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Isatin-5-sulfonamide inhibitor with inhibition effect on MLL (mixed lineage leukemia) key protein

A technology of sulfonamides and isatins, applied in the field of isatin-5-sulfonamide inhibitors, can solve the problems of lack of specificity

Inactive Publication Date: 2018-07-20
TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the lack of specific DOT1L inhibitors, the current main goal is to find some effective and low toxicity small molecule inhibitors of DOT1L

Method used

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  • Isatin-5-sulfonamide inhibitor with inhibition effect on MLL (mixed lineage leukemia) key protein
  • Isatin-5-sulfonamide inhibitor with inhibition effect on MLL (mixed lineage leukemia) key protein
  • Isatin-5-sulfonamide inhibitor with inhibition effect on MLL (mixed lineage leukemia) key protein

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 1-(2-Naphthylmethyl)-5-(N-methylpiperazinylsulfonyl)isatin

[0041]

[0042] Specific steps:

[0043]1. Under nitrogen and ice bath, 20.0ml (302mmol) chlorosulfonic acid was added dropwise to 3.6g (24.5mmol) isatin. Then, the mixture was heated to 70°C for 3 hours. The mixture was cooled to room temperature and poured carefully into 100 g of ice. The resulting yellow solid was filtered and washed with cold water. After dissolving in ethyl acetate and drying with Na2SO4, the mixture was purified by column chromatography (petroleum ether and ethyl acetate) to give compounds 1 (3.8 g) and 2 (410 mg). 1 or 2 can react with secondary amines, and 2 can directly generate compound 4 in high yield. The obtained precipitate was used for the next reaction without separation. Compound 1 was a light yellow powder, and Compound 2 was a yellow powder.

[0044] 2. Under nitrogen, the mixture of 1 and 2 (2.0 mmol) was dissolved in 6 ml of dry THF at 0°C. Then, in 1 ml of THF so...

Embodiment 2

[0073] The equilibrium dissociation constants of isatin-5-sulfonamide compounds were measured according to the equilibrium dissociation constant test method between the above-mentioned compounds and DOT1L, and the compounds with inhibitory activity on DOT1L were obtained as follows.

[0074]

[0075] KD value is 6.75e-6 (6.78μM)

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Abstract

The invention provides an application of a compound with isatin-5-sulfonamide as a parent nucleus to resistance to MLL (mixed lineage leukemia). The isatin-5-sulfonamide compound can be used for inhibiting activity of an MLL associated protein, namely, histone lysine methyltransferase DOT1L (disruptor of telomeric silencing 1-like). Therefore, the compound is probably used for preparing a small-molecule inhibitor for the MLL.

Description

technical field [0001] The invention relates to a class of isatin-5-sulfonamide inhibitors capable of inhibiting mixed lineage leukemia-associated protein histone lysine methyltransferase DOT1L, and belongs to the field of medicinal chemistry. Background technique [0002] Mixed lineage leukemia (Mixed Lineage Leukemia, MLL) is a hematological malignancy. It is named after the formation of MLL fusion protein after MLL gene rearrangement. The MLL gene is located on chromosome 11, region 2, band 3 (11q23). Associated with hematologic malignancies. Acute leukemia positive for MLL gene rearrangement can occur from birth to adulthood, manifested as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (acutelymphoblastic leukemia, ALL). Although there will be certain errors, in a research survey of related literature, it was found that 11q23 chromosomal translocation or MLL gene rearrangement occurred in 22% of ALL patients after integrating the data of 7969 AML patients ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/38C07D401/12A61K31/5377A61K31/496A61K31/454A61P35/02
CPCC07D209/38C07D401/12
Inventor 杨诚刘祥徐晓林李和义李召赵换
Owner TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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