors (both natural and synthetically designed inhibitors) of viral glycosylation for Covid-19 and provide a future perspective. It could be an important strategy in targeting the various emerging SARS-CoV-2 variants of concern (VOCs), as these inhibitors are postulated to aid in reducing the viral load as well as infectivity.

Antiproliferative Potential of Gloriosine: A Lead for Anticancer Drug Development.

Gloriosine, a colchicine-like natural product, is widely obtained from Gloriosa superba roots. Despite having remarkable anticancer potential, colchicine could not pave its way to the clinic, while gloriosine is yet to be investigated for its pharmacological effects. In the present work, 14 compounds, including gloriosine, were isolated from the G. superba roots and were characterized by NMR spectroscopy. Gloriosine (11) was evaluated for its antiproliferative activity against a panel of 15 human cancer cell lines of different tissues and normal breast cells. Gloroisine (11) displayed significant antiproliferative activity against various cancer cell lines selectively, with IC50 values ranging from 32.61 to 100.28 nM. Further, gloriosine (11) was investigated for its apoptosis-inducing ability and found to form apoptotic bodies. It also inhibited A549 cell migration in the wound healing assay. Finally, molecular docking studies were performed to explore the possible binding modes of gloriosine with the colchicine-binding site of tubulin protein. Our findings suggested that gloriosine might be a potential lead for anticancer drug discovery.

Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-An update on clinical trials.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer with a tobacco consumption and infection with high-risk human papillomavirus (HPV) being major risk factors. Despite advances in numerous therapy modalities, survival rates for HNSCC have not improved considerably; a vast number of clinical outcomes have demonstrated that a combination strategy (the most well-known docetaxel, cisplatin, and 5-fluorouracil) is the most effective treatment choice. Immunotherapy that targets immunological checkpoints is being tested in a number of clinical trials, either alone or in conjunction with chemotherapeutic or targeted therapeutic drugs. Various monoclonal antibodies, such as cetuximab and bevacizumab, which target the EGFR and VEGFR, respectively, as well as other signaling pathway inhibitors, such as temsirolimus and rapamycin, are also being studied for the treatment of HNSCC. We have reviewed the primary targets in active clinical studies in this study, with a particular focus on the medications and drug targets used.

Virtual screening and molecular simulation study of natural products database for lead identification of novel coronavirus main protease inhibitors.

3CL like protease (3CLpro or Mpro) is one of the main proteases of 2019-nCoV. The 3CLpro is a nonstructural protein of SARS-CoV and has an essential role in viral replication and transcription, thus, could be a potential target for anti-SARS drug development. The present study employed ligand- and structure-based approaches to identify the potent inhibitors of 2019-nCoV protease. The e-pharmacophore developed from 3CLpro-1 yielded virtual hits, that were subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads- MolPort-000-410-348 and MolPort-002-530-156. The compounds MolPort-000-410-348 and MolPort-002-530-156 displayed good docking score of -12.09 and -13.38 Kcal/mol and free binding energy of -63.34 ± 2.03 and -61.52 ± 2.24 Kcal/mol, respectively. The compounds also exhibited satisfactory predicted ADMET profile and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with 3CLpro protein and ligand RMSD in acceptable limits. Communicated by Ramaswamy H. Sarma.

Identification and Evaluation of Apoptosis-Inducing Activity of Ipomone from Ipomoea nil: A Novel, Unusual Bicyclo-[3.2.1] Octanone Containing Gibberic Acid Diterpenoid.

Ipomone (1), a novel diterpenoid along with seven known compounds (2-8), was isolated for the first time from the acidified hydroalcoholic extract of Ipomoea nil seeds. The structures of the isolated compounds were elucidated via comprehensive NMR spectroscopic data. The absolute configuration of 1 was ascertained through NOESY, NMR, and ECD analyses. Compound 1 was found to contain an unusual bicyclo-[3.2.1] octanone, which appeared first time in any natural product that might be an artifact resulting from the acid-catalyzed 1,2 alkyl shift/rearrangement. The novel compound was screened for cytotoxic activity against a panel of 12 human cancer cell lines and exhibited weak cytotoxicity with IC50 values in the range of 34-86 µM (except for HEK-293 cells). Microscopic studies revealed that compound 1 induced apoptosis and autophagy in A549 cells. To further explore the signaling pathway involved, immunoblot analysis was performed that confirmed inhibition of apoptotic proteins PARP-1 and caspase-3 expression and upregulation of LC3B expression by compound 1. The compound was further subjected to molecular docking studies to evaluate its binding affinity with p110α, PARP-1, and caspase-3 proteins.

Glycorandomization: A promising diversification strategy for the drug development.

Glycorandomization is a natural product derivatization strategy in which different sugar moieties are linked to the aglycone part of the naturally existing glycosides to create glycorandomized libraries. Sugars attached to the natural products are responsible for affecting their solubility, mechanism of action, target recognition, and toxicity and thus, by changing the sugar part, these properties could be modified. Glycorandomization can be done via two approaches (i) a synthetic approach known as neoglycorandomization, and (ii) chemoenzymatic approach including in-vitro and in-vivo glycorandomization. Glycorandomization can be a promising technology for the drug discovery that has proved its potential to improve pharmacokinetic (solubility) and pharmacodynamic profile (mechanism of action, toxicity, and target recognition) of the parent compounds. The substrate flexibility of glycosyltransferases and other enzymes towards sugars and/or aglycone substrates has made this technique versatile. Further, the enzymes can be altered by genetic engineering to generate glycorandomized libraries of diverse natural product scaffolds. This technique has the potential to produce new compounds that can be helpful to the mankind by treating the threatening disease states. This review covers the different strategies for glycorandomization as a tool in drug discovery and development. The fundamentals of glycorandomization, different types, and further development of differentially glycorandomized libraries of natural products and small molecule based drugs have been discussed.

Anticancer Activity of Diosgenin and Its Semi-synthetic Derivatives: Role in Autophagy Mediated Cell Death and Induction of Apoptosis.

During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

Drug Discovery of Small Molecules for the Treatment of COVID-19: A Review on Clinical Studies.

Recently, a sudden outbreak of novel coronavirus disease (COVID-19) was caused by a zoonotic virus known as severe acute respiratory syndrome coronavirus (SARS-CoV-2). It has caused pandemic situations around the globe affecting the lives of millions of people. So far, no drug has been approved for the treatment of SARS-CoV-2 infected patients. As of now, more than 1000 clinical trials are going on for repurposing of FDA-approved drugs and for evaluating the safety and efficiency of experimental antiviral molecules to combat COVID-19. Since the development of new drugs may require months to years to reach the market, this review focusses on the potential of existing small molecule FDA approved drugs and the molecules already in the clinical pipeline against viral infections like HIV, hepatitis B, Ebola virus, and other viruses of coronavirus family (SARS-CoV and MERS-CoV). The review also discusses the natural products and traditional medicines in clinical studies against COVID-19. Currently, 1978 studies are active, 143 completed and 4 posted results (as of June 13, 2020) on clinicaltrials.gov.

Therapeutic Potential of Genus Pongamia and Derris: Phytochemical and Bioactivity.

Genus Pongamia and Derris belong to the Leguminosae family and are reported synonymously in literature. Although many compounds have been isolated from different plant parts but seed oil is known to produce non-edible medicinally important furanoflavonoids. The seed oil, commonly known as Karanj oil in Ayurvedic and Siddha traditional systems of medicine, is reported for the treatment of various skin infections and psoriasis. Several phytopharmacological investigations have proved the medicinal potential of furanoflavonoids in the skin and other disorders. Not only furanoflavonoids but several other important phenolic constituents such as chalcones, dibenzoylmethanes, aurones, isoflavones, flavanone dihydroflavonol, flavans, pterocarpans, rotenoids, coumarins, coumestans, stilbenoids and peltygynoids and their glycosides have been reported for different biological activities including antihyperglycemic, anti-inflammatory, anticancer, insecticidal, anti-alzheimer's, gastro protective, antifungal, antibacterial, etc. In the present review, the phytochemistry and pharmacological activities of the genera Pongamia and Derris have been summarized.

In-vitro antitumor activity of compounds from Glycyrrhiza glabra against C6 glioma cancer cells: identification of natural lead for further evaluation.

A HP20 resin-based unique method was adopted to get an active fraction of the hydroalcoholic extract of G. glabra roots. The fraction showed potent cytotoxicity against cancer cell line and was further subjected to detailed phytochemical investigation to obtain ten biomarkers. The isolated compounds were also tested for the cytotoxicity against the C6 glioma cell line in vitro using MTT assay. Among the isolated compounds, glycyrrhetic acid (1), glabrol (6), and glabridin (9) exhibited significant cytotoxicity. The compounds showed a dose-dependent decrease in cell viability. The active compounds were subjected to molecular docking study against topoisomerase I and topoisomerase II to support the mechanism of antitumor activity.