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Novel carbonic anhydrase IX targeted photosensitizer and application thereof in field of medicine

A kind of technology of pheophorbide and chlorophyllin

Pending Publication Date: 2022-04-12
SHANGHAI XIANHUI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Xu Deyu, Zhang Hao and others in our team developed hematoporphyrin monomethyl ether (Chinese Journal of Pharmaceutical Industry, 1989, 20(2): 60-63), also known as Hemoporfin (HMME, Hemoporfin), and its compound composition is clear , short light-proof period after administration and other obvious advantages, becoming the first photosensitive drug in the country to treat port wine stains (Chinese Journal of Laser Medicine, 2018, 27(1): 01-05), but hematoporphyrin monomethyl ether still exists The composition is a pair of isomers, the structure is not very stable and other disadvantages
[0004] Most current PDT drugs mainly work through an oxygen-dependent type II mechanism, which leads to severe intratumoral hypoxia
This in turn limits the therapeutic effect of photodynamic therapy
PDT-induced hypoxia may result from direct oxygen consumption by photosensitizers or indirectly through degeneration of the vasculature

Method used

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  • Novel carbonic anhydrase IX targeted photosensitizer and application thereof in field of medicine
  • Novel carbonic anhydrase IX targeted photosensitizer and application thereof in field of medicine
  • Novel carbonic anhydrase IX targeted photosensitizer and application thereof in field of medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl) pyropheophytin (I):

[0037]

[0038]Add pyropheophorbide-a (107 mg, 200 μmol) and 40 mL of anhydrous acetonitrile into a round bottom flask, then add 1,3,4-thiadiazole-2-sulfonamide (52 mg, 240 μmol), and then add three Ethylamine (0.1 mL, 800 μmol), stirred at room temperature for 30 min. Finally, HATU (56 mg, 240 μmol) was added, and the reaction was stirred at room temperature for 16 h. After the completion of the reaction was monitored by TLC, 100-200 mL of saturated sodium chloride solution was added, and then 2M HCl solution was added to adjust the pH to acidity. Then it was extracted with ethyl acetate (100 mL×3) and washed with water. The organic phase was collected and washed with anhydrous Na 2 SO 4 Dry, filter, and evaporate the solvent under reduced pressure. The obtained residue was separated and purified by column chromatography to obtain compound I (74 mg, 53%) as a green solid powder. 1 H NMR ...

Embodiment 2

[0040] N-[2-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl]pyropheophytin (II 1 ) preparation:

[0041]

[0042] Compound II was prepared by the synthetic method of compound I 1 . 1 H NMR (400MHz, DMSO-d 6 )δ: 13.10(s,1H), 9.74(s,1H), 9.46(s,1H), 8.92(s,1H), 8.38(s,1H), 8.30(s,2H), 8.29–8.17(m ,1H),6.40(d,J=17.8Hz,1H),6.22(d,J=11.6Hz,1H),5.25(d,J=20.2Hz,1H),5.13(d,J=20.1Hz,1H ),4.61(d, J=7.6Hz,1H),4.35(s,1H),4.06(s,2H),3.80–3.66(m,2H),3.63(s,3H),3.45(s,3H) ,3.23(s, 3H),2.67(s,1H),2.33(s,1H),2.20(s,2H),1.80(d,J=7.3Hz,3H),1.64(d,J=7.5Hz, 3H),0.28(s,1H),-1.94(s,1H). 13 C NMR (151MHz, DMSO-d 6 )δ:195.28,172.76,172.13,170.01,164.03, 161.43,153.69,149.61,147.81,144.24,140.57,136.88,135.49,134.96,134.66,131.50,128.91, 127.50,122.52,105.87,103.63,96.11,93.61,51.23 , 49.38, 47.55, 42.50, 32.29, 30.21, 22.90, 18.38, 17.33, 11.93, 11.52, 10.59. HRMS (MALDI-TOF) m / z: calcd for C 37 h 40 N 9 o 5 S 2 [M] + 754.25883, found 754.25598.

Embodiment 3

[0044] N-[3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino)-3-oxopropyl]pyropheophytin (II 2 ) preparation:

[0045]

[0046] Compound II was prepared by the synthetic method of compound I 2 . 1 H NMR (600MHz, DMSO-d 6 )δ: 13.00(s,1H), 9.65(s,1H), 9.38(s,1H), 8.88(s,1H), 8.27(s,2H), 8.18(dd,J=17.8,11.6Hz,1H ),8.07(s,1H), 6.36(d,J=17.9Hz,1H),6.19(d,J=11.6Hz,1H),5.21(s,1H),5.13(s,1H),4.53(d ,J=7.7Hz, 1H), 4.25(d, J=8.9Hz, 1H), 3.64(d, J=8.1Hz, 2H), 3.59(s, 3H), 3.42(s, 3H), 3.41(s ,1H),3.17(s,3H),2.68(d,J=7.2Hz,2H),2.61(q,J=5.5,4.9Hz,1H),2.38(s,2H),2.12-2.08(m, 2H), 1.74 (d, J=7.4Hz, 3H), 1.59(s, 3H), 0.18(s, 1H), -2.03(s, 1H). 13 C NMR (151MHz, DMSO-d 6 )δ: 195.30,172.07,170.73,164.29,161.46,161.12,147.82,144.34,140.57,136.95,135.59,134.71, 131.52,128.92,122.57,105.89,103.76,96.20,93.63,51.19,49.40,47.52,35.26,34.54 , 32.32, 30.21, 22.83, 18.40, 17.34, 11.92, 11.52, 10.61. HRMS (MALDI-TOF) m / z: calcd for C 38 h 42 N 9 o 5 S 2 [M] + 768.27448,found 768.27272.

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Abstract

The invention relates to novel pyropheophorbide amide derivatives (I, II and III) targeting carbonic anhydrase IX and application of the novel pyropheophorbide amide derivatives (I, II and III) in the field of medicines. The compounds have the following structures: the invention relates to the field of photosensitive medicines and photodynamic therapy, and particularly relates to novel pyropheophorbide amide derivatives (I, II and III). In particular to a novel pyropheophorbide amide derivative targeting carbonic anhydrase IX and application of the pyropheophorbide amide derivative in the field of medicine. The compound prepared by the invention is single in component, stable in property, controllable in quality, simple and convenient in preparation method and relatively good in photodynamic activity, and can be used as a photodynamic therapeutic drug for diseases such as tumors, retina macular degeneration, actinic keratosis, nevus flammeus and condyloma acuminata.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, relates to photosensitizer medicine and photodynamic therapy, in particular to a novel carbonic anhydrase IX (CAIX) targeted photosensitizer and its application in the medical field. Background technique [0002] Photodynamic therapy (Photodynamic Therapy, PDT) is a light-activated photosensitizer-based treatment method, which has been identified as a safe mode of ablation for a variety of tumors (NatRev Clin Oncol, 2020, 17, 657-674). Efficient light on enables highly controllable and minimally invasive treatments in space and time. In current clinical PDT, light-excited photosensitizers generate cytotoxic free radicals by interacting with bioactive molecules (type I mechanism), or in type II mechanisms, convert ground-state oxygen ( 3 o 2 ) directly into highly reactive cytotoxic excited state singlet oxygen ( 1 o 2 ). PDT can not only directly kill tumor cells, but also cau...

Claims

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Application Information

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IPC IPC(8): C07D487/22A61K41/00A61P35/00A61P27/02A61P17/00A61P17/12A61P31/14
Inventor 陈志龙王锋严懿嘉许淘梁宏玉江颖陈婷
Owner SHANGHAI XIANHUI MEDICAL TECH
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