Squaramide-bisbenzimidazole conjugates with pH-dependent anion transmembrane transport activity, and methods for their synthesis

A technology of bisbenzimidazole and transmembrane transport, applied in the fields of drug combination, organic chemistry, antitumor drugs, etc., can solve the problems of large molecular weight, complex drug synthesis, low antitumor activity, etc., and achieve the effect of promoting transmembrane transport

Active Publication Date: 2022-03-22
WUYI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some innovative drugs have been developed to take advantage of the low pHe value outside the tumor cells for drug delivery to specific sites, such as nanogels, polymersomes and micelles, etc., most of the drugs are more complicated to synthesize, have larger molecular weights, and Can only help to improve the enrichment of existing drugs in tumor cells, with low anti-tumor activity

Method used

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  • Squaramide-bisbenzimidazole conjugates with pH-dependent anion transmembrane transport activity, and methods for their synthesis
  • Squaramide-bisbenzimidazole conjugates with pH-dependent anion transmembrane transport activity, and methods for their synthesis
  • Squaramide-bisbenzimidazole conjugates with pH-dependent anion transmembrane transport activity, and methods for their synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] This embodiment provides the synthesis of compound 14-26

[0044]

[0045] Compound 14: Weigh N-Boc-gly (805mg, 4.59mmol), EDC (1.77g, 9.23mmol), HOBt (936mg, 6.92mmol) and DMAP (30mg, 0.24mmol) into a 100mL reaction flask, and use CH 2 Cl2 (40mL) dissolved;

[0046] After stirring at room temperature for 10 min, the mixture was transferred to a dropping funnel, and slowly (1 drop / 6s) was added dropwise to a solution of o-phenylenediamine (500 mg, 4.62 mmol) and DMF (1.5 mL);

[0047] The resulting mixed solution was stirred and reacted at room temperature for 3 days. After the mixed solution was removed under reduced pressure, ethyl acetate (20 mL) was added, and saturated NaCl aqueous solution (20 mL×2), saturated NH 4 Cl aqueous solution (20mL×2) and saturated NaHCO 3 After washing with aqueous solution (20 mL×2), it was washed with saturated aqueous NaCl solution (20 mL). use Na 2 SO 4 After drying, ethyl acetate was removed under reduced pressure;

[0048]...

Embodiment 2

[0062] This example provides the synthesis of compounds 27-29

[0063]

[0064] Compound 27: Weigh compound 14 (60mg, 0.24mmol) in a 25mL reaction vial, 3After OH (3 mL) was dissolved, HCl (2M, 3 mL) was added and stirred at room temperature for 1 h. After the solvent was removed under reduced pressure, aqueous ammonia (3 mL×2) was added to the reaction flask, stirred at room temperature for 15 min, and then the aqueous ammonia was removed under reduced pressure. Add methanol (2mL) to dissolve, separate by column chromatography (dichloromethane / methanol / ammonia, 24 / 3 / 1, v / v / v), and freeze-dry to obtain compound 27 (39mg, 45%). 1 H NMR (500 MHz, MeOD) δ 7.54 (dd, J=6.0, 3.2 Hz, 2H), 7.22 (dd, J=6.0, 3.2 Hz, 2H), 4.05 (s, 2H).

[0065] Compound 28: Synthesized similarly to Compound 27, 40 mg, 72%. 1 H NMR (CD 3 OD, 400MHz) δ7.30(d, J=8.2Hz, 1H), 7.21(s, 1H), 6.95(d, J=8.2Hz, 1H), 3.91(s, 2H), 2.34(s, 3H) .

[0066] Compound 29: Synthesized similarly to Compound 27, 55 m...

Embodiment 3

[0078] Synthesis of compounds 1-13

[0079]

[0080] Compound 1: Dissolve compound 27 (39 mg) in ethanol (3 mL), then add triethylamine (300 μL), react at room temperature for 30 minutes, add 3,4-diethoxy Cyclobut-3-ene-1,2-dione (21 mg, 0.12 mmol) in ethanol (270 μL). After reacting at room temperature for 23 h, suction filtration under reduced pressure gave a white solid, compound 1 (12 mg, 31%). 1 H NMR (DMSO-d 6 , 400MHz, see figure 1 )δ12.57(s,2H),8.25(s,2H),7.54(s,4H),7.19(s,4H),5.03(s,4H); 13 C NMR (DMSO-d 6 ,100MHz)δ183.4,168.2,151.9,122.2,115.9,115.4; negative ESI-MS: m / z 371.07 ([M-H] – ) and negative HR-ESI-MS for C 20 h 16 N 6 o 2 ([M-H] – ) Calcd: 371.12510, Found: 371.12570.

[0081] Compound 2: Synthesized similarly to Compound 1, 35 mg, 79%. 1 H NMR (DMSO-d 6 , 400MHz, see figure 2 )δ12.33(s,2H),8.21(s,2H),7.51–7.20(m,4H),7.00(s,2H),4.99(s,4H),2.40(s,6H); 13 CNMR (DMSO-d 6 ,100MHz) δ183.3, 168.2, 132.3, 111.5, 21.6; negativeESI-MS: m / z 399.0...

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Abstract

The present invention relates to a square amide-bisbenzimidazole conjugate with pH-dependent anion transmembrane transport activity and a synthesis method thereof. The present invention designs and synthesizes 13 square amide-bisbenzimidazole conjugates. The invented and synthesized square amide-bisbenzimidazole conjugate has moderate affinity for chloride ions, and promotes the transmembrane transport of chloride ions through an anion exchange mechanism. The chloride ion concentration of each conjugate under acidic pH conditions The transport activities were all higher than those at physiological pH, and the synthesized conjugates also showed moderate toxicity to selected solid tumor cells.

Description

technical field [0001] The invention relates to the field of potential anti-tumor small molecule drugs, in particular to a square amide-bisbenzimidazole conjugate with pH-dependent anion transmembrane transport activity and a synthesis method thereof. Background technique [0002] Cells are the smallest functional units of organisms. The balance of anions inside and outside the cells is the premise for cells to maintain their physiological functions. If the balance of anions is broken, the cells will die. [0003] Chloride is the most abundant anion in extracellular fluid. Under the regulation of chloride ion channels on the cell membrane, the concentration of chloride ion inside and outside the cell is 4-60mM and 120mM respectively. Abnormal function of anion transporters or mutations in genes related to chloride transporters can lead to various life-threatening conditions such as myotonia congenita, cystic fibrosis, Bartter syndrome, Gitelman syndrome, Dent's disease, re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/14A61P35/00
CPCC07D235/14A61P35/00
Inventor 王忠堃陈文华
Owner WUYI UNIV
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