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Derivatives of amanita toxins and their conjugation to a cell binding molecule

a technology of amanita toxins and cell binding molecules, which is applied in the field of cytotoxic agents and derivatives of amanita toxins, can solve the problems of low yield from isolation and fermentation, and the field is incredibly challenging

Active Publication Date: 2020-03-12
HANGZHOU DAC BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about new compounds that can stop cells from multiplying and spreading. These compounds are called amatoxins, phallotoxins, and virotoxins. They can be used alone or attached to a cell-binding agent to block cell proliferation. The patent also describes the structure of these compounds and their various forms. The technical effect of this patent is the discovery of powerful cytotoxic agents that can be used to treat cancer and other diseases where unwanted cell growth is a problem.

Problems solved by technology

Indeed, the complexity of antibody-drug conjugates with its four moving repertoires of cytotoxic agents, linker technologies, antibody properties, and conjugation methods makes this field incredibly challenging yet full of potential for innovation (Perez, H. L., et al.
However the yields from these isolation and fermentation were quite low (less than 5 mg / L culture).

Method used

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  • Derivatives of amanita toxins and their conjugation to a cell binding molecule
  • Derivatives of amanita toxins and their conjugation to a cell binding molecule
  • Derivatives of amanita toxins and their conjugation to a cell binding molecule

Examples

Experimental program
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Effect test

example 1

Synthesis of (S)-3-(1H-indol-2-yl)-2-(tritylamino)propanoic acid (1)

[0201]

[0202]Chlorotrimethylsilane (3.4 mL, 26.9 mmol) was added slowly to a suspension of L-tryptophan (5.00 g, 24.5 mL) in methylene chloride (40 mL) at r.t. The mixture was continuously stirred for 4.5 h and triethylamine (6.8 mL, 49.0 mmol) was added, followed by a solution of triphenylmethyl chloride (7.17 g, 25.7 mmol) in methylene chloride (20 mL). The mixture was stirred at r.t. for 20 h and then quenched with methanol (25 mL). The reaction was concentrated to near dryness and re-dissolved in methylene chloride, washed with 5% citric acid solution (3×) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further dissolved in methylene chloride and filtered over a celite pad and the filtrate was concentrated to give a pale white foam (11.8 g), which was used directly in the next step. ESI MS m / z 446.5 ([M+H]+).

example 2

Synthesis of (S)-methyl 2-(3-(1H-indol-2-yl)-2-(tritylamino)propan amido)acetate (2)

[0203]

[0204]To a solution of acid (9.27 g, 30.7 mmol) in THF (30 mL) was added glycine methyl ester hydrochloride (2.85 g, 22.8 mmol) and HOBt (3.08 g, 22.8 mmol). The mixture was cooled to 0° C. and triethylamine (7.4 mL, 51.9 mmol) was added, followed by EDC.HCl (4.38 g, 22.8 mmol) in portions. The mixture was allowed to warm to r.t. and stirred for 20 h and then concentrated and redissolved in methylene chloride and washed with 5% citric acid solution (3×) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate and a white solid was collected by filtration (6.46 g, 65% yield over two steps). ESI MS m / z 518.2 ([M+H]+).

example 3

Synthesis of Dimethyldioxirane (DMDO)

[0205]Distilled water (20 mL), acetone (30 mL), and NaHCO3 (24 g, 0.285 mol) were combined in a 1-L round-bottomed flask and chilled in an ice / water bath with magnetic stirring for 20 min. After 20 min, stirring was halted and Oxone (25 g, 0.0406 mol) was added in a single portion. The flask was loosely covered and the slurry was stirred vigorously for 15 min while still submerged in the ice bath. The flask containing the reaction slurry was then attached to a rotary evaporator with a bath at room temperature. The bump bulb (250 mL) was chilled in a dry ice / acetone bath and a vacuum of 165 mtor was applied via a benchtop diaphragm pump. After 15 min, the bath temperature was raised to 40° C. over 10 min. When the bath reached 40° C., the distillation was halted immediately via releasing the vacuum and raising the flask from the heated water bath. The pale yellow acetone solution of DMDO was decanted from the bump bulb directly into a graduated cy...

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Abstract

The present invention is related to novel cytotoxic agents, derivatives of Amanita toxins of Formula (I), wherein , - - - , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, L, m, n and Q are defined herein, the preparation and the therapeutic uses in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

Description

FIELD OF THE INVENTION[0001]The present invention relates to novel cytotoxic agents, derivatives of Amanita toxins and their uses to specifically target cell population by chemically linking these derivatives to a cell binding agent.BACKGROUND OF THE INVENTION[0002]Antibody-drug conjugates (ADCs), which utilize the targeting ability of monoclonal antibodies (mAbs) to deliver highly toxic drugs to targeted tumor cells, have been proof that the products are technically feasible, therapeutically effective, and able to get regulatory approval after Seattle Genetics / Takeda's Brentuximab vedotin (Adcetris) and ImmunoGen / Roche's Trastuzumab emtansine (Kadcyla) are on the market (Sassoon, I. and Blanc, V. Laurent Ducry (ed.), Antibody-Drug Conjugates, Methods in Molecular Biology, vol. 1045, p 1-27). Currently there are more than 50 ADC drugs in the clinic trials according to www.clinictrails.gov and many big pharmas and biotech firms, as well as plenty of small start-ups have a lot of ince...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K7/64C07K16/32
CPCC07K7/64A61K38/00C07K16/32A61K47/6415A61P37/06A61P1/18A61P31/12A61P35/00A61P13/12A61P35/02A61P25/28A61P25/00A61P7/00A61P19/08A61P31/04A61P29/00Y02A50/30
Inventor ZHAO, ROBERT YONGXINYANG, QINGLIANGHUANG, YUANYUANGAI, SHUNYE, HANGBOYANG, CHENGYUGUO, HUIHUIZHOU, XIAOMAIXIE, HONGSHENGTONG, QIANQIANCAO, MINJUNZHAO, LINYAOJIA, JUNXIANGLI, WENJUNZUO, XIAOTAOLIN, CHENXU, YIFANGGUO, ZIXIANG
Owner HANGZHOU DAC BIOTECH
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