Pre-mRNA splicing

In a human normal fibroblast cell line, WI-38, herboxidiene (24 hours) produces both G1 and G2/M arrest with an IC50 of 7.6 nM[3]. With IC50s of 3.7, 21, and 51 nM, respectively, herboxidiene demonstrates cytotoxicity against A431, A549, and DLD-1 cells[3].

The anticancer efficacy of herboxidiene (GEX1A) (1 mg/kg; ip; once) is noteworthy[3].

Animal/Disease Models: balb/c (Bagg ALBino) mouse: (bearing SVT2 murine fibrosarcoma)[3]
Doses: 1 mg/kg
Route of Administration: Ip; once
Experimental Results: demonstrated significant antitumor activity on day 4.

[1]. Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide. Appl Microbiol Biotechnol. 2015;99(20):8351‐8362.

[2]. 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;55(10):855‐862.

[3]. Herboxidiene, a new herbicidal substance from Streptomyces chromofuscus A7847. Taxonomy, fermentation, isolation, physico-chemical and biological properties. J Antibiot (Tokyo). 1992;45(6):914‐921.

Herboxidiene has been reported to exist in Streptomyces chromofuscus, and relevant data are available.
See also: Gex1Q1 (note moved here).

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Herboxidiene is a polyketide compound with various activities, including herbicidal, cholesterol-lowering, and inhibitory effects on precursor mRNA splicing. Therefore, there is a large demand for its industrial-scale production, and various rational metabolic engineering methods have been employed to increase its yield. Directing precursor and cofactor libraries to the production of polyketides provides a theoretical basis for developing excellent hosts for polyketide production. Due to the diverse potential biological activities of herboxidiene, efforts have been made in recent years to produce various herboxidiene derivatives in order to find the key to improving its potency and introducing new activities. This study attempts to utilize combinatorial biosynthesis to heterologously express the substrates flexible glucosyltransferase (GT) and cytochrome P450 in Streptomyces chromofuscus to generate structurally and functionally diverse herboxidiene derivatives, thereby achieving structural diversification. The success of this attempt confirms that the strain can heterologously express exogenous polyketide synthase (PKS) or PKS post-modification genes, laying the foundation for the generation of novel or hybrid polyketide compounds. [1]

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Six structurally related antitumor antibiotics were isolated from the culture medium of Streptomyces sp. and named GEX1 compounds. GEX1A was identified as the known herbicide herboxidiene, characterized by a tetrahydropyran moiety and a side chain containing a conjugated diene. GEX1Q1 to Q5 were identified as novel compounds related to herboxidiene. All GEX1 compounds showed cytotoxicity against human tumor cell lines in vitro, with IC50 values ranging from 0.0037 to about 0.99 μM, but no activity against Gram-positive or Gram-negative bacteria. Although GEX1A/herboxidiene showed antitumor activity in a mouse tumor transplantation model, GEX1Q3 and GEX1Q5 did not show antitumor activity. [2]

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Herboxidiene, a novel polyketide compound, was discovered from an actinomycete identified as a member of the genus Streptomyces chromofuscus during microbial fermentation broth screening for hericidal activity. Herboxidiene fermentation yield was increased 14 to 20 times through culture medium optimization. Herboxidiene was purified by sequential reversed-phase C18 column chromatography and Sephadex LH-20 column chromatography. Its molecular formula, C25H42O6, was determined by high-resolution fast atom bombardment mass spectrometry (HRFAB-MS). Herboxidiene exhibited exceptionally potent and selective hericidal activity against a variety of weeds, even at application rates up to 5.6 kg/ha, without effect on wheat. [3]

C25H42O6

438.60

438.298

C, 68.46; H, 9.65; O, 21.89

142861-00-5

6438496

White to yellow solid powder

1.056g/cm3

567.9ºC at 760 mmHg

181.9ºC

2.92E-15mmHg at 25°C

1.497

4.362

2

6

11

31

658

9

O1[C@]([H])([C@]([H])(C([H])([H])[H])[C@]([H])([C@@]([H])(C([H])([H])[H])O[H])OC([H])([H])[H])[C@@]1(C([H])([H])[H])C([H])([H])[C@@]([H])(/C(/[H])=C(\[H])/C(/[H])=C(\C([H])([H])[H])/[C@]1([H])[C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[C@]([H])(C([H])([H])C(=O)O[H])O1)C([H])([H])[H]

ISZXEMUWHQLLTC-LSIVYLFASA-N

InChI=1S/C25H42O6/c1-15(14-25(6)24(31-25)18(4)23(29-7)19(5)26)9-8-10-16(2)22-17(3)11-12-20(30-22)13-21(27)28/h8-10,15,17-20,22-24,26H,11-14H2,1-7H3,(H,27,28)/b9-8+,16-10+/t15-,17+,18-,19-,20-,22-,23-,24-,25-/m1/s1

2-[(2R,5S,6S)-6-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R,4R)-4-hydroxy-3-methoxypentan-2-yl]-2-methyloxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-5-methyloxan-2-yl]acetic acid

GEX1A; Tan1609; Tan-1609; Herboxidiene; 142861-00-5; QSB7EM5EUD; 2-[(2R,5S,6S)-6-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R,4R)-4-hydroxy-3-methoxypentan-2-yl]-2-methyloxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-5-methyloxan-2-yl]acetic acid; TAN 1609; GEX1A compound; (+)-Herboxidiene; UNII-QSB7EM5EUD; Tan 1609; Herboxidiene

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)