Incorporation of cinnamic acid-2-[14C] into tylophorine

Tylophora indica plants have been shown to contain phenanthroindolizidine alkaloids of the tylophorine type. Cinnamic acid-[2-¹⁴C]was incorporated efficiently into these alkaloids supporting the hypothesis that ring A and C-10 and C-6$\text{\$}\text{?}$of tylophorine are derived from phenylalanine.     

Alkaloids from Tylophora hirsuta

Five novel phenanthroindolizidine alkaloids, namely tylohirsutinine, 13a-methyltylohirsutine, 13a-methyltylohirsutinidine, tylohirsutinidine and 13a-hydroxysepticine, isolated from Tylophora hirsuta together with two unidentified bases are described. Structural studies indicate that the first four alkaloids possess the dibenzo [f, h]-pyrrolo-[1,2b]isoquinoline skeleton present in other Tylophora species, but differ in the presence of unsaturation in ring E or in the presence of an angular methyl function. The fifth alkaloid has been shown to be the 13a-hydroxy analogue of septicine.     

Structure-activity studies of phenanthroindolizidine alkaloids as potential antitumor agents

Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structure-activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7) were among the most active compounds against tumor growth both in vitro and in vivo. In the hepatocellular carcinoma cell line HepG2, the GI(50)s of DCB-3503 and PA-7 were 35+/-5 nM and 11+/-5 nM, respectively. DCB-3503 and PA-7 significantly inhibited HepG2 tumor growth in nude mice at a dose of 9 mg/kg given by intraperitoneal (ip) injections twice a day every third day for a total of four cycles (P<0.05 for DCB-3503 and P<0.01 for PA-7). Their potent antitumor activities correlated with their potent NF-kappaB-inhibitory effects and their cyclin D1 down-regulatory effects.     

Alkaloids of Pergularia pallida

Five phenanthroindolizidine alkaloids namely tylophorine, tylophorinidine, pergularinine, desoxypergularinine and an unidentified base (M⁺ 409) have been isolated from the roots of Pergularia pallida plants.     

Inhibition of Lipopolysaccharide‐Induced Nitric Oxide Production by Antofine and Its Analogues in RAW 264.7 Macrophage Cells

Based on the anti‐inflammatory activity of phenanthroindolizidine alkaloids, the inhibitory effect of antofine and its analogues on lipopolysaccharide (LPS)‐induced nitric oxide (NO) production was examined, and structure–activity relationships are discussed. Antofine and several analogues suppressed NO production in LPS‐stimulated RAW 264.7 cells. The MeO group at C(2), and the bulkiness of the substituents at C(3) and C(6) in the phenanthrene ring might be critical for this effect. Besides, regulation of iNOS expression might be involved in the inhibitory effect of antofine on LPS‐induced NO production in macrophage cells.     

Oviposition-stimulatory activity of phenanthroindolizidine alkaloids of host-plant origin to a danaid butterfly, Ideopsis similis

Oviposition response of Ideopsis similis (L.) (Lepidoptera: Danaidae) was examined for 12 phenanthroindolizidine alkaloids present in its host plant, Tylophora tanakae (Maxim.) (Asclepiadaceae). At least five alkaloids, i.e. (+)‐isotylocrebrine (3,4,6,7‐tetramethoxyphenanthroindolizidine; l ), (+)‐3‐demethyliso‐ tylocrebrine ( 3 ), (+)‐isotylocrebrine N‐oxide ( 5 ), (+)‐6‐demethyltylocrebrine ( 8 ) and (–)‐7‐demethyltylophorine ( 10 ), were found to individually stimulate oviposition by females. Of these, compounds 1, 3 and 10 were regarded as key components most responsible for host recognition or preference. However, female egg‐laying was much higher in response to a mixture of the five alkaloids. In two‐choice bioassays, more eggs were deposited on samples comprising the five alkaloids than on samples consisting of a single alkaloid. This suggests strongly that host selection by the butterfly is mediated by the synergistic action of several phenanthroindolizidine alkaloids present in the host plant.     

卵叶娃儿藤中的抗癌活性生物碱

从卵叶娃儿藤(Tylophora ovata (Lindl.) Hook. ex Steud.)根中分离得到 4个菲骈吲哚里西丁类生物碱,分别为tylophoridicine A (1)、娃儿藤宁(2)、氧甲基娃儿藤定(3)和娃儿藤定(4).经波谱分析并结合化学方法鉴定,其结构分别为:(13aR)-6-羟基-3,7-二甲氧基菲骈吲哚里西丁、 (13aS ,14R)-14-羟基-3,6,7-三甲氧基-菲骈吲哚里西丁、(13aS, 14S)-14-羟基-3,6,7-三甲氧基-菲骈吲哚里西丁和(13 aS,14S)-6,14-二羟基-3,7-二甲氧基-菲骈吲哚里西丁.化合物1为新化合物,化合物2-4为首次从该植物得到的化合物.经药理筛选,化合物1、3和4显示很强的抗癌活性.     

Insecticidal and antifeedant effects of two alkaloids from Cynanchum komarovii against larvae of Plutella xylostella L

A bioassay‐guided fractionation of Cynanchum komarovii crude alkaloid extract led to the isolation of two alkaloids. The isolated alkaloids were identified as 7‐demethoxytylophorine (1) and 6‐hydroxyl‐2,3‐dimethoxy phenanthroindolizidine (2) based on the comparison of their spectroscopic characteristics with the literature data. Insecticidal, antifeedant and growth inhibitory effects of these two alkaloids against the 3rd instar larvae of Plutella xylostella L. (Lepidoptera: Plutellidae) were examined. The results showed that alkaloid 1 was more toxic than alkaloid 2 against the 3rd instar larvae of Plutella xylostella L., but both alkaloids were less toxic than the total alkaloid fraction. For antifeedant activity, alkaloid 1 showed AFC₅₀ of 1.82 mg/ml at 24 h after treatment, alkaloid 2 showed 3.89 mg/ml, while total alkaloids showed 1.56 mg/ml. In dipping toxicity test, alkaloids 1 and 2 produced 93.3% and 63.3% mortality at 72 h after treatment, respectively, while total alkaloids produced 96.7% mortality. The LC₅₀ values for alkaloids 1, 2 and the total alkaloids were 3.54, 9.21 and 2.63 mg/ml, respectively. The development of larvae was also inhibited, and the growth inhibition rates at the concentration of 15.00 mg/ml were 92.8%, 78.2% and 98.6% for alkaloids 1, 2 and total alkaloids, respectively, at 72 h after treatment. Compared with antifeedant and dipping effect, the alkaloids 1, 2 and total alkaloid fraction revealed weak feeding toxicity, and their corrected mortality rates at the concentration of 15.00 mg/ml were 60.0%, 40.0% and 63.3% at 7 days after treatment. The LC₅₀ values for alkaloids 1, 2 and total alkaloids were 12.58, 32.37 and 8.88 mg/ml, respectively, at 7 days after treatment.     

A benzopyrroloisoquinoline alkaloid from Ficus fistulosa

A new benzopyrroloisoquinoline alkaloid, fistulosine (1), was isolated from the stem-bark of Ficus fistulosa (Moraceae) collected in Singapore, along with three known phenanthroindolizidine alkaloids, (?)-13aα-antofine (2), (?)-14β-hydroxyantofine (3) and (?)-13aα-secoantofine (4). (?)-13aα-Antofine (2) accounted for the antifungal activity against Aspergillus fumigatus and Candida albicans originally observed in the crude alkaloid extract.     

卵叶娃儿藤中的抗癌活性生物碱

从卵叶娃儿藤 (Tylophoraovata (Lindl.)Hook .exSteud .)根中分离得到 4个菲骈吲哚里西丁类生物碱 ,分别为tylophoridicineA (1)、娃儿藤宁 (2 )、氧甲基娃儿藤定 (3)和娃儿藤定 (4 )。经波谱分析并结合化学方法鉴定 ,其结构分别为 :(13aR)_6_羟基_3,7_二甲氧基菲骈吲哚里西丁、(13aS ,14R)_14_羟基_3,6 ,7_三甲氧基_菲骈吲哚里西丁、(13aS ,14S)_14_羟基_3,6 ,7_三甲氧基_菲骈吲哚里西丁和 (13aS ,14S)_6 ,14_二羟基_3,7_二甲氧基_菲骈吲哚里西丁。化合物 1为新化合物 ,化合物 2 - 4为首次从该植物得到的化合物。经药理筛选 ,化合物 1、3和 4显示很强的抗癌活性。     

Synthesis of indolizidinone analogues of cytotoxic alkaloids: monocyclic precursors are also active

Readily available proline derivatives can be transformed in just two steps into analogues of cytotoxic phenanthroindolizidine alkaloids. The key step uses a sequential radical scission-oxidation-alkylation process, which yields 2-substituted pyrrolidine amides. A second process effects the cyclization to give the desired alkaloid analogues, which possess an indolizidine core. The major and minor isomers (dr 3:2 to 3:1) can be easily separated, allowing their use to study structure-activity relationships (SAR). The process is versatile and allows the introduction of aryl and heteroaryl groups (including biphenyl, halogenated phenyl, and pyrrole rings). Some of these alkaloid analogues displayed a selective cytotoxic activity against tumorogenic human neuronal and mammary cancer cells, and one derivative caused around 80% cell death in both tumor lines at micromolar doses. The cytotoxicity of some monocyclic precursors was also studied, being comparable or superior to the bicyclic derivatives.     

Comparative biosynthesis of quinolizidine alkaloids from dl-lysine in five species of Leguminosae

Five species of the leguminosae produced radioactive lupine alkaloids after feeding with dl-lysine-[2-¹⁴C]. Saturated alkaloids and compounds with a pyridone ring were radioactive. The specific radioactivity of the isolated compounds provides evidence that conversion of lysine into the saturated alkaloids, and by further oxidation to compounds both with a pyridone ring and without a d ring.     

Synthesis and evaluation of the anti-proliferative and NF-κB activities of a library of simplified tylophorine analogs

Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort. Here, we present a concise synthetic approach to N-substituted phenanthropiperidines, which enabled a systematic investigation of structure-activity relationships at an underexplored region of the tylophorine scaffold. This work suggests that ring E of tylophorine is essential for the anti-proliferative activity of the 6,7,10,11-tetramethoxy-1,2,3,4-tetrahydrodibenzo[f,h]isoquinoline core scaffold.     

Cytotoxic labdane alkaloids from an ascidian Lissoclinum sp.: isolation, structure elucidation, and structure-activity relationship

Four labdane alkaloids, haterumaimides N-Q (1-4), were isolated from an ascidian Lissoclinum sp. and their structures were elucidated by chemical and spectral analyses. Investigation of the structure-activity relationships of haterumaimides J-K, N-Q, and 14 related compounds suggested that the presence of hydroxyl groups at C-6, C-7, C-12, and C-18, a chlorine atom at C-2, and an imido NH in ring C should be essential for cytotoxicity against P388 cells.     

Dimeric sesquiterpene thioalkaloids with potent immunosuppressive activity from the rhizome of Nuphar pumilum: structural requirements of nuphar alkaloids for immunosuppressive activity

Potent immunosuppressive dimeric sesquiterpene thioalkaloids, 6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, 6-hydroxythionuphlutine B and 6'-hydroxythionuphlutine B, were isolated from the rhizome of Nuphar pumilum together with five inactive quinolizidine alkaloids, neothiobinupharidine, nupharidine, deoxynupharidine, 7-epideoxynupharidine and nupharolutine. These dimeric sesquiterpene thioalkaloids were found to significantly inhibit anti-sheep erythrocyte plaque forming cell formation in mouse splenocytes at 1 microM. At this concentration. 6-hydroxythiobinupharidine, 6-hydroxythionuphlutine B and 6'-hydroxythionuphlutine B did not show cytotoxic effects to mouse splenocytes, and 6,6'-dihydroxythiobinupharidine also showed only minor or minimal cytotoxicity. By comparison of the inhibitory activity of several Nuphar alkaloids on anti-sheep erythrocyte plaque forming cell formation, some structural requirements of Nuphar alkaloids for immunosuppressive activity were obtained. Namely, the 6- or 6'-hydroxyl group at the quinolizidine ring of dimeric sesquiterpene thioalkaloids is essential for the immunosuppressive effect. The number of hydroxyl groups appears to be related to the cytotoxicity, and the influence on splenocytes is greater with increasing numbers of hydroxyl groups.     

New skeletons and new concepts in Amaryllidaceae alkaloids

The Amaryllidaceae alkaloids, represent a group of isoquinoline alkaloids, which are produced almost solely by members of the Amaryllidaceae family. The alkaloids of this family have attracted considerable amount of interest due to some important pharmacological activities they were shown to possess. In the last decade, our phytochemical studies on four Galanthus (Amaryllidaceae) species of Turkish origin have yielded quite a number of new alkaloids with diverse structures. Among these alkaloids, gracilines and plicamines constitute two new subgroups for the Amaryllidaceae alkaloids. The gracilines contain an incorporated 10b,4a-ethanoiminodibenzo[b,d]pyrane skeleton. The plicamines are dinitrogenous compounds, where the oxygen atom in position 7 of a tazettine skeleton is replaced by a nitrogen atom substituted by a pendant 4-hydroxyphenethyl moiety. One of the new alkaloids, galanthindole, which possesses a nonfused indole ring, unlike the already known subgroups of Amaryllidaceae alkaloids, may be considered as the prototype of a third new subgroup of the Amaryllidaceae alkaloids. Additionally, two known isoquinoline alkaloids which do not possess one of the established skeletons of the Amaryllidaceae alkaloids, namely ( − )-capnoidine and (+)-bulbocapnine, have been isolated from a Turkish Galanthus species. Totally, 21 new, 20 known alkaloids and 2 known lignans have been characterized. In this review, the isolation and structure elucidation of these compounds with interesting chemical structures are described.     

Chemical constituents from Cynanchum paniculatum (Bunge) Kitag

Twenty-nine compounds, including five acetophenone derivatives (1–5), three phenanthroindolizidine alkaloids (12–14), seven pentacyclic triterpenoids (15–21) and five C₂₁ steroidal sapogenins (22–26), were isolated from the root of Cynanchum paniculatum (Bunge) Kitag. Their structures were determined by spectroscopic methods and comparison with reported data. Moreover, the chemotaxonomic relationships were also discussed. As a result, acetophenone derivatives, pentacyclic triterpenoids and C₂₁ pregnane sapogenins can be recognized as chemotaxonomic markers for Cynanchum genus, and C. paniculatum has close relationships with some species of genus Cynanchum.     

Biotechnology and genetics of ergot alkaloids

Ergot alkaloids, i.e. ergoline-derived toxic metabolites, are produced by a wide range of fungi, predominantly by members of the grass-parasitizing family of the Clavicipitaceae. Naturally occurring alkaloids like the D-lysergic acid amides, produced by the "ergot fungus" Claviceps purpurea, have been used as medicinal agents for a long time. The pharmacological effects of the various ergot alkaloids and their derivatives are due to the structural similarity of the tetracyclic ring system to neurotransmitters such as noradrenaline, dopamine or serotonin. In addition to "classical" indications, e.g. migraine or blood pressure regulation, there is a wide spectrum of potential new applications of this interesting group of compounds. The biotechnology of ergot alkaloids has a long tradition, and efficient parasitic and submerse production processes have been developed; the biochemistry of the pathway and the physiology of production have been worked out in detail. The recent identification of a cluster of genes involved in ergot alkaloid biosynthesis in C. purpurea and the availability of molecular genetic techniques allow the development of strategies for rational drug design of ergoline-related drugs by enzyme engineering and by biocombinatorial approaches.     

Synthesis of phenanthroindolizidine alkaloids and evaluation of their antitumor activities and toxicities

We previously reported that phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem. To address this problem, new phenanthroindolizidine derivatives were synthesized and their antitumor activities and toxicities were evaluated. This study describes the relationship between the chemical structures, antitumor activities, and toxicities of these phenanthroindolizidine derivatives. Based on its properties, compound 8 was found to be the most suitable potential antitumor agent.     

Sativanine-a and sativanine-b,two new cyclopeptide alkaloids from the bark of Zizyphus sativa

From the bark of Zizyphus sativa, in addition to already described cyclopeptide alkaloids, two new compounds of this class, sativanine-A(1) and sativanine-B(2), were isolated. Both alkaloids contain 14-membered ring systems. 1 belongs to the integerrine type, while 2 is similar to nummularine-G, with an additional ring in the side chain.