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CN-117777214-B - Naphthopyrimidino fused aza-sugar derivative and synthetic method and application thereof

CN117777214BCN 117777214 BCN117777214 BCN 117777214BCN-117777214-B

Abstract

The invention provides a naphthopyrimidine fused aza-azasugar derivative, and a synthetic method and application thereof, and belongs to the technical field of medicines. The naphthopyrimidine fused azasugar derivative has a structure shown in a formula (I) to a formula (IV). The compound is prepared by taking propylene group-protected and p-toluenesulfonylated sugar as a starting material, and carrying out condensation reaction with 1, 8-diaminonaphthalene in an organic solvent under the action of a triflate catalyst to form a ring in one step. The preparation method is efficient and simple. The compound has good activity of resisting proliferation of colon cancer tumor cells.

Inventors

  • CHEN HUA
  • YANG YUPENG
  • WU CHEN
  • XU XIN
  • ZHOU ZIYI

Assignees

  • 河北大学

Dates

Publication Date
20260505
Application Date
20231127

Claims (7)

  1. 1. Naphthopyrimido-fused azasugar derivatives represented by the formula (I) to (IV): 。
  2. 2. The method for synthesizing a naphthopyrimido-fused azasugar derivative according to claim 1, comprising the steps of: The preparation method comprises the steps of taking propylidene-protected p-toluenesulfonylated sugar and 1, 8-diaminonaphthalene as starting materials, dissolving the starting materials in an organic solvent, stirring for reaction under the action of a triflate catalyst, dissolving reaction liquid in an organic alcohol solvent after the reaction is finished, evaporating the solvent under reduced pressure, and separating by column chromatography to obtain compounds shown in formulas (I) - (IV); the synthetic route of the compound shown in the formula (I) is as follows: ; The synthetic route of the compound shown in the formula (II) is as follows: ; Wherein the molar ratio of the compound 1b to the compound 2 is 1:1.2; The synthetic route of the compound shown in the formula (III) is as follows: ; the synthetic route of the compound shown in the formula (IV) is as follows: ; in the synthesis of the compound shown in the formula (I), the formula (III) or the formula (IV), the molar ratio of the compound 1a, the compound 1b or the compound 1c to the compound 2 is 1:0.8.
  3. 3. The method of synthesis according to claim 2, wherein the molar ratio of propylidene-protected and p-toluenesulfonylated saccharide to triflate catalyst is 1:0.1.
  4. 4. The synthetic method according to claim 2, wherein the volume ratio of toluene to methanol in the toluene/methanol mixed solvent is 5:1.
  5. 5. The synthesis method according to claim 2, wherein in the synthesis of the compound represented by the formula (II), the mobile phase of column chromatography is V dichloromethane (dichloromethane) :V Acetic acid ethyl ester = (3-6): 1, and the silica gel column is a 200-300 mesh silica gel column.
  6. 6. The synthesis method according to claim 2, wherein in the synthesis of the compound represented by formula (I), formula (III) or formula (IV), the mobile phase of column chromatography separation is V dichloromethane (dichloromethane) :V methanol = (10-20): 1, and the silica gel column is a 200-300 mesh silica gel column.
  7. 7. Use of a naphthopyrimido-fused azasugar derivative according to claim 1 for the preparation of an anti-colon cancer tumor cell pharmaceutical preparation.

Description

Naphthopyrimidino fused aza-sugar derivative and synthetic method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a naphthopyrimidine fused aza-azasugar derivative, and a synthetic method and application thereof. Background Tumors refer to neoplasms generated by abnormal proliferation of certain cells of organisms under the action of tumorigenic factors, and metastasis and diffusion of malignant tumors are evolved into cancers, so that the tumors become one of the difficult problems puzzling human health in the 21 st century, and therefore, development and application of antitumor drugs are always hot spots for new drug development. The existing antitumor drugs are modified based on natural alkaloids, such as camptothecine, vinblastine, evodiamine and the like, and have good antitumor activity. In recent years, some synthetic nitrogen-containing condensed hetero compounds such as tetrahydroquinoline derivatives, phenanthroline derivatives and the like also have excellent tumor cell inhibitory activity (Noaman, e., et al, eur.j. Med. Chem.,2010,45,1849-1853). Therefore, the nitrogen-containing thick and doped compound with novel and unique structure is designed and synthesized, and research on the proliferation activity of the anti-tumor cells, and has important significance in the research and development of anti-tumor drugs. Azasugars, also known as iminosugars, are sugar compounds obtained by replacing an oxygen atom of an inner ring with a nitrogen atom, and are widely found in plants and microorganisms in nature. Polycyclic (tricyclic or more) fused azasugars are an important branch of azasugars, and the azacyclic ring contained in the azasugars enriches the structure and activity of the azasugars, and the polyhydroxy structure gives the azasugars good water solubility and bioavailability, so that the azasugars are widely focused in the fields of drug synthesis and medicine. The synthesis of polycyclic (tricyclic or higher) fused azasugars has been reported (Baskaran, s., et al, j. Org. Chem.,2018,83,9604-9618), but its antitumor activity has been reported only rarely. Disclosure of Invention The invention aims to provide a naphthopyrimidine fused azasugar derivative, and the chemical structure of the naphthopyrimidine fused azasugar derivative is shown as a formula (I) to a formula (IV): The synthetic method of the naphthopyrimidine fused azasugar derivative comprises the following steps: The preparation method comprises the steps of taking propylidene-protected p-toluenesulfonylated sugar and 1, 8-diaminonaphthalene as starting materials, dissolving the starting materials in an organic solvent, stirring for reaction under the action of a triflate catalyst, dissolving the reaction solution in an organic alcohol solvent after the reaction is finished, evaporating the solvent under reduced pressure, and separating by column chromatography to obtain compounds shown in the formulas (I) - (IV). Preferably, the organic solvent is toluene/methanol mixed solvent or toluene solvent, the triflate catalyst is scandium triflate or nickel triflate, and the organic alcohol solvent is methanol. Preferably, the molar ratio of propylidene-protected and p-toluenesulfonylated saccharide to triflate catalyst is 1:0.1. More preferably, the compound of formula (I) is synthesized by the following route: more preferably, the compound of formula (II) is synthesized by the route: more preferably, the compound of formula (III) is synthesized by the route: more preferably, the compound of formula (IV) is synthesized by the following route: preferably, in the synthesis of the compound shown in the formula (II), the molar ratio of the compound 1b to the compound 2 is 1:1.2. Preferably, in the synthesis of the compound of formula (I), formula (III) or formula (IV), the molar ratio of compound 1a, compound 1b or compound 1c to compound 2 is 1:0.8. Preferably, the volume ratio of toluene to methanol in the toluene/methanol mixed solvent is 5:1. Preferably, in the synthesis of the compound shown in the formula (II), the mobile phase separated by column chromatography is V dichloromethane (dichloromethane) :V Acetic acid ethyl ester = (3-6): 1, and the silica gel column is 200-300 mesh silica gel column. Preferably, in the synthesis of the compound shown in the formula (I), the formula (III) or the formula (IV), the mobile phase of column chromatography separation is V dichloromethane (dichloromethane) :V methanol = (10-20): 1, and the silica gel column is 200-300 mesh silica gel column. The invention also provides application of the naphthopyrimidine fused azasugar derivative in preparing an anti-tumor cell pharmaceutical preparation, in particular application in preparing an anti-colon cancer (HCT 116) tumor cell inhibitor drug. Experiments show that the naphthopyrimidine fused azasugar derivative has good anti-HCT 116 tumor cell proliferation activity.