Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents.

Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (Emax) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.

Correction to "Apoferritin-Encapsulated Jerantinine A for Transferrin Receptor Targeting and Enhanced Selectivity in Breast Cancer Therapy".

[This corrects the article DOI: 10.1021/acsomega.2c00997.].

Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia.

Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 µM, respectively.

A comprehensive review on the chemical constituents, sesquiterpenoid biosynthesis and biological activities of Sarcandra glabra.

Sarcandra glabra (Thunb.) Nakai is a perennial evergreen herb categorised within the Sarcandra Gardner genus under the Chloranthaceae family. Indigenous to tropical and subtropical regions of East Asia and India, this species is extensively distributed across China, particularly in the southern regions (Sichuan, Yunnan, and Jiangxi). In addition to its high ornamental value, S. glabra has a rich history of use in traditional Chinese medicine, evident through its empirical prescriptions for various ailments like pneumonia, dysentery, fractures, bruises, numbness, amenorrhea, rheumatism, and other diseases. Besides, modern pharmacological studies have revealed various biological activities, such as antitumour, anti-bacterial, anti-viral anti-inflammatory and immunomodulatory effects. The diverse chemical constituents of S. glabra have fascinated natural product researchers since the 1900s. To date, over 400 compounds including terpenoids, coumarins, lignans, flavonoids, sterols, anthraquinones, organic acids, and organic esters have been isolated and characterised, some featuring unprecedented structures. This review comprehensively examines the current understanding of S. glabra's phytochemistry and pharmacology, with emphasis on the chemistry and biosynthesis of its unique chemotaxonomic marker, the lindenane-type sesquiterpenoids.

Polyneurines A-H, iboga alkaloids from Tabernaemontana polyneura.

Eight undescribed iboga alkaloids, polyneurines A-H, were isolated from the bark of Tabernaemontana polyneura. The structures of these alkaloids were established by interpretation of the MS and NMR data, while the configurations were determined using GIAO NMR calculations and DP4+ probability analysis, TDDFT-ECD method, or X-ray diffraction analysis. Polyneurine A possesses a γ-lactone unit embedded within the iboga skeleton, while polyneurines D and E incorporate a formylmethyl moiety at C-3 of the iboga skeleton. Biosynthetic pathways towards the formation of polyneurines A, C, D, and E were proposed.

Eugeniifoline, a Pentacyclic Indole Alkaloid from Leuconotis eugeniifolia, and Configurational Revision of Synthetic Eugeniifoline Isolated from a Diversity-Enhanced Extract.

Eugeniifoline (1), a pentacyclic indole alkaloid with a five-membered ring E, was isolated for the first time as a natural product from the stem-bark extract of Leuconotis eugeniifolia. Eugeniifoline (1) was previously reported as a synthetic product from a diversity-enhanced extract, but with the configuration at C-21 reported as S (1a). The configuration at C-21 was revised to R as shown in 1, based on the NOE data, GIAO NMR calculations, and DP4+ probability analysis, as well as the TDDFT-ECD method.

Medicinal Mushrooms and Their Use to Strengthen Respiratory Health during and Post-COVID-19 Pandemic.

COVID-19 infection has been a key threat to the public health system globally, with an estimated 248 million cases worldwide. COVID-19 patients are subject to a higher risk of developing chronic respiratory disorders that are closely associated with long-term disability, multi-morbidity, and premature mortality. Although there have been recent advancements in respiratory treatment regimens, there has also been increased interest in the use of medicinal mushrooms in bridging the unaddressed pathways of action within the treatment algorithms. In this review, we provide a collection of medicinal mushrooms that are beneficial in promoting respiratory health and potentially reducing COVID-19 symptoms in patients who are newly diagnosed and those who have recovered. While reviewing the use of immunomodulatory pathways, which have shown promising results in tackling side effects and post-COVID syndromes, we also provide insights into how the antioxidant elements present in medicinal mushrooms help to achieve the same results, especially in the prophylactic and therapeutic management of COVID-19 infection. To date, medicinal mushrooms are regarded as a functional food, which, however, need further quality, safety, and efficacy assessments. These requirements are also highlighted in the present review to promote the future development and application of medicinal mushrooms for better respiratory health.

Apoferritin-Encapsulated Jerantinine A for Transferrin Receptor Targeting and Enhanced Selectivity in Breast Cancer Therapy.

The O-acetyl (or acetate) derivative of the Aspidosperma alkaloid Jerantinine A (JAa) elicits anti-tumor activity against cancer cell lines including mammary carcinoma cell lines irrespective of receptor status (0.14 < GI50 < 0.38 µM), targeting microtubule dynamics. By exploiting breast cancer cells' upregulated transferrin receptor 1 (TfR1) expression and apoferritin (AFt) recognition, we sought to develop an AFt JAa-delivery vehicle to enhance tumor-targeting and reduce systemic toxicity. Optimizing pH-mediated reassembly, ∼120 JAa molecules were entrapped within AFt. Western blot and flow cytometry demonstrate TfR1 expression in cancer cells. Enhanced internalization of 5-carboxyfluorescein-conjugated human AFt in SKBR3 and MDA-MB-231 cancer cells is observed compared to MRC5 fibroblasts. Accordingly, AFt-JAa delivers significantly greater intracellular JAa levels to SKBR3 and MDA-MB-231 cells than naked JAa (0.2 µM) treatment alone. Compared to naked JAa (0.2 µM), AFt-JAa achieves enhanced growth inhibition (2.5-14-fold; <0.02 µM < GI50 < 0.15 µM) in breast cancer cells; AFt-JAa treatment results in significantly reduced clonal survival, more profound cell cycle perturbation including G2/M arrest, greater reduction in cell numbers, and increased apoptosis compared to the naked agent (p < 0.01). Decreased PLK1 and Mcl-1 expression, together with the appearance of cleaved poly (ADP-ribose)-polymerase, corroborate the augmented potency of AFt-JAa. Hence, we demonstrate that AFt represents a biocompatible vehicle for targeted delivery of JAa, offering potential to minimize toxicity and enhance JAa activity in TfR1-expressing tumors.

Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects.

This study investigated the vasorelaxant effects of schwarzinicine A, an alkaloid recently reported from Ficus schwarzii Koord. Regulation of calcium homeostasis in vascular smooth muscle cells (VSMC) is viewed as one of the main mechanisms for controlling blood pressure. L-type voltage-gated calcium channel (VGCC) blockers are commonly used for controlling hypertension. Recently, the transient receptor potential canonical (TRPC) channels were found in blood vessels of different animal species with evidence of their roles in the regulation of vascular contractility. In this study, we studied the mechanism of actions of schwarzinicine A focusing on its regulation of L-type VGCC and TRPC channels. Schwarzinicine A exhibited the highest vasorelaxant effect (123.1%) compared to other calcium channel blockers. It also overtly attenuated calcium-induced contractions of the rat isolated aortae in a calcium-free environment showing its mechanism to inhibit calcium influx. Fluorometric intracellular calcium recordings confirmed its inhibition of hTRPC3-, hTRPC4-, hTRPC5- and hTRPC6-mediated calcium influx into HEK cells with IC50 values of 3, 17, 19 and 7 µM, respectively. The evidence gathered in this study suggests that schwarzinicine A blocks multiple TRPC channels and L-type VGCC to exert a significant vascular relaxation response.

Chinese Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycota), Cold-Water Extract Relaxes the Rat Isolated Bladder.

Ophiocordyceps sinensis is a popular medicinal mushroom used for various health conditions, including alleviation of frequent urination, which is a major symptom of overactive bladder (OAB) syndrome. This study aimed to investigate the effect of O. sinensis (OCS02 cultivar) cold-water extract (CWE) against bladder contractility using the organ bath technique. The bladder was removed from male Sprague-Dawley rats and cut into longitudinal strips of 2 mm × 8 mm. In some experiments, the urothelium was removed to study its role in CWE-induced responses. CWE elicited a biphasic response consisting of an immediate, transient contraction that was followed by a sustained relaxation in bladder strips precontracted with carbachol, a muscarinic agonist. Removal of urothelium did not alter the magnitude of the contractile response but significantly attenuated the relaxation response. In the presence of L-NAME (nitric oxide synthase inhibitor) and sodium nitroprusside (nitric oxide donor), CWE-induced transient contraction was enhanced, whereas the relaxation response was significantly reduced. Following preincubation with CWE, the amplitude and the frequency of the spontaneous myogenic contractions induced by carbachol, as well as the contractile response toward calcium, were significantly suppressed. Findings from this study show that the urothelium plays a role in the relaxant effect of CWE. Its mechanisms of action include the regulation of nitric oxide and inhibition of calcium influx.

Pentacyclic and hexacyclic cucurbitacins from Elaeocarpuspetiolatus.

Four undescribed cucurbitacins, designated as petiolaticins A-D, and four known cucurbitacins were isolated from the bark and leaves of Elaeocarpus petiolatus (Jack) Wall. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The absolute configuration of petiolaticin A was also determined by X-ray diffraction analysis. Petiolaticin A represents a cucurbitacin derivative incorporating a 3,4-epoxyfuranyl-bearing side chain, while petiolaticin B possesses a furopyranyl unit fused to the tetracyclic cucurbitane core structure. Petiolaticins A, B, and D were evaluated in vitro against a panel of human breast, pancreatic, and colorectal cancer cell lines. Petiolaticin A exhibited the greatest cytotoxicity against the MDA-MB-468, MDA-MB-231, MCF-7, and SW48 cell lines (IC50 7.4, 9.2, 9.3, and 4.6 µM, respectively). Additionally, petiolaticin D, 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one, and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside were tested for their ability to inhibit cell entry of a pseudotyped virus bearing the hemagglutinin envelope protein of a highly pathogenic avian influenza virus. Petiolaticin D showed the highest inhibition (44.3%), followed by 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one (21.0%), and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside showed limited inhibition (9.0%). These preliminary biological assays have demonstrated that petiolaticins A and D possess anticancer and antiviral properties, respectively, which warrant for further investigations.

Concise synthesis of the vasorelaxant alkaloids schwarzinicines A and B.

A concise synthesis of the 1,4-diarylbutanoid-phenethylamine alkaloids, schwarzinicines A (1) and B (2), recently isolated from Ficus schwarzii, is reported. Key steps include a Claisen condensation to assemble the 1,4-diaryl-2-butanone intermediate, followed by a reductive amination to furnish the core skeleton of the target compounds. The overall synthetic yields of 1 and 2 were 9.1% and 3.5%, respectively. Synthetic (-)-1, (+)-1 and (±)-1 exhibited comparable vasorelaxation as natural schwarzinicine A on rat isolated aortic rings, suggesting that the observed vasorelaxant effects were not influenced by the chirality at C-2.

Monomeric, Dimeric, and Trimeric Tropane Alkaloids from Pellacalyx saccardianus.

Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.

The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells. METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species. RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC). CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.

Macroline, talpinine, and sarpagine alkaloids from Alstonia penangiana. An NMR-based method for differentiating between A. penangiana and A. macrophylla.

Fourteen previously undescribed alkaloids comprising two N-1-hydroxymethylmacroline alkaloids, one talpinine-type oxindole acetal, a pair of equilibrating talpinine-type oxindole hemiacetals, eight oxidized derivatives of sarpagine- and akuammiline-type indole alkaloids, in addition to alstochalotine a diastereomer of gelsochalotine recently isolated from Gelsemium elegans, were isolated from the leaf and stem-bark extracts of Alstonia penangiana. The structures and relative configurations of these alkaloids were established using NMR, MS, and in one instance, confirmed by X-ray diffraction analysis. An NMR-based method is described as a useful chemotaxonomic tool for differentiating between A. penangiana and A. macrophylla. Several of the alkaloids isolated showed appreciable growth inhibitory effects when tested against a number of human cancer cell lines.

Schwarzinicines A-G, 1,4-Diarylbutanoid-Phenethylamine Conjugates from the Leaves of Ficus schwarzii.

Schwarzinicines A-G (1-7), representing the first examples of 1,4-diarylbutanoid-phenethylamine conjugates, were isolated from the leaves of Ficus schwarzii. The structures of these compounds were determined by detailed analysis of their MS, 1D and 2D NMR data. Compounds 1-4 exhibited pronounced vasorelaxant effects in the rat isolated aorta (Emax 106-120%; EC50 0.96-2.10 µM). However, compounds 1 and 2 showed no cytotoxic effects against A549, MCF-7, and HCT 116 human cancer cells (IC50 > 10 µM).

Lycopodium Alkaloids: Lycoplatyrine A, an Unusual Lycodine-Piperidine Adduct from Lycopodium platyrhizoma and the Absolute Configurations of Lycoplanine D and Lycogladine H.

Three new Lycopodium alkaloids comprising two lycodine-type alkaloids (1, 2) and one fawcettimine alkaloid (3), in addition to 16 known alkaloids, were isolated from Lycopodium platyrhizoma. The structures of these alkaloids were elucidated based on analysis of their NMR and MS data. Lycoplatyrine A (1) represents an unusual lycodine-piperidine adduct. The structures and absolute configurations of lycoplanine D (hydroxy-des- N-methyl-α-obscurine, 10) and lycogladine H (11) were confirmed by X-ray diffraction analysis.

Alstoscholactine and Alstolaxepine, Monoterpenoid Indole Alkaloids with γ-Lactone-Bridged Cycloheptane and Oxepane Moieties from Alstonia scholaris.

Two new monoterpenoid indole alkaloids, alstoscholactine (1) and alstolaxepine (2), were isolated from Alstonia scholaris. Compound 1 represents a rearranged stemmadenine alkaloid with an unprecedented C-6-C-19 connectivity, whereas compound 2 represents a 6,7- seco-angustilobine B-type alkaloid incorporating a rare γ-lactone-bridged oxepane ring system. Their structures and absolute configurations were determined by spectroscopic analyses. Compound 1 was successfully semisynthesized from 19 E-vallesamine. Compound 2 induced marked vasorelaxation in rat isolated aortic rings precontracted with phenylephrine.

Sustainable Syntheses of (-)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site.

The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.

Data on the Lignosus rhinocerotis water soluble sclerotial extract affecting intracellular calcium level in rat dorsal root ganglion cells.

The data in this article contain supporting evidence for the research manuscript entitled "Bronchodilator effects of Lignosus rhinocerotis extract on rat isolated airways is linked to the blockage of calcium entry" by Lee et al. (2018) [1]. The data were obtained by calcium imaging technique with fluorescent calcium indicator dyes, Fura 2-AM, to visualize calcium ion movement in the rat dorsal ganglion (DRG) cells. The effects of L. rhinocerotis cold water extract (CWE1) on intracellular calcium levels in the DRG cells were presented.