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Herboxidiene

(Synonyms: GEX1A) 目录号 : GC40103

A polyketide with diverse biological activities

Herboxidiene Chemical Structure

Cas No.:142861-00-5

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500μg
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1mg
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实验参考方法

Cell experiment [1]:

Hela cells

RAW 264.7 cells

Preparation Method

Hela cells were cultured with 0.4 μM Herboxidiene for 4 h. The spliced and unspliced RNAs for the transcripts of DNAJB1, BRD2 and RIOK3 were detected by RT-PCR.

Reaction Conditions

0.4 μM; 4h

Applications

Herboxidiene inhibited the splicing of other pre-mRNAs.

References:

[1]. Hasegawa M, et al. Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. ACS Chem Biol. 2011 Mar 18;6(3):229-33.

产品描述

Herboxidiene, as a potent antitumor agent, can target the SF3B subunit of the spliceosome. Herboxidiene also induces both G1 and G2/M cell cycle arrest in a human normal fibroblast cell line WI-38.[1].

In vitro, herboxidiene showed cytotoxicity with IC50 of 0.0037 to approximately 0.99 μM against human tumor cell lines, while herboxidiene were not active against both gram-positive and -negative bacteria.[3] in addition, Herboxidiene has cytotoxicity against A431, A549, and DLD-1 cells with IC50s of 3.7, 21, 51 nM, respectively.[6] In vitro efficacy test it shown that in a dose-response assay, 0.5 μM Herboxidiene had substantial inhibitory effects on the plant growth and development comparable to those of 1 μM pladienolide B.[2] In vitro, treatment with herboxidiene at 5 μM had an effect on cell and nuclei shape, suggesting there is a cellular toxicity at high concentrations.[4] In addition, herboxidiene (a less potent, structurally different splicing modulator) at 20?nM (~3 × GI50) in HCT116 cells has the possibility of resistant clone generation.[5] Herboxidiene has a cytostaticity against human umbilical vein endothelial cells with IC50 of 26 nM and has inhibition with VEGF-induced invasion and tube formation of serum-starved HUVECs in a concentration-dependent manner[7].

In vivo experiment it exhibited that treatment with 1 mg/kg herboxidiene intraperitoneally once shown obvious antitumor activity[6].

References:
[1]Ghosh AK, et al. Design and synthesis of herboxidiene derivatives that potently inhibit in vitro splicing. Org Biomol Chem. 2021 Feb 18;19(6):1365-1377.
[2]AlShareef S, et al. Herboxidiene triggers splicing repression and abiotic stress responses in plants. BMC Genomics. 2017 Mar 27;18(1):260.
[3]Sakai Y, et al. GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp. I. Taxonomy, production, isolation, physicochemical properties and biological activities. J Antibiot (Tokyo). 2002 Oct;55(10):855-62.
[4]Granatosky EA, et al. GEX1A, a Polyketide from Streptomyces chromofuscus, Corrects the Cellular Defects Associated with Niemann-Pick Type C1 in Human Fibroblasts. J Nat Prod. 2018 Sep 28;81(9):2018-2025.
[5]Teng T, et al. Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex. Nat Commun. 2017 May 25;8:15522.
[6]Miller-Wideman M, et al. Herboxidiene, a new herbicidal substance from Streptomyces chromofuscus A7847. Taxonomy, fermentation, isolation, physico-chemical and biological properties. J Antibiot (Tokyo). 1992 Jun;45(6):914-21.
[7]Jung HJ, et al. Antiangiogenic activity of herboxidiene via downregulation of vascular endothelial growth factor receptor-2 and hypoxia-inducible factor-1α. Arch Pharm Res. 2015 Sep;38(9):1728-35.

Herboxidiene 作为一种有效的抗肿瘤剂,可以靶向剪接体的 SF3B 亚基。在人正常成纤维细胞系 WI-38 中,Herboxidiene 还诱导 G1 和 G2/M 细胞周期停滞。[1]

在体外,herboxidiene 对人类肿瘤细胞系表现出细胞毒性,IC50 为 0.0037 至约 0.99 μM,而 herboxidiene 对革兰氏阳性和阴性细菌均无活性。[ 3] 此外,Herboxidiene 对 A431、A549 和 DLD-1 细胞具有细胞毒性,IC50 分别为 3.7、21、51 nM。[6]< /sup> 体外药效试验表明,在剂量反应试验中,0.5 μM Herboxidiene 对植物生长发育的抑制作用与 1 μM pladienolide B 相当。[2] 在在体外,用 5 μM herboxoxidene 处理对细胞和细胞核形状有影响,表明在高浓度下存在细胞毒性。[4] 此外,herboxidiene(一种效力较低、结构不同的剪接调节剂) 20 nM (~3 × GI50) 在HCT116细胞中有产生抗性克隆的可能性。[5] Herboxidiene对人脐带有细胞生长抑制作用l 静脉内皮细胞,IC50 为 26 nM,以浓度依赖性方式抑制 VEGF 诱导的血清饥饿 HUVEC 的侵袭和管腔形成[7]

体内实验表明,1 mg/kg herboxoxidiene腹腔注射一次显示出明显的抗肿瘤活性[6]

Chemical Properties

Cas No. 142861-00-5 SDF
别名 GEX1A
化学名 5,6-anhydro-6-C-[(2S,3E,5E)-6-[(2S,3S,6R)-6-(carboxymethyl)tetrahydro-3-methyl-2H-pyran-2-yl]-2-methyl-3,5-heptadien-1-yl]-1,4,7-trideoxy-4-methyl-3-O-methyl-L-glycero-L-gluco-heptitol
Canonical SMILES O=C(O)C[C@@H]1O[C@H](/C(C)=C/C=C/[C@@H](C)C[C@@]2(C)O[C@]2([H])[C@H](C)[C@@H](OC)[C@H](O)C)[C@@H](C)CC1
分子式 C5H42O6 分子量 438.6
溶解度 Soluble in ethanol or methanol or DMSO or dichloromethane 储存条件 Store at -20°C,protect from light
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Research Update

Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide

Appl Microbiol Biotechnol 2015 Oct;99(20):8351-62.PMID:26286508DOI:10.1007/s00253-015-6860-2.

Herboxidiene is a polyketide with a diverse range of activities, including herbicidal, anti-cholesterol, and pre-mRNA splicing inhibitory effects. Thus, production of the compound on the industrial scale is in high demand, and various rational metabolic engineering approaches have been employed to enhance the yield. Directing the precursors and cofactors pool toward the production of polyketide compounds provides a rationale for developing a good host for polyketide production. Due to multiple promising biological activities, the production of a number of Herboxidiene derivatives has been attempted in recent years in a search for the key to improve its potency and to introduce new activities. Structural diversification through combinatorial biosynthesis was attempted, utilizing the heterologous expression of substrate-flexible glucosyltransferase (GT) and cytochrome P450 in Streptomyces chromofuscus to generate structurally and functionally diverse derivatives of Herboxidiene. The successful attempt confirmed that the strain was amenable to heterologous expression of foreign polyketide synthase (PKS) or post-PKS modification genes, providing the foundation for generating novel or hybrid polyketides.

Herboxidiene Features That Mediate Conformation-Dependent SF3B1 Interactions to Inhibit Splicing

ACS Chem Biol 2021 Mar 19;16(3):520-528.PMID:33617218DOI:10.1021/acschembio.0c00965.

Small molecules that target the spliceosome SF3B complex are potent inhibitors of cancer cell growth. The compounds affect an early stage of spliceosome assembly when U2 snRNP first engages the branch point sequence of an intron. Employing an inactive Herboxidiene analog (iHB) as a competitor, we investigated factors that influence inhibitor interactions with SF3B to interfere with pre-mRNA splicing in vitro. Order-of-addition experiments show that inhibitor interactions are long lasting and affected by both temperature and the presence of ATP. Our data are also consistent with the model that not all SF3B conformations observed in structural studies are conducive to productive inhibitor interactions. Notably, SF3B inhibitors do not impact an ATP-dependent rearrangement in U2 snRNP that exposes the branch binding sequence for base pairing. We also report extended structure-activity relationship analysis of the splicing inhibitor Herboxidiene. We identified features of the tetrahydropyran ring that mediate its interactions with SF3B and its ability to interfere with splicing. In the context of recent structures of SF3B bound to inhibitor, our results lead us to extend the model for early spliceosome assembly and inhibitor mechanism. We postulate that interactions between a carboxylic acid substituent of Herboxidiene and positively charged SF3B1 side chains in the inhibitor binding channel are needed to maintain inhibitor occupancy while counteracting the SF3B transition to a closed state that is required for stable U2 snRNP interactions with the intron.

Design and synthesis of Herboxidiene derivatives that potently inhibit in vitro splicing

Org Biomol Chem 2021 Feb 18;19(6):1365-1377.PMID:33480941DOI:10.1039/d0ob02532a.

Herboxidiene is a potent antitumor agent that targets the SF3B subunit of the spliceosome. Herboxidiene possesses a complex structural architecture with nine stereocenters and design of potent less complex structures would be of interest as a drug lead as well as a tool for studying SF3B1 function in splicing. We investigated a number of C-6 modified Herboxidiene derivatives in an effort to eliminate this stereocenter and, also to understand the importance of this functionality. The syntheses of structural variants involved a Suzuki-Miyaura cross-coupling reaction as the key step. The functionalized tetrahydrofuran core has been constructed from commercially available optically active tri-O-acetyl-d-glucal. We investigated the effect of these derivatives on splicing chemistry. The C-6 alkene derivative showed very potent splicing inhibitory activity similar to Herboxidiene. Furthermore, the C-6 gem-dimethyl derivative also exhibited very potent in vitro splicing inhibitory activity comparable to Herboxidiene.

Herboxidiene triggers splicing repression and abiotic stress responses in plants

BMC Genomics 2017 Mar 27;18(1):260.PMID:28347276DOI:10.1186/s12864-017-3656-z.

Background: Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and stresses. Small-molecule inhibitors that perturb splicing provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. Results: Here, we show that Herboxidiene (GEX1A) inhibits both constitutive and alternative splicing. Moreover, GEX1A activates genome-wide transcriptional patterns involved in abiotic stress responses in plants. GEX1A treatment -activated ABA-inducible promoters, and led to stomatal closure. Interestingly, GEX1A and pladienolide B (PB) elicited similar cellular changes, including alterations in the patterns of transcription and splicing, suggesting that these compounds might target the same spliceosome complex in plant cells. Conclusions: Our study establishes GEX1A as a potent splicing inhibitor in plants that can be used to probe the assembly, dynamics, and molecular functions of the spliceosome and to study the interplay between splicing stress and abiotic stresses, as well as having potential biotechnological applications.

Characterization of a methyltransferase involved in Herboxidiene biosynthesis

Bioorg Med Chem Lett 2013 Oct 15;23(20):5667-70.PMID:23992865DOI:10.1016/j.bmcl.2013.08.023.

The Herboxidiene biosynthetic gene cluster contains a regulatory gene and six biosynthetic genes that encode three polyketide synthases (HerB, HerC and HerD) and three tailoring enzymes (HerE, HerF and HerG). Through single crossover recombination, an integrative plasmid was inserted into the genome of Streptomyces chromofuscus ATCC 49982 between herE and herF, resulting in low-level expression of herF and the downstream herG. The mutant strain produced two new compounds, 18-deoxy-25-demethyl-herboxidiene and 25-demethyl-herboxidiene. HerF was expressed in Escherichia coli and biochemically characterized as the dedicated methyltransferase in Herboxidiene biosynthesis. It prefers 25-demethyl-herboxidiene to 18-deoxy-25-demethyl-herboxidiene, suggesting that C-25 methylation is the last tailoring step.