Heliotropium bovei was shown to contain lasiocarpine, europine, 5'-acetyllasiocarpine and a new alkaloid 7-acetyleuropine. Lasiocarpine N-oxide and 5'-acetyllasiocarpine N-oxide are also present in this plant species. These structures were established from spectral and chemical studies including 2D NMR. Europine showed both antifungal and insect antifeedant activity, while 7-acetyleuropine was inactive.
Two new phenanthroquinolizidine alkaloids (1 and 2) and a new piperidine derivative (3) were isolated from the leaves of Pilea aff. martinii together with 3 known alkaloids: julandine (4), cryptopleurine (5), and 1,3,6,6-tetramethyl-5,6,7,8-tetrahydro-isoquinolin-8-one (6). Their structures were determined by spectral data analyses including mass spectrometry and 2-dimensional nuclear magnetic resonance data. The absolute configurations of 1-3 were established by comparison of their experimental circular dichroism data with the calculated electronic circular dichroism spectra. The isolated compounds were evaluated for their cytotoxicity against 4 cancer cell lines: KB (mouth epidermal carcinoma cells), HepG-2 (human liver hepatocellular carcinoma cells), LU-1 (human lung adenocarcinoma cells), and MCF-7 (human breast cancer cells). The new phenanthroquinolizidine pileamartine D (2) showed strong and selective proliferation inhibition toward KB and HepG-2 cells with IC50 values of 25 and 27 nM, respectively. Pileamartine C (1), julandine (4), and cryptopleurine (5) exhibited cytotoxicity against 4 tested cancer cell lines with IC50 values less than 1 mu M.
A striking feature of the metabolite profile of Ancistrocladus likoko (Ancistrocladaceae) is the exclusive production of 5,8'-linked naphthylisoquinoline alkaloids varying in their OMe/OH substitution patterns and in the hydrogenation degree in their isoquinoline portions. Here we present nine new compounds of this coupling type isolated from the twigs of this remarkable Central African liana. Three of them, the ancistrolikokines E (9), E-2 (10), and F (11), are the first 5,8'-linked naphthyldihydroisoquinolines found in nature with R-configuration at C-3. The fourth new metabolite, ancistrolikokine G (12), is so far the only representative of the 5,8'-coupling type that belongs to the very rare group of alkaloids with a fully dehydrogenated isoquinoline portion. Moreover, five new N-methylated naphthyltetrahydroisoquinolines, named ancistrolikokines A(2) (13), A(3) (14), C-2 (5), H (15), and H-2 (16) are presented, along with six known 5,8'-linked alkaloids, previously identified in related African Ancistrocladus species, now found for the first time in A. likoko. The structural elucidation was achieved by spectroscopic analysis (HRESIMS, 1D and 2D NMR) and by chemical (oxidative degradation) and chiroptical (electronic circular dichroism) methods. The new ancistrolikokines showed moderate to good preferential cytotoxic activities towards pancreatic PANC-1 cells in nutrient-deprived medium (NDM), without causing toxicity under normal, nutrient-rich conditions, with ancistrolikokine H-2 (16) being the most potent compound.
Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action against tumoral cell lines. Here, we describe the synthesis and anticancer activity of eight new 3-alkylpyridine alkaloid (3-APA) analogs in four steps and with good yields. The key step for the synthesis of these compounds is a Williamson etherification under phase-transfer conditions. We investigated the influence of the length of the alkyl chain attached to position 3 of the pyridine ring on the cytotoxicity of these compounds. Biological assays demonstrated that compounds with an alkyl chain of ten carbon atoms (4c and 5c) were the most active against two tumoral cell lines: RKO-AS-45-1 and HeLa. Micronucleus and TUNEL assays showed that both compounds are mutagenic and induce apoptosis. In addition, Compound 5c altered the cellular actin cytoskeleton in RKO-AS-45-1 cells. The results suggest that Compounds 4c and 5c may be novel prototype anticancer agents.
<jats:title>Abstract</jats:title><jats:p>A phytochemical investigation of the bulbs of <jats:italic>Crinum asiaticum</jats:italic> L. var. <jats:italic>sinicum</jats:italic> <jats:sc>Baker</jats:sc> resulted in the isolation of two new alkaloids, asiaticumines A and B (<jats:bold>1</jats:bold> and <jats:bold>2</jats:bold>, resp.), together with 21 known compounds, including nine alkaloids, four amides, five phenolic compounds, and three flavonoids. All 23 compounds were isolated for the first time from <jats:italic>Crinum asiaticum</jats:italic> L. var. <jats:italic>sinicum</jats:italic> <jats:sc>Baker</jats:sc>. Their structures were elucidated by spectroscopic methods. In addition, ten alkaloids, <jats:bold>1</jats:bold>–<jats:bold>10</jats:bold>, were evaluated for their cytotoxic activities against human tumor cell lines A549, LOVO, HL‐60, and 6T‐CEM. Compounds <jats:bold>3, 4</jats:bold>, and <jats:bold>7</jats:bold>–<jats:bold>10</jats:bold> selectively showed remarkable inhibition against one or more of the tested cell lines.
CONSPECTUS: Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues.With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach.
Tabercorymines A (1) and B (2), two new vobasinyl-ibogan-type bisindole alkaloids with.an unprecedented skeleton, were isolated from Tabernaemontana corymbosa. Their structures were established by a combination of spectroscopic data, chemical transformation, single-crystal X-ray diffraction, and ECD calculation. Compound 1 represents a novel bisindole alkaloid, characterized by a caged heteropentacyclic ring system incorporating an unprecedented C-7/C-20 bond in the vobasinyl unit. Alkaloids 1 and 2 showed potent antiproliferative activity against several human cancer cell lines, including vincristine-resistant KB.
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated9 (Cas9) endonuclease system is a powerful RNA-guided genome editing tool. CRISPR/Cas9 has been well studied in model plant species for targeted genome editing. However, few studies have been reported on plant species without whole genome sequence information. Currently, no study has been performed to manipulate metabolic pathways using CRISPR/Cas9. In this study, the type II CRISPR/SpCas9 system was used to knock out, via nonhomologous end-joining genome repair, the 4'OMT2 in opium poppy (Papaver somniferum L.), a gene which regulates the biosythesis of benzylisoquinoline alkaloids (BIAs). For sgRNA transcription, viral-based TRV and synthetic binary plasmids were designed and delivered into plant cells with a Cas9 encoding-synthetic vector by Agrobacterium-mediated transformation. InDels formed by CRISPR/Cas9 were detected by sequence analysis. Our results showed that the biosynthesis of BIAs (e.g. morphine, thebaine) was significantly reduced in the transgenic plants suggesting that 4'OMT2 was efficiently knocked-out by our CRISPR-Cas9 genome editing approach. In addition, a novel uncharacterized alkaloid was observed only in CRISPR/Cas9 edited plants. Thus, the applicabilitiy of the CRISPR/Cas9 system was demonstrated for the first time for medicinal aromatic plants by sgRNAs transcribed from both synthetic and viral vectors to regulate BIA metabolism and biosynthesis.
