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Design and synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs

A technology of compounds and hydrates, applied in the field of design and synthesis of novel tubulin polymerization inhibitors benzoylphenylurea (BPU) sulfur analogues

Inactive Publication Date: 2009-10-07
CHAMPIONS BIOTECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although some of these substances have been used as antiproliferative agents in the treatment of human malignancies, they also suffer from drug resistance mediated through the expression of efflux pumps

Method used

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  • Design and synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs
  • Design and synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs
  • Design and synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs

Examples

Experimental program
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Effect test

Embodiment 1

[0258] Embodiment 1: the general method of synthesizing BPU sulfur analog

[0259] The new analogs were synthesized in good yields by coupling the corresponding benzoyl isocyanate or benzoyl isothiocyanate with aniline derivatives. Sulfur analogs of aniline intermediates were synthesized by reacting substituted aminothiophenols with aryl halides. Sulfoxide or sulfone derivatives are prepared by oxidation of sulfide ( figure 1 ). All compounds were characterized by NMR and LC-MS studies.

[0260] Unless otherwise stated, reactions were performed in oven-dried round bottom flasks under an atmosphere of ultra-high purity (UHP) argon. All reactive liquid reagents were transferred by syringe or cannula and added to flasks through rubber septa. THF was freshly distilled from the benzophenone carbonyl radical immediately before use. All other solvents and reagents were used as received unless otherwise stated. n-BuLi was obtained commercially and titrated with N-pivaloyl-O-t...

Embodiment 2

[0281] Example 2: Cytotoxic evaluation of BPU sulfur analogues

[0282] The cytotoxicity of eight of these analogues 6d, 6h, 6n, 6g, 7b, 7d, 8g and 8h in seven pancreatic cell lines ASPC1, Panc1, Panc203, Panc430, Pane1005, MiaPaca2 and HS766T was determined using the MTT assay. Trypsinize the cells to 5 x 10 3 Cells / well were seeded in 96-well plates and cells were allowed to grow in 10% FBS for 24 hours before treatment with exponentially increasing drug concentrations. After a 96 hour treatment period, 20 μl of MTT solution (5 mg / ml in PBS) was added to each well and the plates were incubated at 37° C. for 3 hours. The medium in each well was then replaced with 100 μl of DMSO. The plate was shaken and the optical density was measured at 570 nm using a multiwell plate reader (Bio-Rad, Model 550, Bio-Rad Inc., Hercules, CA). Each experiment was performed in triplicate for each drug concentration and performed independently at least 3 times. IC 50 Values ​​are defined a...

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Abstract

The invention relates to a design and synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (BPU) sulfur analogs. This invention provides a series of BPU analogues; their synthesis and evaluated biological activity. BPU sulfur analogues were found to possess up to 20 fold increased potency, when compared to reference compound 1, in various cancerous cell lines.

Description

technical field [0001] Efficacy of benzoylphenylurea (BPU) sulfur analogues in the treatment of various types of cancer. technical background [0002] The present invention relates to the design and synthesis of novel benzoylphenylurea (BPU) and benzoylphenylthiourea (BPTU) oxygen, sulfur, sulfoxide and sulfonyl analogs with enhanced potency and increased water solubility. More particularly, the invention is directed to the synthesis of sulfur, hydroxamic and boronic acid analogs of BPU. [0003] In the treatment of cancer, the lack of selectivity for many cancer drugs and the emergence of intrinsic or acquired resistance of tumors to chemotherapy represent major obstacles. Microtubules, the basic components of cells, play important roles in various cellular physiological processes, including mitosis and cell differentiation. Antimitotic agents can be divided into two categories: (1) microtubule stabilizers, such as paclitaxel and docetaxel, which prevent the depolymerizat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/32A61K31/506A61P35/00
CPCC07D239/34C07D239/38A61P35/00A61P43/00
Inventor S·R·卡恩G·阿吕M·伊达尔戈A·西梅诺
Owner CHAMPIONS BIOTECH
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