Monoterpene Alkaloid Research Articles

Endosomal pH, Redox Dual-Sensitive Prodrug Micelles Based on Hyaluronic Acid for Intracellular Camptothecin Delivery and Active Tumor Targeting in Cancer Therapy

Background: CPT is a pentacyclic monoterpene alkaloid with a wide spectrum of antitumor activity. Its clinical application is restricted due to poor water solubility, instability, and high toxicity. We developed a new kind of multifunctional micelles to improve its solubility, reduce the side effecs, and obtain enhanced antitumor effects. Methods: We constructed HA-CPT nano-self-assembly prodrug micelles, which combined the advantages of pH-sensitivity, redox-sensitivity, and active targeting ability to CD44 receptor-overexpressing cancer cells. To synthesize dual sensitive HA-CPT conjugates, CPT was conjugated with HA by pH-sensitive histidine (His) and redox-sensitive 3,3′-dithiodipropionic acid (DTPA). In vitro, we studied the cellular uptake and antitumor effect for tumor cell lines. In vivo, we explored the bio-distribution and antitumor effects of the micelles in HCT 116 tumor bearing nude mice. Results: The dual-sensitive and active targeting HA-His-ss-CPT micelles was proved to be highly efficient in CPT delivery by the in vitro cellular uptake study. The HA-His-ss-CPT micelles escaped from endosomes of tumor cells within 4 h after cellular uptake due to the proton sponge effect of the conjugating His and then quickly released CPT in the cytosol by glutathione (GSH). In mice, HA-His-ss-CPT micelles displayed efficient tumor accumulation and conspicuous inhibition of tumor growth. Conclusions: The novel, dual-sensitive, active targeting nano-prodrug micelles exhibited high efficiency in drug delivery and cancer therapy. This “all in one” drug delivery system can be realized in an ingenious structure and avoid intricate synthesis. This construction strategy can illume the design of nanocarriers responding to endogenous stimuli in tumors.

The Chemistry of the Defensive Secretions of Three Species of Millipedes in the Genus Brachycybe.

Millipedes have long been known to produce a diverse array of chemical defense agents that deter predation. These compounds, or their precursors, are stored in high concentration within glands (ozadenes) and are released upon disturbance. The subterclass Colobognatha contains four orders of millipedes, all of which are known to produce terpenoid alkaloids-spare the Siphonophorida that produce terpenes. Although these compounds represent some of the most structurally-intriguing millipede-derived natural products, they are the least studied class of millipede defensive secretions. Here, we describe the chemistry of millipede defensive secretions from three species of Brachycybe: Brachycybe producta, Brachycybe petasata, and Brachycybe rosea. Chemical investigations using mass spectrometry-based metabolomics, chemical synthesis, and 2D NMR led to the identification of five alkaloids, three of which are new to the literature. All identified compounds are monoterpene alkaloids with the new compounds representing indolizidine (i.e. hydrogosodesmine) and quinolizidine alkaloids (i.e. homogosodesmine and homo-hydrogosodesmine). The chemical diversity of these compounds tracks the known species phylogeny of this genus, rather than the geographical proximity of the species. The indolizidines and quinolizidines are produced by non-sympatric sister species, B. producta and B. petasata, while deoxybuzonamine is produced by another set of non-sympatric sister species, B. rosea and Brachycybe lecontii. The fidelity between the chemical diversity and phylogeny strongly suggests that millipedes generate these complex defensive agents de novo and begins to provide insights into the evolution of their biochemical pathways.

Minor alkaloids from an aqueous extract of the hook-bearing stem of Uncaria rhynchophylla

Seven new monoterpene alkaloids (1 − 7), along with 16 known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis, single crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are stereoisomers belonging to a novel type of pseudoindoxyl monoterpene alkaloids, 3 is the first monoterpene furoindole alkaloid from nature, and 4 − 7 are derivatives of the known monoterpene alkaloids featuring different structures.

Total Synthesis of Altemicidin: A Surprise Ending for a Monoterpene Alkaloid.

Monoterpene alkaloids encompass distinct chemical diversity and wide-ranging bioactivity. Their compact complexity has made them popular as synthetic targets and has inspired many distinct strategies and tactics in the field of heterocyclic chemistry. This article documents the evolution of a synthetic program aimed at accessing the unusual sulfonamide-containing natural product altemicidin, which was generally believed to be a monoterpene alkaloid throughout our entire synthetic investigations but has recently been found to originate through an unexpected and quite disparate biosynthetic pathway. By leveraging a pyridine dearomatization/cycloaddition strategy, we developed a concise pathway to the 5,6-fused bicyclic azaindane core and, after significant experimentation, an ultimate synthesis of altemicidin itself. Tactics to productively manipulate the multiple functional groups present on this highly polar scaffold proved challenging but were eventually realized via several carefully orchestrated and chemoselective transformations-investments that paid dividends in the form of significantly shorter chemical synthesis. Surprisingly, the bond-forming logic between our presumed abiotic synthetic strategy to this alkaloid class and its subsequently identified biosynthetic pathway is eerily similar.

The Genome-Wide Identification, Characterization, and Expression Analysis of the Strictosidine Synthase-like Family in Maize (Zea mays L.).

Maize is often subjected to various environmental stresses. The strictosidine synthase-like (SSL) family is thought to catalyze the key step in the monoterpene alkaloids synthesis pathway in response to environmental stresses. However, the role of ZmSSL genes in maize growth and development and its response to stresses is unknown. Herein, we undertook the systematic identification and analysis of maize SSL genes. Twenty SSL genes were identified in the maize genome. Except for chromosomes 3, 5, 6, and 10, they were unevenly distributed on the remaining 6 chromosomes. A total of 105 SSL genes from maize, sorghum, rice, Aegilops tauschii, and Arabidopsis were divided into five evolutionary groups, and ZmSSL gene structures and conserved protein motifs in the same group were similar. A collinearity analysis showed that tandem duplication plays an important role in the evolution of the SSL family in maize, and ZmSSL genes share more collinear genes in crops (maize, sorghum, rice, and Ae. tauschii) than in Arabidopsis. Cis-element analysis in the ZmSSL gene promoter region revealed that most genes contained many development and stress response elements. We evaluated the expression levels of ZmSSL genes under normal conditions and stress treatments. ZmSSL4-9 were widely expressed in different tissues and were positively or negatively regulated by heat, cold, and infection stress from Colletotrichum graminicola and Cercospora zeina. Moreover, ZmSSL4 and ZmSSL5 were localized in the chloroplast. Taken together, we provide insight into the evolutionary relationships of the ZmSSL genes, which would be useful to further identify the potential functions of ZmSSLs in maize.

A New Monoterpene Alkaloid from Incarvillea sinensis with Migration Inhibitory Activity on Cancer Cell.

A novel monoterpene alkaloid, named incarvine G, was isolated from the Incarvillea sinensis Lam. Its chemical structure was elucidated using comprehensive spectroscopic methods. Incarvine G is an ester compound comprised of a monoterpene alkaloid and glucose. This compound showed evident inhibition on cell migration, invasion, and cytoskeleton formation of human MDA-MB-231 with low cytotoxicity.

Antifibrotic pyridine-containing monoterpene alkaloids from Caryopteris glutinosa

Three undescribed dimeric pyridine-containing alkaloids, caryopterisines C – E, and four unreported cyclopenta[c]pyridine-derived alkaloids, caryopterisines F – I, were identified from Caryopteris glutinosa Rehder (Lamiaceae), together with two known monoterpene alkaloids. Caryopterisine C, featuring with an unprecedented 6/5/6/6/5 pentacyclic rings scaffold, may biosynthetically stem from a Diels-Alder reaction of two cyclopenta[c]pyridine-containing monomers and a following aromatization rearrangement reaction. Caryopterisines D and E, possessing an unprecedented 6/6/6/6/5 fused rings framework, may originate from a same Diels-Alder reaction of two monomers and subsequent aromatization arrangement, Baeyer-Villiger oxidation, and a set of tailoring reactions. Caryopterisine C showed strong inhibition on collagen accumulation in NIH3T3 cells (IC50 = 14.26 ± 1.46 μM). Caryopterisines G and I reduce collagen accumulation with IC50 values 88.91 ± 0.95 μM and 33.09 ± 1.38 μM, respectively. The Western blotting of the transforming growth factor-β-activated signaling pathways revealed that caryopterisine C inhibits collagen expression and accumulation via suppression of the phosphorylation of ERK1/2, P38, and SMAD2/3. The present works indicate caryopterisine C is a potential lead compound for the development of antifibrotic drugs.

In Vitro and In Silico Antistaphylococcal Activity of Indole Alkaloids Isolated from Tabernaemontana cymosa Jacq (Apocynaceae)

The species of the genus Tabernaemontana have a long tradition of use in different pathologies of infectious origins; the antibacterial, antifungal, and antiviral effects related to the control of the pathologies where the species of this genus are used, have been attributed to the indole monoterpene alkaloids, mainly those of the iboga type. There are more than 1000 alkaloids isolated from different species of Tabernaemontana and other genera of the Apocynaceae family, several of which lack studies related to antibacterial activity. In the present study, four monoterpene indole alkaloids were isolated from the seeds of the species Tabernaemontana cymosa Jacq, namely voacangine (1), voacangine-7-hydroxyindolenine (2), 3-oxovoacangine (3), and rupicoline (4), which were tested in an in vitro antibacterial activity study against the bacteria S. aureus, sensitive and resistant to methicillin, and classified by the World Health Organization as critical for the investigation of new antibiotics. Of the four alkaloids tested, only voacangine was active against S. aureus, with an MIC of 50 µg/mL. In addition, an in silico study was carried out between the four isolated alkaloids and some proteins of this bacterium, finding that voacangine also showed binding to proteins involved in cell wall synthesis, mainly PBP2 and PBP2a.

Monoterpene Alkaloids from Incarvillea delavayi Bureau et Franchet and Their Inhibition against LPS Induced NO Production in BV2 Cells.

Three new monoterpene alkaloids, delavatines C-E (1-3), along with five known ones (4-8), were separated from the whole plants of Incarvillea delavayi. All compounds were deduced by interpretation of comprehensive NMR spectral data and X-Ray single crystal diffraction, in combination with a quantum chemical calculation of NMR chemical shift coupled with an advanced statistical procedure DP4+. Compounds 1-8 were assessed NO suppressive effect in LPS-stimulated BV2 microglia cells. Compounds 2, 3, 6, and 8 exhibited significant inhibition against NO production in LPS-induced BV2 cells with IC50 values of 25.62, 17.29, 19.94 and 23.88 μM, stronger than or comparable to the positive control (AG) with IC50 value of 26.13 μM.

New phenylpropanoids and monoterpene alkaloids with vasorelaxant activities from the branches of Alstonia scholaris

Two new phenylpropanoids (1–2), one new nor-monoterpenoid alkaloid (3), one new monoterpene alkaloid (4), together with nine known compounds (5–13) were obtained from the branches of Alstonia scholaris. The structures of the undescribed compounds were determined by extensive spectroscopic analysis. Alkaloid 3 represented the first example of C-4 methylated nor-monoterpenoid alkaloids. A possible biosynthetic pathway for this new type of monoterpene alkaloids was proposed. All the isolates were evaluated for vasorelaxant activity against phenylephrine-induced contraction of rat mesenteric arteries. Compounds 1, 4, 9, 12, and 13 showed significant vasorelaxant activity with relaxation rates above 90% at 200 μM and exhibited moderate vasorelaxant activity with IC50 values ranging from 41.87 to 93.30 μM by further studies. It was the first report on the potential vasorelaxant activity of monoterpene alkaloids. Monoterpene alkaloids 3 and 4 may be served as the potential lead compounds for the discovery of vasodilators, due to their simple and optimizable structures.

A comprehensive review on phytochemistry and pharmacology of genus Kopsia: monoterpene alkaloids - major secondary metabolites.

Kopsia belongs to the family Apocynaceae, which was originally classified as a genus in 1823. Kopsia consists of medicinal plants that can be traditionally used to treat rheumatoid arthritis, pharyngitis, tonsillitis, and dropsy. More than one hundred and twenty-five publications have been documented relating to the phytochemical and pharmacological results, but a systematic review is not available. The goal of this study is to compile almost all of the secondary metabolites from the plants of genus Kopsia, as well as the coverage of their pharmacological research. The document findings were conducted via reliable sources, including Web of Science, Sci-Finder, Science Direct, PubMed, Google Scholar, and publishers, while four words “Kopsia”, “monoterpene alkaloids”, “Phytochemistry” and “Pharmacology” are key factors to search for references. Most Kopsia secondary metabolites were collected. A total of four hundred and seventy-two, including four hundred and sixty-six monoterpene alkaloids, five triterpenoids, and one sterol, were summarized, along with their resource. Kopsia monoterpene alkaloids presented in various skeletons, but aspidofractinines, eburnamines, and chanofruticosinates are the three major backbones. Mersinines and pauciflorines are new chemical classes of monoterpene alkaloids. With the rich content of monoterpene alkaloids, Kopsia constituents were also the main objects in pharmacological studies since the plant extracts and isolated compounds were proposed for anti-microbial, anti-inflammatory, anti-allergic, anti-diabetic, anti-manic, anti-nociceptive, acetylcholinesterase (AChE) inhibitory, cardiovascular, and vasorelaxant activities, especially cytotoxicity.

Bioguided Isolation of Alkaloids and Pharmacological Effects of the Total Alkaloid Fraction from Aspidosperma pyrifolium Mart. (Apocynaceae).

Aspidosperma pyrifolium is used in traditional medicine to treat inflammatory disorders. The aim of the study was to perform phytochemical characterization and evaluate the anti-inflammatory, anti-nociceptive and acute toxicity effects of the total alkaloid fraction (TAF-Ap) from stem barks. Two monoterpenic indole alkaloids were isolated by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and the structural elucidation was performed using 1D and 2D NMR analysis. As for toxicity, no animals died at 50 mg kg−1 and this concentration presented mild sedation and forced breathing within the first 24 h. The lethal dose capable of killing 50% of the animals (LD50) was estimated to be 160 mg kg−1. In the pharmacological tests, the models used were 1% carrageenan-induced paw edema and peritonitis, 1% formalin-induced nociception and 1% acetic acid-induced abdominal writhing in Swiss mice. The study made it possible to isolate 15-methoxyaspidospermine and 15-methoxypyrifolidine, corroborating the results of pharmacological assays, which showed anti-inflammatory and analgesic potential, especially at 30 mg kg−1 (p < 0.001). Thus, the species was shown to be a promising source of active substances, with special attention paid to its toxicological potential.

(±)-Caryopterisines A and B, dimeric monoterpene alkaloids with unprecedented 6/5/5/5/6 pentacyclic rings scaffold from Caryopteris glutinosa

(±)-Caryopterisines A (1) and B (2) featuring an unprecedented 6/5/5/5/6 pentacyclic rings system were isolated from Caryopteris glutinosa. The structures were determined by spectroscopic and X-ray crystallographic data analyses as well as theoretical calculations. Chiral HPLC resolution of both racemic 1 and 2 afforded their corresponding enantiotropic enantiomers. A plausible biogenesis for 1 and 2 may be originated from Diels-Alder reaction between pyridine-containing oxerine derivatives. The enantiotropic conversion mechanism of the enantiomers was demonstrated by H-D exchange and 18O incorporation studies. Compounds 1 and 2 showed moderate inhibition of estrogen E2 biosynthesis in human ovarian granulosa-like KGN cells. These two alkaloids reduced kynurenine biosynthesis at moderate level via inhibition of indoleamine 2,3-dioxygenase. Alkaloid 2 exhibited moderate inhibition of the release of interleukin-1β.

Dearomative Synthetic Entry into the Altemicidin Alkaloids.

Altemicidin and related Streptomyces-derived monoterpene alkaloids possess dense, highly polar azaindane cores as well as potent cytotoxic and tRNA synthetase inhibitory properties. The congested α-amino acid motif decorating their presumed iridoid-like core structure has proven to be both a synthetic challenge and a biosynthetic mystery to date. Herein, we report a distinct, abiotic strategy to these alkaloids resulting in a concise synthesis of altemicidin from simple chemical feedstocks. Key chemical findings include the exploitation of a dearomative pyridinium addition and dipolar cycloaddition sequence to stereospecifically install the quaternary amine moiety, and a chemoselective molybdenum-mediated double reduction to establish the fully functionalized azaindane nucleus with minimal redox manipulations.

Structural, electronic, and spectroscopic study on 1,5-methanoazocino[4,3-b]indole synthesized by TFB-based route

This work proposed a new route to synthesizing pharmaceutical important molecules just in three steps. This synthetic route provides an economical way for synthetic chemistry to get the key products concerning the biochemical importance economically including the monoterpene alkaloids, uleine, tubifolidine. This route involves ring closure and the reaction also involved a cyclization reaction tetrahydrocarbazole with an amine side chain at the C-2 position, and this cyclization was mediated by tetrafluoro-1,4-benzoquinone (TFB). In proposed TFB-based route, (4) (2-(2,3,4,9-tetrahydro-1H-carbazol-2-yl)ethan-1-amine), (5) 2,3,4,5,6,7-hexahydro-1H-1,5-methanoazocino[4,3-b]indole, (6) methyl (1R,5S)-1,3,4,5,6,7-hexahydro-2H-1,5-methanoazocino[4,3-b]indole-2-carboxylate, (7) methyl (1R,5S)-6-oxo-1,3,4,5,6,7-hexahydro-2H-1,5-methanoazocino[4,3-b]indole-2-carboxylate compounds were synthesized and characterized by FTIR and NMR (1H and 13C) spectroscopic tools. Besides, the essential intramolecular interactions, chemical reactivity behavior, and the optical property of (7) as a final production of this work have been investigated by NBO, FMO, and NLO analyses, respectively, and the theoretical calculations were performed by both the B3LYP and M06-HF at 6–311 + G(d,p) basis set.

Characterization of MYB35 regulated methyl jasmonate and wound responsive Geraniol 10-hydroxylase-1 gene from Bacopa monnieri.

BmG10H-1 transcript from B. monnieri was functionally active. BmG10H-1 promoter drives GUS activity in response to MeJA and wounding. BmMYB35 regulates BmG10H-1 transcript by binding to its promoter. Geraniol 10-hydroxylase (G10H) is one of the important regulatory cytochrome P450 monooxygenase, which is involved in the biosynthesis of monoterpene alkaloids. However, G10H is not characterized at the enzymatic or at the regulatory aspect in B. monnieri. In the present study, we have identified two transcripts of BmG10H (BmG10H-1and BmG10H-2) and characterized the methyl jasmonate (MeJA) and wound responsive BmG10H-1 transcript from B. monnieri. BmG10H-1 showed induced expression after 3h of MeJA and wounding treatment in the shoot. Yeast purified recombinant BmG10H-1 protein is enzymatically active, having Vmax of 0.16µMsec-1μg-1 protein and catalyzes the hydroxylation of geraniol to 10-hydroxy geraniol. The BmG10H-1 promoter was isolated by using the genome walking method. BmG10H-1 promoter can drive GUS expression in transgenic Arabidopsis thaliana. GUS activity of MeJA and wound-treated Arabidopsis seedlings were found to be increased as compared to the control untreated seedlings, whereas no GUS activity was found in deleted MeJA responsive and W-box cis-elements. This shows that the BmG10H-1 promoter contains functional MeJA (TGACG) and wound responsive (TGACCT) cis-elements. Further, shoot specific and MeJA responsive recombinant BmMYB35 protein was purified, which binds with the MYB recognition cis-element (TGGTTA) present in the BmG10H-1 promoter and transcriptionally activates the reporter gene in yeast. In conclusion, the characterization of MeJA and wound responsive BmG10H-1 provides novel information about its transcriptional regulation by binding with MYB transcription factor in B. monnieri.

Minor alkaloids from an aqueous extract of the hook-bearing stem of Uncaria rhynchophylla

Seven new monoterpene alkaloids (1−7), along with 18 known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Compound 1 is the first monoterpene 22-norindoloquinolizidine alkaloid with a ketene unit, while 2 and 3 are unusual indoloquinolizidine alkaloids having an oxazinane ring.

New Phenylpropanoids and Monoterpene Alkaloids with Vasorelaxant Activities from the Branches of &lt;i&gt;Alstonia Scholaris&lt;/i&gt;

New Phenylpropanoids and Monoterpene Alkaloids with Vasorelaxant Activities from the Branches of &lt;i&gt;Alstonia Scholaris&lt;/i&gt;

Monoterpene alkaloid glycosides from the leaves of Nauclea orientalis

Abstract Four new monoterpene alkaloid glycosides, kanluaengosides A–D (1, 2, 8, and 9), were isolated from the leaves of Nauclea orientalis. Additionally, the 12 known compounds were identified as (3S)-pumiloside (3), strictosamide (4), vincosamide (5), 10-hydroxystictosamide (6), 10-hydroxyvincoside lactam (7), paratunamide B (10), paratunamide C (11), vitexin (12), vicenin-2 (13), kaempferol 3-O-rutinoside (14), rutin (15) and eugenyl β-rutinoside (16). Their structures were determined based on the physical data and the spectroscopic evidence including 1D and 2D NMR experiments.

Stereoselective synthesis of an eleganine A core.

A synthetic approach towards the core of a structurally unique cytotoxic indole alkaloid eleganine A has been accomplished for the first time. The synthesis features a stereoselective Ireland-Claisen rearrangement as the key step, enabling the installation of 2 stereogenic centers and a stereodefined double bond in a single step. Furthermore, a SnCl4 promoted acylation of the indole C-2 position allows the coupling of a highly functionalized 4-ethylidene proline fragment with the indole part.