Analogue of Nanocystin A as well as preparation method and application of analogue

A technology of analogues and compounds, applied in the field of analogues of NannocystinA and its preparation, can solve the problems of limited natural product sources and difficulty in obtaining sufficient quantities of compounds, and achieve the effects of simple structure, short synthetic route and high target yield

Inactive Publication Date: 2021-02-05
PEKING UNIV SHENZHEN GRADUATE SCHOOL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In addition, since Nannocystin A is a natural product, but the source of natural products is relatively limited, it is difficult to obtain a sufficient amount of the compound through separation and extraction for subsequent pharmacological and toxicological studies

Method used

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  • Analogue of Nanocystin A as well as preparation method and application of analogue
  • Analogue of Nanocystin A as well as preparation method and application of analogue
  • Analogue of Nanocystin A as well as preparation method and application of analogue

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preparation example Construction

[0048] Therefore, based on the above-mentioned retrosynthetic analysis, the preparation method process of the analogue of Nannocystin A in the above invention embodiment is as follows figure 1 shown, including the following steps:

[0049] S01: Compound A is subjected to the first deprotection group reaction to remove -TBS group and -TMSE group to generate compound B;

[0050] S02: performing a first amidation reaction on compound B and compound C in step S01 to generate ring-closing precursor D;

[0051] S03: performing a Suzuki coupling reaction on the ring-closing precursor D to generate a target product I; wherein the target product I is an analog of Nannocystin A according to any one of claims 1-4;

[0052] According to the preparation method of the analogue of above-mentioned Nannocystin A, its synthetic route is as follows:

[0053]

[0054] Wherein, the first deprotection group reaction in step S01 can follow the method of removing -TBS group (tert-butyldimethylsi...

Embodiment 1

[0084] The embodiment of the present invention provides an analogue of Nannocystin A and a preparation method thereof. Wherein, the molecular structural formula of the analogue of Nannocystin A is shown in the following Ia.

[0085] The analog Ia preparation method of the Nannocystin A comprises the following steps:

[0086] S1. Synthesis of compound 9a:

[0087]

[0088] At 0°C, compound 6 (268 mg, 0.96 mmol) was dissolved in DCM (6 mL), and PyAOP (834 mg, 1.6 mmol) and DIPEA (0.7 mL, 4.0 mmol) were gradually added to the reaction system. The fully deprotected acid (0.8 mmol) was then dissolved in DCM (2 mL) and added to the reaction. The reaction was warmed to room temperature and stirring was continued for 12 hours. saturated NH 4 Cl solution (20 mL) quenched the reaction. Repeated extraction with ethyl acetate (3 x 30 mL). The combined organic phases were sequentially washed with saturated NaHCO 3 solution (30mL) and saturated brine (30mL), washed with anhydrous ...

Embodiment 2

[0101] The embodiment of the present invention provides an analogue of Nannocystin A and a preparation method thereof. Wherein, the molecular structural formula of the analogue of Nannocystin A is shown in Ib below.

[0102] The analog Ib preparation method of the Nannocystin A comprises the following steps:

[0103] S1. Synthesis of compound 5b':

[0104]

[0105] Paraformaldehyde (2.6g, 29.3mmol) and p-toluenesulfonic acid (77.5mg, 0.45mmol) were sequentially added to a toluene solution (45mL) of compound 13 (2g, 4.5mmol), and heated to reflux for 4 hours. After the reaction was complete, it was cooled to room temperature and extracted repeatedly with ethyl acetate (3 x 30 mL). Combine the organic phases and wash with NaHCO 3 Saturated solution (30mL) washed, anhydrous Na 2 SO 4 dry. After spin-drying, put it directly into the next step of reaction;

[0106] The obtained five-membered ring compound (1.5g, 3.3mmol) was dissolved in DCM (10mL), TFA (5.4mL, 72.6mmol) ...

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Abstract

The invention discloses an analogue of Nannocystin A as well as a preparation method and application of the analogue. The analogue of the Nanocystin A has a molecular structural formula as shown in ageneral formula I in the specification, wherein R in the general formula I is arbitrary one of -H, C1-C15 alkyl, aryl, C1-C15 alkoxy, halogen, hydroxyl, amino, nitro, cyano and sulfydryl. The analogueof Nannocystin A has a simple structure, has a biological effect of inhibiting the activity of cancer cells, and can optimize the biological activity of Nannocystin A by regulating the variety of R contained in Nannocystin A. The analogue of the Nannocystin A further confirms the structure-activity relationship, and lays an excellent foundation for searching compounds with better anti-cancer activities. The preparation method has a short synthesis circuit, high target yield and few byproducts.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and medicinal chemistry, and in particular relates to an analog of Nannocystin A and its preparation method and application. Background technique [0002] In 2015, Mark Bronstrup (Holger Hoffmann, et al. Angew. Chem. Int. Ed. 2015, 54, 10145-10148) and others isolated a macrocyclic lipopeptide compound Nannocystin from myxobacterial genus, Nannocystis sp. A, The molecule has a novel 21-membered ring backbone containing a tripeptide and a polyketide segment with epoxyamide. In September 2016, our research group (Tao Ye, etal. Angew. Chem. Int. Ed. 2016, 55, 13263–13266) completed the first total synthesis of this molecule. [0003] In terms of biological activity testing, the article shows that Nannocystin A not only has strong antibacterial activity, but also inhibits cell proliferation by inducing apoptosis at the nanomolar level. In July of the same year, Dominic Hoepfner (PhilippKra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/087C07K5/083C07K1/06A61K38/06A61P35/00
CPCC07K5/0812C07K5/0808A61K38/00
Inventor 叶涛郭益安廖林萍廖晓云
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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