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Erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivatives, and preparation method and application thereof

A technology of boron-fluorodipyrrole conjugates and dipyrrole-fluoroborate, which is applied in the field of dipyrrole-fluoroborate derivatives, can solve problems such as weak tissue penetration ability, skin phototoxicity, and uncertain composition of photosensitizers, and it is not easy to achieve Effects of skin phototoxicity, enhanced selective uptake, and low cost

Inactive Publication Date: 2015-03-04
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Porphyrin, chlorophyll, hypocrellin, etc. are traditional photosensitizers. The composition of these photosensitizers is uncertain, the maximum absorption wavelength is near the short wavelength, and the tissue penetration ability is weak. Photodynamic therapy is likely to cause skin phototoxicity. Not an ideal photosensitizer

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) P-Hydroxybenzaldehyde (2.50 g, 20 mmol), compound (7.00 g, 25 mmol) and K 2 CO 3 (8.28 g, 60 mmol) dissolved in 20 mL DMF, N 2 React overnight at 90°C under protection. After the reaction was completed, the DMF was removed by rotary evaporation, and water was added with CH 2 Cl 2 (3×50 mL) extracted three times, combined the organic layers and washed with anhydrous Na 2 SO 4 After drying and concentrating by rotary evaporation under reduced pressure, the 2 Cl 2 As the eluent, the compound 1 was obtained as light yellow viscous liquid by silica gel column chromatography: (5.80 g, 95%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.98 (s, 1 H, CHO), 7.82 (d, J = 8.4 Hz, 2 H, ArH), 7.02 (d, J = 8.4 Hz, 2 H, ArH), 4.22 (t, J = 4.8 Hz, 2 H, OCH 2 ), 3.90 (t, J = 4.8 Hz, 2 H, OCH 2 ), 3.67-3.76 (m, 6 H, OCH 2 ), 3.38 (t, J = 4.8 Hz, 2 H, CH 2 N); 13 C NMR (100.6 MHz, CDCl 3 ): δ 190.44 163.61, 131.62, 129.79, 114.65, 70.60, 70.40, 69.79, 69.24, 67.54, 50.39;...

Embodiment 2

[0042] (1) Compound (10.2 mg, 0.1 mmol) and compound 2 (113 mg, 0.1 mmol) in a molar ratio of 1:1, added to 7 mL CHCl 3 , ethanol and water mixture, in which CHCl 3 -EtOH-H 2 O (12:1:1, v / v / v, 7 mL), stir well and add crushed CuSO 4 ·5H 2 O (15 mg, 0.06 mmol) and sodium ascorbate (24 mg, 0.12 mmol) powder were stirred for 24 h in the dark; 2 Cl 2 and water extraction; organic layer with anhydrous Na 2 SO 4 After drying, spin dry under reduced pressure; then use dichloromethane-methanol 20:1 as the eluent, and separate by silica gel column chromatography to obtain the green compound: (66 mg, 80%).

[0043] 1 H NMR (400 MHz, CDCl 3 ): δ 8.13 (d, J = 16.8 Hz, 2 H, CH=CH), 8.04 (s, 1 H, triazole-H), 7.60 (d, J = 8.8 Hz, 4 H, ArH), 7.59 (d, J = 16.8 Hz, 2 H, CH=CH), 7.40 (d, J = 7.2 Hz, 2 H, ArH), 7.30-7.22 (m, 3 H, ArH), 7.17 (d, J = 8.8 Hz, 2 H, ArH), 7.04 (d, J = 8.8 Hz, 2 H, ArH), 6.97 (d, J = 8.4 Hz, 4 H, ArH), 4.20 (t, J = 4.8 Hz, 4 H, OCH 2 ), 3...

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Abstract

The invention discloses erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivatives, and a preparation method and application thereof. According to the invention, erlotinib which is a listed small-molecule inhibitor is used as a tumor target and is covalently connected to a 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene photosensitizer capable of being used for photodynamic therapy by the click reaction so as to obtain third-generation anti-tumor photosensitizers capable of being used for targeted therapy, namely, a double-erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivative and a single-erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivative. Meanwhile, by using the erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivatives as research objects and respectively using human body hepatoma carcinoma cells HepG2 and HELF (Human Embryonic Lung Fibroblast) as tested cell strains, research on in vitro anti-tumor activity of the erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivatives is developed, a prodrug suitable for molecular targeted therapy is screened out and the foundation is laid for application of the erlotinib modified 4-difluoro-4-borata-3a-azonia-4a-aza-s-indacene derivatives to targeted therapy of cancers. A synthetic method of the derivatives is simple; raw materials of the derivatives are easy to obtain and low in cost, have few side effects and high yield, are easy to purify and are beneficial to industrial production.

Description

technical field [0001] The invention belongs to the field of design and synthesis of anticancer drugs, and in particular relates to erlotinib-modified fluborordipyrrole derivatives and their preparation and application. Background technique [0002] Tumor is one of the diseases with the highest mortality rate in the world. Photodynamic therapy (PDT) is a new type of medical technology, which has shown unique advantages in the treatment of tumor and non-tumor diseases, and has attracted extensive attention from researchers. . The photosensitizer is a key factor affecting the effect of photodynamic therapy, which can be selectively enriched in tumor tissue, reduce damage to surrounding normal tissues, and produce ideal biological effects. Porphyrin, chlorophyll, hypocrellin, etc. are traditional photosensitizers. The composition of these photosensitizers is uncertain, the maximum absorption wavelength is near the short wavelength, and the tissue penetration ability is weak. P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K41/00A61K47/48A61P35/00
Inventor 刘见永卢源朱春晖叶发荣薛金萍
Owner FUZHOU UNIV
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