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Furazan derivative of coumarin parent nucleus and antineoplastic activity

A technology of coumarin and derivatives, which is applied in the direction of antineoplastic drugs, organic active ingredients, drug combinations, etc., can solve the problems of drug resistance, reduced selectivity, and severe toxic and side effects, and achieve the activity inhibition of tumor cells, The effect of novel structure

Active Publication Date: 2015-12-16
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This new compound described by this patented inventive molecule can effectively stop cancer from growing or spreading throughout your body without affecting healthy tissues like skin. It also works well against certain types of drugs that are commonly used with chemotherapy treatments such as alkylating agents (methotrexate) which target DNA replication enzymes involved in cell division process.

Problems solved by technology

The technical problem addressed in this patented text relating to finding novel drugs capable of effectively treating various types of diseased states caused by abnormal regulation mechanisms involving protein targets involved in different functions like inflammation, angiotensisthesis, mitochondrial membrane transport proteins, etc., including those associated with certain enzyme systems called α-,β-coupled receptor families. These agents could potentially lead to improved therapuction strategics against multiple disease conditions.

Method used

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  • Furazan derivative of coumarin parent nucleus and antineoplastic activity
  • Furazan derivative of coumarin parent nucleus and antineoplastic activity
  • Furazan derivative of coumarin parent nucleus and antineoplastic activity

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Experimental program
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Effect test

Embodiment 1

[0046] A compound 4-(4-methyl-2H-chromene-2-dione-7-oxyl group)-3-(benzenesulfonyl)-1,2,5-oxa in compound 6a-c in general formula 2 Synthesis of oxadiazole 2-oxide (6b)

[0047] 7-Hydroxy-4-methyl-coumarin (5b, 300mg, 1.2mmol) and benzenesulfonylfurazan N-oxide (4, 256mg, 1.0mmol) and DBU (2.0mmol) in dichloromethane (6mL ) solvent, react at room temperature for 3 hours; then wash away the DBU with 3×5ml water, distill off the solvent under reduced pressure to obtain an oily liquid. A small amount of methanol was added to precipitate a white solid, which was filtered and recrystallized with ethyl acetate to obtain product 6b (320mg), with a yield of 90% and a melting point of 201-203°C. ESI-MSm / z 401.0[M+H] + ; 1 HNMR (400MHz, CDCl 3 )δ2.46(s,CH 3 C=),6.32(s,1H,-CH 3 C=CHCOO), 7.31(m, 2H, ArH), 7.68(m, 3H, ArH), 7.81(t, 1H, ArH, J=6.4Hz), 8.10(d, 2H, ArH, J=7.48Hz) .

Embodiment 2

[0049] Compound 4-(2-ethyl-4H-chromene-4-one-7-oxyl group)-3-(benzenesulfonyl)-1,2,5-oxadiazole 2-oxide ( 15) Synthesis of

[0050] 7-Hydroxy-2-ethyl-coumarin (14, 300mg, 1.2mmol) and benzenesulfonylfurazan N-oxide (4, 256mg, 1.0mmol) and DBU (2.0mmol) in dichloromethane (6mL ) solvent, react at room temperature for 3 hours; then wash away the DBU with 3×5ml water, distill off the solvent under reduced pressure to obtain an oily liquid. A small amount of methanol was added, and a white solid was precipitated. After filtration, it was recrystallized with ethyl acetate to obtain product 15 (280 mg). The yield is 89%, and the melting point is 159-161°C. ESI-MSm / z415.0[M+H] + ; 1 HNMR (400MHz, CDCl 3 )δ1.32(t,3H,CH 2 CH 3 , J=7.56Hz), 2.47(q,2H,CH 2 CH 3, J=7.56Hz), 6.21(s, 1H, OC=CH), 7.32(dd, 1H, ArH, J=8.80, 2.36Hz), 7.46(d, 1H, ArH, J=2.32Hz), 7.66( t,2H,ArH,J=8.28Hz),7.81(t,1H,ArH,J=7.56Hz),8.08(dd,2H,ArH,J=1.28,8.48Hz),8.27(d,1H,ArH, J = 8.80 Hz).

Embodiment 3

[0052] Synthesis of a compound 4-methyl-7-hydroxyethylamino-coumarin (7g) in compound type 7a-g in general formula two

[0053] Starting material 4-methyl-7-amino-coumarin (5e, 300mg, 1.56mmol), 2-bromoethanol (975mg, 7.80mmol), potassium carbonate (372mg, 4.68mmol) and potassium iodide (51mg, 0.31mmol) were dissolved In acetone (10 mL), reflux reaction for 10 hours, after filtration, the solvent was distilled off under reduced pressure, separated and purified by chromatography to obtain 7 g (212 mg) of a light yellow solid product, with a yield of 40%. ESI-MSm / z220.1[M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ7.40 (d, 1H, ArH, J = 8.7Hz), 6.61 (dd, 1H, ArH, J = 8.7, 1.7Hz), 6.41 (d, 1H, ArH, J = 1.7Hz), 5.89(s, 1H, -CH=), 3.54(t, 2H, -OCH 2 CH 2 O-,J=5.8Hz),3.19–3.10(m,2H,-OCH 2 CH 2 O-),2.28(s,3H,-CH 3 ).

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a furazan derivative which is prepared by combining a coumarin parent nucleus and an isomer of the coumarin parent nucleus with a furazan oxide through linking of groups with different lengths and structures. It is proved by the experiments that the furazan derivative has excellent effects on inhibiting sensitive human tumour cells and drug-resistant tumor strains, and on inhibiting activity of normal growth of HUVEC for measuring an inhibiting action of neovascularization, and on inhibiting activity of cell proliferation of cis-platinum-resistant A2780 cell strains and gemcitabine-resistant HM231 cell strains. It is shown by an initial pharmacological mechanism that by releasing nitric oxide with the high concentration, the furazan derivative can induce apoptosis of cancer cells, inhibits MEK activity, and obviously inhibits phosphorylation of MEK in an MAPK/ERK channel, thereby generating a significant effect on inhibiting growth of a tumor. According to the composition in the invention, excellent basis for obtaining candidate medicines having inhibition activity of sensitive and drug-resistant tumors and for illustrating the pharmacological action is provided.

Description

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Claims

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Application Information

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Owner FUDAN UNIV
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