bisindole alkaloids

  • 文章类型: Journal Article
    十一种未描述的单萜双吲哚生物碱,alstophylinesA-K(1-11),从大叶Alstonia的叶子和茎皮中分离出三种已知的类似物。化合物1-3是前所未有的二聚化生物碱,它通过C-C键结合了大线型基序和ajmaline型基序。通过广泛的光谱分析阐明了它们的结构和绝对构型,电子圆二色性(ECD)计算,和CD激子手性方法。化合物1-3对AChE具有潜在的抑制生物活性,IC50值为4.44±0.35、3.59±0.18和3.71±0.23μM。分别。酶动力学研究揭示化合物1-3作为混合竞争性AChE抑制剂。此外,化合物8和12-14对人癌细胞系HT-29的细胞毒性优于顺铂。流式细胞术数据显示,化合物8、13和14以浓度依赖性方式显著诱导HT-29细胞停滞在G0/G1期。
    Eleven undescribed monoterpenoid bisindole alkaloids, alstomaphyines A-K (1-11), along with three known analogues were isolated from the leaves and stem bark of the Alstonia macrophylla. Compounds 1-3 were unprecedented dimerization alkaloids incorporating a macroline-type motif with an ajmaline-type motif via a C-C linkage. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and CD exciton chirality method. Compounds 1-3 displayed potential inhibitory bioactivity against AChE with IC50 values of 4.44 ± 0.35, 3.59 ± 0.18, and 3.71 ± 0.23 μM, respectively. Enzyme kinetic study revealed compounds 1-3 as mixed competitive AChE inhibitors. Besides, compounds 8 and 12-14 exhibited better cytotoxicity against human cancer cell line HT-29 than cisplatin. Flow cytometry data revealed that compounds 8, 13, and 14 significantly induced the HT-29 cells arrest in G0/G1 phase in a concentration-dependent manner.
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  • 文章类型: Journal Article
    天然产物对抗癌治疗有很大贡献;植物界提供了重要的分子来源。Conofolidine是一种新型的Aspidosperma-Aspidosperma双吲哚生物碱,分离自马来亚植物TabernaemontanaCorymbosa。在这里,我们报道了与其他三种双吲哚-康茶碱一起具有广谱抗癌活性,leuchyllidine,和双茶碱-针对人类乳腺,结直肠,胰腺,和肺癌细胞系。值得注意的是,conofolidine能够诱导细胞凋亡(例如,在MDA-MB-468乳房中)或衰老(例如,在HT-29结直肠中)在癌细胞中。膜联蛋白V-FITC/PI,caspase激活,PARP裂解证实了前者,而阳性β-gal染色证实了后者。细胞周期扰动是明显的,包括S相耗尽,伴随着CDK2和细胞周期蛋白(A2,D1)下调,p21上调。HCT-116细胞的共聚焦成像揭示了异常有丝分裂表型-膜起泡的诱导,DNA片段化与偶尔的多核化。在HCT-116,MDA-MB-468,MIAPaCa-2和HT-29细胞中的DNA完整性评估显示在G1细胞周期期间荧光γ-H2AX增加;通过共聚焦显微镜在HCT-116和MDA-MB-468细胞中验证了γ-H2AX灶。Conopolidine增加氧化应激,在大多数癌细胞系中,先前的凋亡和衰老诱导,如ROS水平增强伴随NQO1表达增加所见。总的来说,我们提出了一种推定的有效抗癌剂,能够在体外诱导异质模式的癌细胞死亡,鼓励对这种天然产品进行进一步的临床前评估。
    Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine\'s broad-spectrum anticancer activity together with that of three other bisindoles-conophylline, leucophyllidine, and bipleiophylline-against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product.
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  • 文章类型: Journal Article
    六种未描述的双吲哚生物碱,即taberdiinsA-F(1-6),是从Tabernaemontanadivaricata\'Dwaft\'的叶子中分离出来的。其中,生物碱1和2是具有两种C-C连接模式的strychnos-iboga型生物碱的第一个例子。生物碱3,一种带有呋喃环的新型天冬草,以及其他三个未描述的被披露。通过全面的光谱分析阐明了它们的结构。生物碱1和5在体内对节食夜蛾的Sf9细胞和卵具有杀虫活性,这可能解释了植物抗虫性的潜力。
    Six undescribed bisindole alkaloids, namely taberdisines A-F (1-6), were isolated from the leaves of Tabernaemontana divaricata \'Dwaft\'. Among them, alkaloids 1 and 2 were the first examples of strychnos-iboga type alkaloid with both C-C linkage patterns. Alkaloid 3, a new type of aspidosperma-iboga with a furan-ring, as well as other three undescribed ones was disclosed. Their structures were elucidated by comprehensive spectroscopic analyses. Alkaloids 1 and 5 showed insecticide activity on Sf9 cell and eggs of Spodoptera frugiperda in vivo, which might explain the potential of the plants for insect resistance.
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  • 文章类型: Journal Article
    海洋来源的双吲哚表现出结构多样性,并通过多种机制发挥抗癌作用。综合研究表明,源自海洋天然产物的药物的开发成功率是其他天然衍生物的四倍。目前,有20种海洋衍生药物用于临床实践,其中11种具有抗肿瘤作用。本文对167种天然海洋双吲哚产品及其衍生物的抗肿瘤研究进展进行了全面综述。恩扎塔林不仅进入了临床实践,但是还有一种成功上市的海洋衍生双吲哚化合物,称为midostaurin,用于治疗急性髓细胞性白血病。总之,对海洋衍生双吲哚的生物活性和临床进展的研究表明,它们具有显著的选择性,最小的毒性,和对各种癌细胞的功效。因此,它们在抗肿瘤药物开发领域表现出巨大的潜力,尤其是在抗肿瘤耐药领域。在未来,这些化合物可能是发现和开发新的癌症治疗方法的有希望的线索。
    Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.
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  • 文章类型: Journal Article
    目前,全球新的癌症病例和死亡人数逐年增加。除了预防癌症的要求,当务之急仍然是寻求癌症的有效治愈方法。在半个多世纪的不断探索中,天然产物优异的抗癌活性日益受到重视,随着越来越多的天然产物被分离,识别和检测。对于这项研究,焦点在于双吲哚的天然产物,其中两个吲哚分子间接连接或直接聚合,发展结构和机制的多样性,伴随着比单体更好的抗癌活性。在癌症治疗中使用靛玉红和长春新碱已经有很长的历史,验证双吲哚的抗癌作用。Vincribine,midostaurin和其他抗癌药物也已开发并商业化。在本文中,对从各种天然产物中提取的双吲哚生物碱的潜在治疗效果进行了综述,其中介绍了242种双吲哚生物碱用于癌症治疗的研究进展。这些化合物将来可能用作临床研究的药用产品。
    Currently, the number of new cancer cases and deaths worldwide is increasing year on year. In addition to the requirement for cancer prevention, the top priority is still to seek the effective cure of cancer. In over a half century of constant exploration, increasing attention has been paid to the excellent anticancer activity of natural products, with more and more natural products isolated, identified and detected. For this study, the focus lies the natural products of bisindole, where two indole molecules are indirectly linked or directly polymerized, developing the diversity of structure and mechanism, accompanied with the better anticancer activity than monomers. There has been a long history of applying indirubin and vincristine in cancer treatment, verifying the anticancer effect of bisindoles. Vincribine, midostaurin and other anticancer drugs have also been developed and commercialized. In this paper, a review regarding the potential therapeutic effect of bisindole alkaloids extracted from various natural products was carried out, in which the progress made in research of 242 bisindole alkaloids for cancer treatment was introduced. These compounds may be applicable as medicinal products for clinical research in the future.
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  • 文章类型: Journal Article
    Vindoline is an important alkaloid produced in Catharanthus roseus leaves. It is the more important monomer of the scarce and costly anticancer bisindole alkaloids, vincristine, and vinblastine, as unlike catharanthine (the other monomer), its biosynthesis is restricted to the leaves. Here, biotic (bacterial endophyte, phytoplasma, virus) and abiotic (temperature, salinity, SA, MeJa) factors were studied for their effect on vindoline accumulation in C. roseus. Variations in vindoline pathway-related gene expression were reflected in changes in vindoline content. Since allene oxide cyclase (CrAOC) is involved in jasmonate biosynthesis and MeJa modulates many vindoline pathway genes, the correlation between CrAOC expression and vindoline content was studied. It was taken up for full-length cloning, tissue-specific expression profiling, in silico analyses, and upstream genomic region analysis for cis-regulatory elements. Co-expression analysis of CrAOC with vindoline metabolism-related genes under the influence of aforementioned abiotic/biotic factors indicated its stronger direct correlation with the tabersonine-to-vindoline genes (t16h, omt, t3o, t3r, nmt, d4h, dat) as compared to the pre-tabersonine genes (tdc, str, sgd). Its expression was inversely related to that of downstream-acting peroxidase (prx) (except under temperature stress). Direct/positive relationship of CrAOC expression with vindoline content established it as a key gene modulating vindoline accumulation in C. roseus.
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  • 文章类型: Journal Article
    Phytochemical investigation of Melodinus fusiformis led to a new aspidosperma-aspidosperma bisindole alkaloid (BIA), bis-19β-hydroxyvenalstonidine (1), together with three known BIAs (2-4). The structures were established by extensive analysis of their HRESIMS, NMR data, and comparing with the reported data. BIA 1 is an almost symmetrical structure, linked by C3-C14\' bond, while BIAs 2-4 are reported for the first time from the plant. The cytotoxic, immunosuppressive and anti-inflammatory activities of BIAs 1-4 were evaluated in vitro. BIAs 1, 3 and 4 showed good toxicity against MOLT-4 cell lines with IC50 values in the range of 1.5-17.5 -M. BIA 2 exhibited the strongest inhibitory effect against MCF-7 cell lines with an IC50 value of 7.1 μM. BIA 1 significantly inhibited Con A-stimulated mice splenocytes proliferation equal to that of the positive control (DXM) in a concentration-dependent manner. BIAs 1 and 2 were able to decrease the NO production in LPS-induced RAW 264.7 cells at 30 μM concentration. BIA 2 showed similar inhibition of nitric oxide release, compared to that of DXM. Furthermore, BIA 2 remarkably inhibited the levels of IL-6 and TNF-α compared to the LPS induced group. Interestingly, BIA 2 displayed an inhibitory effect on TNF-α production similar to that of dexamethasone at a concentration of 20 μM.
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  • 文章类型: Journal Article
    The Melodinus species have been proved to be good resources of bisindole alkaloids. Six bisindole alkaloids were isolated from the leaves and stems of Melodinus cochinchinensis (Lour.) Merr. guided by HRESIMS data analysis. Among them, melokhanines K-M, epi-scandomelonine, and epi-scandomeline possessed aspidosperma-scandine skeleton linked by a C-C bond while meloyine II had a scandine-scandine skeleton. The structures were established by extensive spectroscopic analysis of their HRESIMS and NMR data. Melokhanines K-M were undescribed compounds, while epi-scandomelonine, epi-scandomeline and meloyine II were known compounds, which were reported from Melodinus species for the first time. The anti-inflammatory and cytotoxic activities of the isolates were also evaluated in vitro. Melokhanine K and meloyine II showed potent inhibitory activity on the production of nitric oxide, interleukin-6, and tumor necrosis factor-α in LPS-induced RAW 264.7 macrophages, whereas epi-scandomelonine and epi-scandomeline exhibited certain cytotoxic activity against MOLT-4 cells with IC50 values 5.2 and 1.5 μM, respectively.
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  • 文章类型: Journal Article
    Streptomyces sp. SCSIO 03032, isolated from a deep-sea sediment sample (-3412 m) from the Indian Ocean, produces several classes of bioactive compounds including α-pyridone antibiotics (piericidins), polycyclic macrolactams (heronamides) and bisindole alkaloids (spiroindimicins, indimicins and lynamicins). Here we report the complete genome sequence of Streptomyces sp. SCSIO 03032, which consists of a 6,287,975 bp linear chromosome. The genome analysis reveals the presence of 29 putative biosynthetic gene clusters for secondary metabolites, including those for piericidins, heronamides and spiroindimicins/indimicins/lynamicins. The genome sequence suggests that Streptomyces sp. SCSIO 03032 could be a producer for novel bioactive natural products with potential applications in drug discovery.
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  • 文章类型: Journal Article
    Two new bisindole alkaloids, 12\'-O-demethyl-vobtusine-5-lactam and isovobtusine-N-oxide (1 and 2), were isolated from the leaves of Voacanga grandifolia, together with two known bisindole alkaloids. Their structures were elucidated on the basis of 1D and 2D NMR data. 1 and 2 showed potent antimalarial activity against Plasmodium falciparum 3D7 and very low cytotoxic activity against a human cell line, HepG2 cells.
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