New ring-A modified cycloartane triterpenoids from Dysoxylum malabaricum bark: Isolation, structure elucidation and their cytotoxicity.

The Genus Dysoxylum (Meliaceae) consists of approximately 80 species that are abundant in structurally diverse triterpenoids. The present study focused on isolating new triterpenoids from the bark of Dysoxylum malabaricum, one of the predominant species of Dysoxylum present in India. The methanol-dichloromethane bark extract was subjected to LCMS profiling followed by silica gel column chromatography and HPLC analysis to target new compounds. Two new ring A-modified cycloartane-type triterpenoids (1 and 2) were isolated from the bark extract. Spectroscopic methods like NMR, HRESIMS data, and electronic circular dichroism calculations elucidated the structuresandabsolute configurations of the isolated compounds. These compounds were evaluated for their cytotoxic potential against breast cancer cells and displayed notable cytotoxicity. Compound 1 exhibited the highest cytotoxicity against the MDA-MB-231 cells and induced apoptotic cell death. Also, it was able to inhibit glucose uptake and increase nitric oxide production in breast cancer cells.

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.

Identifying inflammation-related targets of natural lactones using network pharmacology, molecular modeling and in vitro approaches.

Natural lactones have been used in traditional and folklore medicine for centuries owing to their anti-inflammatory properties. The study uses a multifaceted approach to identify lead anti-inflammatory lactones from the SISTEMATX natural products database. The study analyzed the natural lactone database, revealing 18 lactones linked to inflammation targets. The primary targets were PTGES, PTGS1, COX-2, ALOX5 and IL1B. STX 12273 was the best hit, with the lowest binding energy and potential for inhibiting the COX-2 enzyme. The study suggested natural lactone, STX 12273, from the SISTEMATX database with anti-inflammatory potential and postulated its use for inflammation treatment or prevention.Communicated by Ramaswamy H. Sarma.

Mahamanalactone A, a new triterpenoid from Dysoxylum malabaricum bark: a case study for rapid identification of new metabolites via LC-HRMS profiling and database mining strategy.

In this recent investigation, the focus centred on exploring the potential phytoconstituents within the bark of Dysoxylum malabaricum. A profiling strategy employing LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry) was implemented for the rapid identification of compounds from the bark extract. The crude extract underwent fractionation, resulting in the isolation of four previously known compounds (1-4) and a novel cycloartane triterpenoid named Mahamanalactone A (5). Compound 5 represents a cycloartane triterpenoid with a modified ring-A, featuring £-caprolactone fusion at positions 4 and 5, distinguishing it from other reported compounds where £-caprolactone is typically fused at positions 3 and 4. Cytotoxicity assessment revealed that the newly identified compound 5 exhibited a moderate cytotoxic profile (IC50 29 to 78 µM) against a panel of cancer cell lines.

Isolation, Cytotoxicity, and In-silico Screening of Coumarins from Psoralea corylifolia Linn.

Psoralea corylifolia (syn. Cullen corylifolium), commonly called bawachi, is a medicinal plant extensively used for skin conditions like leukoderma, vitiligo, and psoriasis. It is notably rich in valuable bioactive compounds, particularly coumarins and furanocoumarins. This study isolated fourteen coumarins from P. corylifolia which were tested for cytotoxicity using the MTT assay, with compound 10 showing good cytotoxicity against A549 cells (IC50 0.9 µM), while compound 1, compound 2, and compound 3 displaying potential cytotoxicity against MDA-MB-231 cells (IC50 0.49 µM, 0.56 µM, and 0.84 µM respectively). Additionally, the compounds' interaction with Epidermal Growth Factor Receptor (EGFR) protein, highly expressed in both cell lines, was investigated through molecular modeling studies, that aligned well with cytotoxicity results. The findings revealed the remarkable cytotoxic potential of four coumarins 1, 2, 3, and 10 against A549 and MDA-MB-231 cell lines.

In silico analysis, isolation, and cytotoxicity evaluation of the coumestans from Cullen corylifolium (L.) Medik.

Cullen corylifolium is well known for diverse phytoconstituents that possess multifaceted pharmacology, and one such less explored class is coumestans, which have not been well explored for their anticancer activities. One of the popular cancer targets is the Epidermal Growth Factor Receptor, a tyrosine kinase involved in various cancers, especially breast and lung cancer hence, a crucial cancer target. This work is focussed on molecular docking and molecular simulation studies on coumestans against EGFR. The rigorous docking studies resulted in two coumestans (1 and 5) with binding energy less than Gefitinib and Erlotinib. Compounds 1 and 5 were subjected to molecular simulation, binding free energy calculation, per-residue energy decomposition, and in silico ADMET prediction. The best hit, compound 1 was evaluated for its cytotoxicity against MDA-MB-231 and A549 cells via in vitro assay. The ligand-protein complex exhibited good stability, binding free energies, better in silico pharmacokinetics, low toxicity, and good cytotoxicity.

Phytochemical and Pharmacological Aspects of Psoralen - A Bioactive Furanocoumarin from Psoralea corylifolia Linn.

Since long ago, medicinal plants have played a vital role in drug discovery. Being blessed and rich in chemovars with diverse scaffolds, they have unique characteristics of evolving based on the need. The World Health Organization also mentions that medicinal plants remain at the center for meeting primary healthcare needs as the population relies on them. The plant-derived natural products have remained an attractive choice for drug development owing to their specific biological functions relevant to human health and also the high degree of potency and specificity they offer. In this context, one such esteemed phytoconstituent with inexplicable biological potential is psoralen, a furanocoumarin. Psoralen was the first constituent isolated from the plant Psoralea corylifolia, commonly known as Bauchi. Despite being a life-saver for psoriasis, vitiligo, and leukoderma, it also showed immense anticancer, anti-inflammatory, and anti-osteoporotic potential. This review brings attention to the possible application of psoralen as an attractive target for rational drug design and medicinal chemistry. It discusses the various methods for the total synthesis of psoralen, its extraction, the pharmacological spectrum of psoralen, and the derivatization done on psoralen.

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.

Synthesis of amides directly from carboxylic acids and hydrazines.

The method for amide bond synthesis described here utilizes carboxylic acids and hydrazines in the presence of a catalytic amount of ZnCl2. This is the first report that highlights the use of hydrazine as an amine partner for amide synthesis directly with carboxylic acids. Ammonia (gas) is the only by-product in this method. The methodology is simple and could help in the synthesis of peptides and natural product derivatives.

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.

Rottlerin renders a selective and highly potent CYP2C8 inhibition to impede EET formation for implication in cancer therapy.

CYP2C8 is a crucial CYP isoform responsible for the metabolism of xenobiotics and endogenous molecules. CYP2C8 converts arachidonic acid to epoxyeicosatrienoic acids (EETs) that cause cancer progression. Rottlerin possess significant anticancer actions. However, information on its CYP inhibitory action is lacking in the literature and therefore, we aimed to explore the same using in silico, in vitro, and in vivo approaches. Rottlerin showed highly potent and selective CYP2C8 inhibition (IC50 < 0.1 µM) compared to negligible inhibition (IC50 > 10 µM) for seven other experimental CYPs in human liver microsomes (HLM) (in vitro) using USFDA recommended index reactions. Mechanistic studies reveal that rottlerin could reversibly (mixed-type) block CYP2C8. Molecular docking (in silico) results indicate a strong interaction could occur between rottlerin and the active site of human CYP2C8. Rottlerin boosted the plasma exposure of repaglinide and paclitaxel (CYP2C8 substrates) by delaying their metabolism using the rat model (in vivo). Multiple-dose treatment of rottlerin with CYP2C8 substrates lowered the CYP2C8 protein expression and up-regulated & down-regulated the mRNA for CYP2C12 & CYP2C11 (rat homologs), respectively, in rat liver tissue. Rottlerin substantially hindered the EET formation in HLM. Overall results of rottlerin on CYP2C8 inhibition and EET formation insinuate further exploration for cancer therapy.

A machine learning-based KNIME workflow to predict VEGFR-2 inhibitors.

Vascular endothelial growth factors (VEGFs) are specific cytokines involved in angiogenesis and do so via binding to vascular endothelial growth factor receptors (VEGFRs), a type of receptor tyrosine kinase. VEGFs are reported to facilitate angiogenesis in physiological (embryogenesis) and pathological (tumor) conditions. The overexpression of VEGFs and consequently VEGFRs is reported in tumorigenic conditions. Several VEGFR inhibitors currently used as anticancer drugs to prevent angiogenesis are sunitinib, sorafenib, etc. To identify new potential candidates as VEGFR inhibitors, a classification study using a large and diverse dataset of VEGFR inhibitors from the BindingDB database has been conducted. The KNIME platform was used to calculate molecular and fingerprint-based descriptors and several classification algorithms viz. linear regression (LR), k-nearest neighbor (kNN), decision tree (DT), random forest (RF), and gradient boosted tree (GBT) were employed to build the classification model. The model performance was evaluated by accuracy, precision, recall, and F1 score of the test set. The best LR, kNN, DT, RF, and GBT classifiers had the F1 score of 0.81, 0.87, 0.82, 0.87, and 0.87, respectively. The assorted 5120 VEGFR inhibitors were clustered into 10 subsets, and the structural features of each subset were assessed along with the identification of significant fragments in active and inactive compounds. The automated classifier model developed using the KNIME platform could serve as an important platform for screening and designing molecules as VEGFR inhibitors.

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.

Correction to "LC-PDA-MS/MS-Based Dereplication Guided Isolation of a New Optical Isomer of 19,20-Epoxycytochalasin-N and Its Cytotoxic Activity".

[This corrects the article DOI: 10.1021/acsomega.2c03037.].

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.

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.

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.

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.

Correction: Chrysomycins A-C, antileukemic naphthocoumarins from Streptomyces sporoverrucosus.

[This corrects the article DOI: 10.1039/C3RA42884B.].

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.