Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Bioorg Med Chem Lett ; 76: 128989, 2022 11 15.
Article in English | MEDLINE | ID: mdl-36150638

ABSTRACT

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.


Subject(s)
Codon, Nonsense , Quinazolines , Quinazolines/pharmacology , Pyrimidines/pharmacology , Guanidines , Nitrogen , Amines
2.
PLoS One ; 13(10): e0206158, 2018.
Article in English | MEDLINE | ID: mdl-30359426

ABSTRACT

Nonsense mutations, resulting in a premature stop codon in the open reading frame of mRNAs are responsible for thousands of inherited diseases. Readthrough of premature stop codons by small molecule drugs has emerged as a promising therapeutic approach to treat disorders resulting from premature termination of translation. The aminoglycoside antibiotics are a class of molecule known to promote readthrough at premature termination codons. Gentamicin consists of a mixture of major and minor aminoglycoside components. Here, we investigated the readthrough activities of the individual components and show that each of the four major gentamicin complex components representing 92-99% of the complex each had similar potency and activity to that of the complex itself. In contrast, a minor component (gentamicin X2) was found to be the most potent and active readthrough component in the gentamicin complex. The known oto- and nephrotoxicity associated with aminoglycosides preclude long-term use as readthrough agents. Thus, we evaluated the components of the gentamicin complex as well as the so-called "designer" aminoglycoside, NB124, for in vitro and in vivo safety. In cells, we observed that gentamicin X2 had a safety/readthrough ratio (cytotoxicity/readthrough potency) superior to that of gentamicin, G418 or NB124. In rodents, we observed that gentamicin X2 showed a safety profile that was superior to G418 overall including reduced nephrotoxicity. These results support further investigation of gentamicin X2 as a therapeutic readthrough agent.


Subject(s)
Codon, Nonsense/chemical synthesis , Genetic Diseases, Inborn/drug therapy , Gentamicins/pharmacology , Protein Synthesis Inhibitors/pharmacology , Aminoglycosides/pharmacology , Aminoglycosides/therapeutic use , Animals , Antibiotics, Antineoplastic/pharmacology , Cells, Cultured , Codon, Terminator/chemical synthesis , Embryo, Nonmammalian , Gentamicins/chemistry , Gentamicins/therapeutic use , Humans , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Male , Open Reading Frames/drug effects , Open Reading Frames/genetics , Protein Synthesis Inhibitors/therapeutic use , Rats , Rats, Sprague-Dawley , Zebrafish/embryology
3.
J Med Chem ; 57(5): 2121-35, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24266880

ABSTRACT

A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC50 = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats.


Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Sulfonamides/pharmacology , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Area Under Curve , Biological Availability , Dogs , Haplorhini , Humans , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics
4.
Bioorg Med Chem Lett ; 23(13): 3947-53, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23683597

ABSTRACT

A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.


Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Indoles/pharmacology , Pyridines/pharmacology , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Biological Availability , Dose-Response Relationship, Drug , Hepacivirus/genetics , Humans , Indoles/chemical synthesis , Indoles/chemistry , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/genetics
5.
Org Lett ; 15(8): 1882-5, 2013 Apr 19.
Article in English | MEDLINE | ID: mdl-23574146

ABSTRACT

Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5-carboxaldehyde with various hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective and high-yielding manner are presented. For aromatic hydrazines, the reaction is performed in the absence of an external base, which promotes exclusive hydrazone formation. The hydrazones subsequently cyclize at an elevated temperature to form the desired pyrazolo[3,4-d]pyrimidine products. For aliphatic hydrazines, the reaction sequence proceeds as a single step in the presence of an external base.


Subject(s)
Heterocyclic Compounds, 2-Ring/chemical synthesis , Hydrazines/chemistry , Hydrocarbons, Chlorinated/chemistry , Hydrocarbons, Chlorinated/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Heterocyclic Compounds, 2-Ring/chemistry , Molecular Structure , Pyrazoles/chemistry
6.
Org Lett ; 9(8): 1505-8, 2007 Apr 12.
Article in English | MEDLINE | ID: mdl-17362023

ABSTRACT

[reaction: see text] 1-Benzyl-3,4-unsaturated-4-piperidinyl benzyldimethylsilane has been prepared and observed to readily undergo palladium-catalyzed cross-coupling reactions with a variety of aryl iodides and aryl bromides to generate 3,4-unsaturated 4-arylpiperidines, often at ambient temperature.


Subject(s)
Benzyl Compounds/chemistry , Cross-Linking Reagents/chemistry , Piperidines/chemistry , Piperidones/chemistry , Silanes/chemistry , Bromides/chemistry , Molecular Structure , Piperidines/chemical synthesis
7.
J Org Chem ; 71(20): 7813-25, 2006 Sep 29.
Article in English | MEDLINE | ID: mdl-16995691

ABSTRACT

The scope of the triphenylsilyl perrhennate (O3ReOSiPh3, 1) catalyzed 1,3-isomerization of allylic alcohols has been thoroughly explored. It was found to be effective for a wide variety of secondary and tertiary allylic alcohol substrates bearing aryl, alkyl, and cyano substituents. Two general reaction types were found which gave high levels of product selectivity: those driven by formation of an extended conjugated system and those driven by selective silylation of a particular isomer. The efficiency of chirality transfer with various substrates was investigated, and conditions were found in which secondary and tertiary allylic alcohols could be formed with high levels of enantioselectivity. Consideration of selectivity trends with respect to the nature of the substituents around the allylic system revealed that this is a reliable and predictable method for allylic alcohol synthesis.


Subject(s)
Alcohols/chemistry , Rhenium/chemistry , Catalysis , Silanes/chemistry , Stereoisomerism
8.
J Am Chem Soc ; 127(9): 2842-3, 2005 Mar 09.
Article in English | MEDLINE | ID: mdl-15740106

ABSTRACT

Two reaction strategies are developed to promote the highly selective 1,3-isomerization of a variety of allylic alcohols using O3ReOSiPh3 as a catalyst. The first strategy utilizes substrates whose 1,3-regioisomer contains a conjugated alkene, which relies on thermodynamics to obtain high selectivity. The second strategy employs N,O-bis(trimethylsilyl)acetamide as an additive to selectively and irreversibly remove the product from the reaction equilibrium and works well for the isomerization of tertiary allylic alcohols into primary allylic alcohols containing trisubstituted alkene components. High stereoselectivity is also observed in the 1,3-isomerization of enantioenriched allylic alcohols.


Subject(s)
Alcohols/chemistry , Allyl Compounds/chemistry , Rhenium/chemistry , Catalysis , Isomerism
9.
J Org Chem ; 68(15): 6031-4, 2003 Jul 25.
Article in English | MEDLINE | ID: mdl-12868943

ABSTRACT

Functionalized vinyl pinacol boronates suitable for Suzuki cross-coupling reactions are synthesized using ruthenium-catalyzed olefin cross-metathesis of 1-propenyl pinacol boronate and various alkenes, including functionalized and 1,1-disubstituted alkenes. The resultant boronate cross products are stereoselectively transformed into predominantly Z-vinyl bromides and E-vinyl iodides. The vinyl bromides may be synthesized in a two-step, one-pot synthesis from a variety of olefins, resulting in a Z-selective formal vinyl bromide cross-metathesis reaction.


Subject(s)
Alkenes/chemistry , Boronic Acids/chemical synthesis , Ruthenium , Vinyl Compounds/chemical synthesis , Anions , Boronic Acids/chemistry , Catalysis , Indicators and Reagents , Models, Molecular , Vinyl Compounds/chemistry
10.
Org Lett ; 4(1): 67-70, 2002 Jan 10.
Article in English | MEDLINE | ID: mdl-11772092

ABSTRACT

[reaction: see text] The selective ring opening cross metathesis of 1,5-cyclooctadiene and trisubstituted cycloolefins with acroyl species is described. The ring-opened products contain electronically differentiated olefins suitable for additional metathesis reactions. Trisubstituted cycloolefins open regioselectively, placing the acroyl cap on the less-substituted terminus.


Subject(s)
Alkadienes/chemistry , Cycloparaffins/chemical synthesis , Catalysis , Cycloparaffins/chemistry , Models, Molecular , Ruthenium
SELECTION OF CITATIONS
SEARCH DETAIL
...