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Phenoxy thiophene sulfonamides and other compounds for use as inhibitors of bacterial glucuronidase

a technology of phenoxy thiophene sulfonamide and other compounds, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, instruments, etc., can solve the problems of double-strand dna breakage and apoptosis, poor bioavailability and toxic side effects, and severe limitation of cpt-11 efficacy, so as to prevent dose-limiting diarrhea

Inactive Publication Date: 2016-08-18
NORTH CAROLINA CENTRAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In a first aspect, the present invention relates to compounds that are effective as inhibitors of bacterial glucuronidase activity. In this respect, the inventors have found that compounds that have GUS inhibitory activity can be used to prevent dose-limiting diarrhea to the irinotecan therapy.
[0010]In another aspect, the present invention relates to a compound for use with camptothecin-derived anticancer drugs. Use of a compound of the invention with an camptothecin-derived anticancer drug like CPT-11 for treating cancer reduces the dose-limiting side effects and improves the efficacy of CPT-11. In an aspect of the invention the compound is of formula (I) as described below, which are phenoxy thiophene sulfonamides. In another aspect of the invention, the compound may be a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and / or thiazole carbonyl. In still another aspect of the invention, the compound of formula (I), or a compound that is a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and / or thiazole carbonyl, is administered prior to, at the same time as or following administration of CPT-11. The present invention also relates to a method for synthesizing compounds for inhibiting glucuronidases. In an aspect of the invention the compound used of formula (I) as described below, which is a phenoxy thiophene sulfonamide. In another aspect of the invention the compound used may be a pyridine sulfonyl, benzene sulfonyl, thiophene sulfonyl, thiazole sulfonyl, thiophene carbonyl, and / or thiazole carbonyl.
[0018]The compounds of the invention are useful in eliminating or reducing the diarrhea associated with CPT-11 use for the treatment of cancer.

Problems solved by technology

It showed strong anti-neoplastic activity but poor bioavailability and toxic side effects.
Such immobilized macromolecular adducts act as roadblocks to the progression of DNA replication and transcription complexes, causing double-strand DNA breaks and apoptosis.
CPT-11 efficacy is severely limited by delayed diarrhea that accompanies treatment.
While an early cholinergic syndrome that generates diarrhea within hours can be successfully treated with atropine, the diarrhea that appears ˜2-4 days later is significantly more debilitating and difficult to control.
Thus, the partial or complete removal of gastrointestinal bacteria is non-ideal for patients already challenged by neoplastic growths and chemotherapy.
Second, it is well established that the elimination of the symbiotic gastrointestinal flora from even healthy patients significantly increases the chances of infections by pathogenic bacteria, including enterohemorrhagic E. coli and C. dificile.
Third, bacterial antibiotic resistance is a human health crisis, and the unnecessary use of antimicrobials is a significant contributor to this problem.

Method used

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  • Phenoxy thiophene sulfonamides and other compounds for use as inhibitors of bacterial glucuronidase
  • Phenoxy thiophene sulfonamides and other compounds for use as inhibitors of bacterial glucuronidase
  • Phenoxy thiophene sulfonamides and other compounds for use as inhibitors of bacterial glucuronidase

Examples

Experimental program
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Effect test

example 1

β-Glucuronidase Activity Assay

[0120]Expression and Purification of E. coli β-Glucuronidase. The full-length E. coli β-glucuronidase gene was obtained from bacterial genomic DNA and was cloned into the pET-28a expression plasmid (Novagen) with an N-terminal 6×-Histidine tag. BL21-DE3 competent cells were transformed with the expression plasmid and grown in the presence of kanamycin (25 ug / ml) in LB medium with vigorous shaking at 37° C. until an OD600 of 0.6 was attained. The expression was induced with the addition of 0.3 mM isopropyl-1-thio-D-galactopyranoside (IPTG) and further incubated at 37° C. for 4 hours. Cells were collected by centrifugation at 4500×g for 20 min at 4° C. Cell pellets were resuspended in Buffer A (20 mM Potassium Phosphate, pH 7.4, 25 mM Imidazole, 500 mM NaCl), along with PMSF (2 μL / mL from 100 mM stock) and 0.05 μL / mL of protease inhibitors containing 1 mg / mL of aprotinin and leupeptin. Resuspended cells were sonicated and centrifuged at 14,500×g for 30 mi...

example 2

Preparation of Analogs of BRITE-355252

[0123]General procedures for the preparation of analogs of BRITE-355252 All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise stated. All reactions were performed in oven-dried glassware (either in RB flasks or 20 ml vials equipped with septa) under an atmosphere of nitrogen and the progress of reactions was monitored by thin-layer chromatography and LC-MS. Analytical thin-layer chromatography was performed on precoated 250 μm layer thickness silica gel 60 F254 plates (EMD Chemicals Inc.). Visualization was performed by ultraviolet light and / or by staining with phosphomolybdic acid (PMA) orp-anisaldehyde. All the silica gel chromatography purifications were carried out by using Combiflash® Rf (Teledyne Isco) and CombiFlash® Companion® (Teledyne Isco) either with EtOAc / hexane or MeOH / CH2Cl2 mixtures as the eluants. Melting points were measured on a MEL-TEMP® capillary melting point ...

example 3

Materials And Methods

[0154]All common reagents such as HEPES, Triton X-100, carbenicillin, and dimethyl sulfoxide (DMSO) were reagent-grade quality and obtained from Thermo Fisher Scientific (Waltham, Mass.) or Sigma-Aldrich (St. Louis, Mo.). 4-methylumbelliferyl glucuronide (4MUG) was obtained from Sigma-Aldrich (St. Louis, Mo.). The solid black 96-well plates (cat#3915) for the assay and 96 well clear plates (cat#9017) for cytotoxicity assay were from Corning Incorporated (Corning, N.Y.). Falcon polypropylene plates (cat#1190) used for serial dilution of compounds were obtained from Becton Dickinson (Franklin Lake, N.J.). Amoxapine, nialamide, isocarboxazid and other compounds for follow-up studies were obtained from Sigma-Aldrich. The Prestwick Chemical Collection was obtained from Prestwick Chemical Company (Washington D.C.). E. coli DH5a (Zymo Research, Irvine, Calif.) was used for the cell-based assay. The expression and purification of GUS enzyme from E. coli carrying an expr...

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Abstract

This invention relates generally to compounds that are glucuronidase inhibitors. The glucuronidase inhibitors include phenoxy thiophene sulfonamides, and other compounds such as pyridine sulfonyls, benzene sulfonyls, thiophene sulfonyls, thiazole sulfonyls, thiophene carbonyls, and thiazole carbonyls. These compounds include nialamide, isocarboxazid, phenelzine, amoxapine, loxapine and mefloquine. Also compositions including one or more of such compounds for use in inhibiting glucuronidase and methods of using one or more of such compounds for selective inhibition of bacterial β-glucoronidase. These compounds may be used as a co-drug in combination with the anticancer drug CPT-11. Also a method for screening compounds to determine their usefulness in reducing diarrhea associated with irinotecan chemotherapy.

Description

RELATED APPLICATION INFORMATION[0001]This application is a CONTINUATION of application Ser. No. 13 / 479,590 filed May 24, 2012 which is a CIP of International Application PCT / US2011 / 027974 filed 10 Mar. 2011 entitled “Phenoxy Thiophene Sulfonamides And Their Use As Inhibitors Of Glucuronidase”, which was published in the English language on 15 Sep. 2011, with International Publication Number WO 2011 / 112858 A1, and which claims priority from U.S. Patent Application No. 61 / 312,512 filed on 10 Mar. 2010, the content of which is incorporated herein by reference.[0002]This invention was supported in part by funds from the U.S. Government (National Cancer Institute 04-051311 and National Institutes of Health grant 1SC2GM081129). The U.S. Government may have certain rights in the invention.[0003]This invention relates generally to phenoxy thiophene sulfonamides and other drugs that inhibit bacterial glucuronidase. This invention also relates to compositions including one or more of such com...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D333/34C12Q1/34C07D417/12C07D409/12C07D413/12
CPCC07D333/34C07D409/12C07D413/12C07D417/12A61K31/42A61K31/137G01N2500/02A61K31/4709A61K31/4409C07D295/135C07D409/06G01N2333/924C12Q1/34A61K31/553A61P35/00
Inventor WILLIAMS, ALFRED L.SCOTT, JOHN E.YEH, LI-ANREDINBO, MATTHEW R.
Owner NORTH CAROLINA CENTRAL UNIVERSITY
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