Beta-elemene derivative with HDACi pharmacophore as well as preparation method and application of beta-elemene derivative

A derivative and pharmacophore technology, applied in the field of beta-elemene derivatives and their preparation, can solve the problems of designing and synthesizing a single anti-tumor molecule, etc.

Pending Publication Date: 2022-06-07
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many research reports on the structural modification of β-elemene, there are no reports on the design and synthesis of a single anti-tumor molecule (ie fusion drug) based on the synergistic effect of β-elemene in combination with other anticancer drugs.

Method used

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  • Beta-elemene derivative with HDACi pharmacophore as well as preparation method and application of beta-elemene derivative
  • Beta-elemene derivative with HDACi pharmacophore as well as preparation method and application of beta-elemene derivative
  • Beta-elemene derivative with HDACi pharmacophore as well as preparation method and application of beta-elemene derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: Preparation of Compound 1

[0067]

[0068] Intermediate 1a

[0069] To a solution of β-elemene (210 mg, 1.029 mmol) in acetic acid (3 mL) under ice bath was added N-bromosuccinimide (NBS, 183 mg, 1.029 mmol). Stir under ice bath condition for 6h. TLC monitoring that the raw materials were not completely reacted, so the reaction solution was warmed to room temperature and stirred overnight (25-28°C). After complete conversion, saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate (3×5 mL). The combined organic phases were washed with saturated brine (2×5 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: n-hexane) to obtain colorless oily liquid 1a (72 mg, yield 25.4%). 1 ...

Embodiment 2

[0080] Example 2: Preparation of Compound 2

[0081]

[0082] Referring to the synthesis method of intermediate 1d in Example 1, compound 2b (252 mg, yield 70.9%) was obtained.

[0083] Referring to the synthesis method of intermediate 1e in Example 1, compound 2c (130 mg, 80.1%) was obtained.

[0084] Referring to the synthesis method of the last step in Example 1, colorless oily liquid 2 was obtained, yield: 58.9%. 1 HNMR (500MHz, CDCl 3 )δ6.35(s, 1H), 5.80(dd, J=17.7, 10.5Hz, 1H), 4.95-4.87(m, 3H), 4.86(s, 1H), 4.82(t, J=1.7Hz, 1H) ),4.57(d,J=1.9Hz,1H),3.85(d,J=5.6Hz,2H),2.29-2.11(m,4H),2.04-1.90(m,2H),1.70(s,3H) , 1.68-1.53(m, 5H), 1.52-1.40(m, 3H), 1.40-1.24(m, 4H), 0.99(s, 3H). 13 C NMR (126MHz, CDCl 3 )δ173.67,171.44,150.52,149.99,147.40,112.27,110.06,108.32,52.67,43.00,42.72,39.85,39.77,36.16,33.11,32.36,27.20,25.08,16.6.89,244 LCMS[M+H] + :377.2.

Embodiment 3

[0085] Example 3: Preparation of Compound 3

[0086]

[0087] Referring to the synthesis method of intermediate 1d in Example 1, compound 3b (216.4 mg, yield 77%) was obtained. 1 HNMR (400MHz, CDCl 3 )δ8.90(s,1H),4.95(s,1H),3.97(t,J=10.2Hz,1H),3.65(dd,J=10.9,5.4Hz,1H),2.34(t,J=7.4 Hz, 2H), 2.12 (t, J=7.4Hz, 2H), 1.91-1.74 (m, 3H), 1.63 (ttd, J=18.5, 13.0, 11.4, 5.6Hz, 7H), 1.35 (p, J= 3.9Hz, 4H).

[0088] Referring to the synthesis method of intermediate 1e in Example 1, compound 3c (140 mg, 80.1%) was obtained.

[0089] Referring to the synthesis method of the last step in Example 1, the difference is that the obtained crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:9) to obtain rust red oily compound 3 (59.6 mg, yield 72.3%) ). 1 H NMR (500MHz, CDCl 3 )δ6.35(s,1H),5.80(dd,J=17.7,10.5Hz,1H),5.00-4.79(m,5H),4.57(s,1H),3.85(d,J=5.6Hz,2H ), 2.23(t, J=7.2Hz, 2H), 2.16(s, 2H), 2.05-1.89(m, 2H), 1.70(s, 3H), 1.69-1.22(m, 14H), 0....

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Abstract

The invention discloses a beta-elemene derivative with an HDACi pharmacophore as well as a preparation method and application of the beta-elemene derivative. The invention provides a beta-elemene derivative with an HDACi pharmacophore as shown in a formula (I), a pharmaceutical composition containing the compound as shown in the formula (I), a hydrate containing the compound as shown in the formula (I), and isotope derivatives, chiral isomers, allosteric substances, different salts, prodrugs, preparations and the like of the compounds. The invention also provides a preparation method and application of the beta-elemene derivative with the HDACi pharmacophore, and the activity of the compounds for inhibiting proliferation of various tumor cell strains. The beta-elemene derivative with the HDACi pharmacophore is expected to become an anti-tumor candidate drug for treating various cancers, such as solid tumors and hematoma.

Description

technical field [0001] The invention belongs to the technical field of preparation of beta-elemene derivatives, in particular to beta-elemene derivatives with HDACi (histone deacetylase inhibitor) pharmacophore, and a preparation method and application thereof. Background technique [0002] Elemene is a sesquiterpenoid extracted and isolated from the ginger plant, Turmeric, and has broad-spectrum antitumor activity. At present, elemene oral emulsion / injection has been approved by the state as a new class II anticancer drug, and has been widely used in clinical practice. However, because its structure only contains two elements, carbon and hydrogen, it belongs to terpenoid volatile oil. largest application. Therefore, it is very necessary to modify the structure of (-)-β-elemene, the main active ingredient in elemene, to improve water solubility, increase biological activity and bioavailability, and enhance clinical antitumor efficacy. [0003] According to literature repo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/06C07D295/185C07D487/04C07D205/04C07D211/58C07D209/52C07D231/12C07D403/08C07D401/08C07D401/12C07D213/74C07D295/155C07D213/78A61P35/00A61P35/02A61K31/44A61K31/4439A61K31/415A61K31/496A61K31/454A61K31/4468A61K31/397A61K31/403A61K31/407A61K31/495A61K31/16
CPCC07C259/06C07D295/185C07D487/04C07D205/04C07D211/58C07D209/52C07D231/12C07D403/08C07D401/08C07D401/12C07D213/74C07D295/155C07D213/78A61P35/00A61P35/02C07C2601/14
Inventor 谢恬叶向阳高园卓晓韬何兴瑞白仁仁党夏雯叶杨罗欣雨向欢林颖
Owner HANGZHOU NORMAL UNIVERSITY
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