Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex

A technology of biological activity and complexes, applied in the direction of platinum organic compounds, platinum group organic compounds, compounds containing elements of group 8/9/10/18 of the periodic table, etc., can solve toxicity, nephrotoxicity, and drug resistance And other issues

Active Publication Date: 2016-06-01
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there are some serious defects in the existing cisplatin drugs: one is to show corresponding toxicity, mainly kidney toxicity and bone marrow toxicity; the other is drug resistance after administration
But so far, there is no platinum (IV) complex that can target or overcome cisplatin resistance as a drug on the market.

Method used

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  • Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex
  • Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex
  • Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0061] The preparation of CUT-OH is carried out by the reaction formula shown in formula V,

[0062]

[0063] The preparation of CUT-OH adopts the following preparation method:

[0064] 1. Add equimolar 2,4-dihydroxybenzaldehyde and acetylglycine and three times the amount of sodium acetate into a certain volume of acetic anhydride, stir and reflux for 4 hours, cool the reaction solution to room temperature, pour it into ice water, and obtain yellow The precipitate was filtered, washed twice with ice water, and the solid was dried to obtain intermediate M1;

[0065] 2. Add M1 to the mixed solution of concentrated hydrochloric acid and ethanol (2:1), reflux for 1h, cool the reaction solution to room temperature, pour it into ice water, and then slowly add twice the amount of sodium nitrite under ice bath conditions After adding and stirring for 15min, slowly add three times the amount of sodium azide, continue to stir for 15min, filter out the brown precipitate, wash with w...

Embodiment 1

[0072] Embodiment 1. Preparation of compound 1

[0073]Dissolve 157.4 mg (0.45 mmol) of CX-OH and 144.5 mg (0.45 mmol) of TBTU in 15 mL of anhydrous DMF, stir at room temperature for 10 min, then add 45.5 mg (0.45 mmol) of TEA, continue stirring for 5 min, and then add 150.0 mg (0.45 mmol) cis, cis, anti-[Pt(NH 3 ) 2 Cl 2 (OH) 2 ], reacted at 50°C for 48h under the protection of nitrogen. The reaction solution was concentrated, and the concentrated solution was separated by silica gel column chromatography, and the eluent was a mixed solvent of dichloromethane and methanol (10:1) to obtain 79.9 mg of a yellow product with a yield of 40%.

[0074] 1 HNMR (DMSO-d6, ppm): δ4.23 (s, 6H), 7.13 (d, J = 7.9, 1H), 7.44 (t, J = 8.0, 1H), 7.97 (d, J = 8.4, 1H) , 8.07(d, J=8.6, 1H), 8.27(m, 2H), 8.46(t, J=2.0, 1H), 8.61(d, J=5.9, 1H), 8.82(d, J=8.5, 1H ), 9.14(d, J=5.9, 1H), 9.7(s, 1H), 10.2(s, 1H). 13 CNMR (DMSO-d6, ppm): δ116.73, 119.53, 120.53, 122.58, 122.75, 122.92, 124.37, ...

Embodiment 2

[0075] Embodiment 2. Preparation of Compound 2

[0076] With reactants cis, cis, trans-[Pt(NH 3 ) 2 Cl 2 (OH)Cl] instead of cis, cis, anti-[Pt(NH 3 ) 2 Cl 2 (OH) 2 ] Prepared with reference to the method described in Example 1 to obtain a yellow product with a yield of 38%.

[0077] 1 HNMR (DMSO-d6, ppm): δ6.38 (s, 6H), 7.16 (d, J = 8.1, 1H), 7.49 (t, J = 8.2, 1H), 7.99 (d, J = 8.4, 1H) , 8.08(d, J=8.4, 1H), 8.3(m, 2H), 8.61(d, J=5.6, 1H), 8.85(d, J=8.5, 1H), 9.01(d, J=5.6, 1H ), 9.7(s, 1H), 10.2(s, 1H). 13 CNMR(DMSO-d6,ppm):δ116.87,119.53,120.52,121.85,122.29,122.60,124.28,125.38,127.58,128.77,130.62,133.28,135.44,142.40,143.48,147.77,148.22,150.41,173.19.ESI -MS: [M-H] + =681.9

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Abstract

The invention discloses a tetravalent platinum complex with a bioactive group and a preparation method of the tetravalent platinum complex. The tetravalent platinum complex is a platinum (IV) complex and has the structure shown in the formula II (please see the formula in the description), wherein in the formula II, Y is OH or Cl, and Bio represents the bioactive group. The platinum (IV) complex is prepared according to the equation in the formula III (please see the formula in the description), wherein in the formula III, Y is OH or Cl, Bio-OH represents a compound with bioactivity, TBTU represents a coupling agent O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, TEA represents a catalyst triethylamine, DMF represents solvent N,N-dimethyl formamide, and DMSO represents solvent dimethylsulfoxide. Cis-platinum is adopted for the bottom face of an octahedron, a small-molecular targeted or medicine active group is introduced to one axial position, a hydroxyl group or helium atom is introduced into another axial position, and the anti-tumor tetravalent platinum complex overcoming cisplatin resistance is provided, so the high-efficiency and low-toxin platinum (IV) complex is obtained.

Description

technical field [0001] The present invention relates to an anti-tumor tetravalent platinum complex, in particular to a cisplatin skeleton as the bottom surface of the tetravalent platinum complex octahedral structure, introducing a single group with biological activity at one axial position, and introducing a single group with biological activity at another axial position. Hydroxyl or chlorine atom to obtain a class of platinum (IV) complexes with anti-tumor activity; the invention also relates to the preparation method and application of the platinum complexes. Background technique [0002] Antitumor bivalent platinum drugs such as cisplatin, carboplatin, and oxaliplatin have been widely used clinically for the treatment of related cancers. As the first metal anti-tumor drug used clinically, cisplatin mainly acts on the guanine N7 target of DNA, and forms adducts through cross-linking with DNA, causing tumor cells to undergo apoptosis, leading to cell stagnation and cell de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61P35/00
CPCC07F15/00C07F15/0093
Inventor 苟少华
Owner SOUTHEAST UNIV
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