Quantification of Anti‐Addictive Alkaloids Ibogaine and Voacangine in In Vivo‐ and In Vitro‐Grown Plants of Two Mexican Tabernaemontana Species

Tabernaemontana alba and Tabernaemontana arborea are Apocynaceae species used in Mexican traditional medicine for which little phytochemical information exists. In this study, preliminary gas chromatography/mass spectrometry analyses of different organs obtained from wild plants of both species identified a total of 10 monoterpenoid indole alkaloids (MIAs) and one simple indole alkaloid, nine of which were reported for the first time in these species. Furthermore, callus cultures were established from T. alba leaf explants and regeneration of whole plants was accomplished via somatic embryogenesis. The anti‐addictive MIAs ibogaine and voacangine were then quantified by gas chromatography with flame ionization detection in wild plants of both species, as well as greenhouse‐grown plants, in vitro‐grown plantlets and embryogenic callus of T. alba. Ibogaine and voacangine were present in most samples taken from the whole plants of both species, with stem and root barks showing the highest concentrations. No alkaloids were detected in callus samples. It was concluded that T. alba and T. arborea are potentially viable sources of ibogaine and voacangine, and that these MIAs can be produced through somatic embryogenesis and whole plant regeneration of T. alba. Approaches to increase MIA yields in whole plants and to achieve alkaloid production directly in cell cultures are discussed.     

Synthesis,antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives

In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong cell growth inhibition and apoptosis induction characteristics are being strongly screened for their cancer chemo-preventive potential. In the present study, N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were designed, synthesized and allowed to evaluate for their anti-proliferative and apoptosis induction potential against cervical (HeLa), breast (MCF-7 and MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells. The MTT assay in conjunction with mitochondrial potential assays and the trypan blue dye exclusion were employed to ascertain the effects of the derivatives on the cancer cells. Further, mechanistic studies were conducted on compound 14a to understand the biochemical mechanisms and functional interactions with various signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced apoptosis via caspase independent pathway through the participation of mitogen-activated protein kinases (MAPK) such as extracellular signal related kinase (ERK) and p38 as well as p53 pathways. It originates the activation of pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the generation of reactive oxygen species. In downstream signaling pathway, activated p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced apoptotic cell death was evidenced by the fact that the inclusion of specific inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125) prevented the compound 14a towards induced apoptosis. The results clearly showed that MAP kinase cascades were crucial for apoptotic response in compound 14a induced cellular killing and were dependent on p53 activity. Based on the results, compound 14a was identified as a promising candidate for cancer therapeutics and these findings furnish a basis for further in vivo experiments on anti-proliferative activity.     

钵水母水螅体横裂诱发条件及调控机制研究进展

横裂是水螅体世代向水母体世代转变的重要阶段.对水螅体横裂诱发条件及调控分子机制的研究不仅对水母爆发生态学和水母人工繁育具有重要意义,而且对比较研究两栖类、昆虫以及刺胞动物等具有复杂生活史生物的变态分子机制起源也具有很好的理论价值.现有研究表明,诱发水螅体横裂的自然环境因素有温度、光照、盐度和共生虫黄藻等,不同门类水母的横裂方式以及环境诱导因素各不相同.能够诱导水螅体横裂的化学因素有吲哚类化合物、9-顺式维甲酸、碘元素和过氧化氢等,其中吲哚类化合物对绝大多数水母水螅体都有诱导作用.尽管水螅体横裂的分子机制尚未明晰,但对海月水母的研究表明,RxR信号通路以及一种横裂诱导激素前体假定蛋白CL390在水母横裂过程中起着重要的作用,提示水母变态分子机制与两栖类和昆虫在分子水平上存在一定程度的共性.     

Cytotoxic monoterpenoid indole alkaloids from the leaves and twigs of Tabernaemontana bovina

Phytochemical investigation of the leaves and twigs of Tabernaemontana bovina led to the isolation of 10 monoterpenoid indole alkaloids, including two new taberbovinines A (1) and B (2) along with eight known analogs: mehranine (3), 14α,15β-dihydroxy-N-methylaspidospermidine (4), (16S*)− 15-epi-E-isositsirikine (5), (16R*)− 15-epi-E-isositsirikine (6), 16 R*-19,20-E-isositsirikine acetate (7), hecubine (8), voafinidine (9), and voacangarine (10). Taberbovinine B (2) represents the first case of an unusual ring C/D cleavage among the natural Corynanthe-type alkaloids. Compounds 2 and 8 exhibited weak cytotoxicity against five human cancer cell lines, including SK-LU-1, HepG2, MCF-7, SK-Mel-2, and LNCaP, with IC₅₀ values ranging from 42.9 to 66.3 μM, whereas compounds 4 − 6 and 9 were cytotoxic toward MCF-7, SK-LU-1 and LNCaP cells, with IC₅₀ values in a range of 51.6–93.3 μM.     

Bioactive monoterpene indole alkaloids from Nauclea officinalis

Two new monoterpene indole alkaloids, naucleaoffines A (1) and B (2), together with six known alkaloids (3–8), were isolated from the stems and leaves of Nauclea officinalis. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with the data reported in literature. All isolated compounds were evaluated for their anti-inflammatory activities and anti-HIV-1 activities. Compounds 1–8 exhibited significant inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with IC₅₀ values comparable to that of hydrocortisone. In addition, compounds 1–8 showed significant anti-HIV-1 activities with EC₅₀ ranged from 0.06 to 2.08 µM. These findings suggest that the discoveries of these indole alkaloids with significant anti-inflammatory activities and anti-HIV-1 activities isolated from N. officinalis could be of great importance to the development of new anti-inflammatory and anti-HIV agents.     

Formicidal activity of indole derivatives on Atta opaciceps (Borgmeier): Lethal,behavioural and locomotive effects

The leaf‐cutting ants of the genus Atta are of extreme importance for agriculture and forestry. Few active products can be employed to control these pests and, therefore, the discovery of new insecticidal products represents a fundamental strategy for its management. In this study, we evaluated the mortality, behaviour and locomotion of workers of Atta opaciceps (Borgmeier) exposed to synthesized indole derivatives. The most active compound was 4d [1‐(1H‐indol‐3‐yl)pentan‐1‐one] (LD₅₀ = 0.018 μg/mg), while the 4e [1‐(1H‐indol‐3‐yl)hexan‐1‐one] (LD₅₀ = 3.82 μg/mg) was the least active compound. These two derivatives reduced the survival of A. opaciceps over time and altered the behaviour and locomotion of these ants. This study demonstrates the potential of indole derivatives to produce new formicidal products, since, in addition to being effective, it also affects the ant's behaviour and locomotion.     

Isolation of a new potent cytotoxic pigment along with indigotin from the pathogenic basidiomycetous fungus Schizophyllum commune

An indole derivative, schizocommunin, was isolated along with indigotin (indigo), indirubin, isatin, and tryptanthrin, from the liquid culture medium in which a culture of Schizophyllum commune, isolated from the bronchus of a human patient with allergic bronchopulmonary mycosis, had been grown. The structure of schizocommunin was established by spectroscopic investigation. Schizocommunin showed the strong cytotoxicity against murine lymphoma cells. The assignments of the ¹H- and ¹³C-NMR signals of indigotin were also listed. This revised version was published online in June 2006 with corrections to the Cover Date.