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Benzenesulphonamide inhibitors of the cytolytic protein perforin

View Article: PubMed Central - PubMed

ABSTRACT

The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility.

No MeSH data available.


Related in: MedlinePlus

Reagents and conditions: (i) 2-furanboronic acid or 2-bromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) NIS, AcOH, CHCl3, RT; (iii) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C; (v) 2,4-dibromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (vi) a. Pyridine, 0–45 °C, b. (chloromethoxy)ethane, NaH, DMF, RT; (vii) a. 78, bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMSO, 90 °C, 3 h; b. 77, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; c. 1:1 3 M HCl and 1,4-dioxane, reflux, 1 h, followed by 2 M NaOH to precipitate the sodium salt.
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f0015: Reagents and conditions: (i) 2-furanboronic acid or 2-bromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) NIS, AcOH, CHCl3, RT; (iii) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C; (v) 2,4-dibromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (vi) a. Pyridine, 0–45 °C, b. (chloromethoxy)ethane, NaH, DMF, RT; (vii) a. 78, bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMSO, 90 °C, 3 h; b. 77, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; c. 1:1 3 M HCl and 1,4-dioxane, reflux, 1 h, followed by 2 M NaOH to precipitate the sodium salt.

Mentions: A small set of analogues where the thiophene of compound 5 was replaced with other heterocycles was also prepared (compounds 19–22, Table 2 and Scheme 2).


Benzenesulphonamide inhibitors of the cytolytic protein perforin
Reagents and conditions: (i) 2-furanboronic acid or 2-bromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) NIS, AcOH, CHCl3, RT; (iii) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C; (v) 2,4-dibromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (vi) a. Pyridine, 0–45 °C, b. (chloromethoxy)ethane, NaH, DMF, RT; (vii) a. 78, bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMSO, 90 °C, 3 h; b. 77, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; c. 1:1 3 M HCl and 1,4-dioxane, reflux, 1 h, followed by 2 M NaOH to precipitate the sodium salt.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5303009&req=5

f0015: Reagents and conditions: (i) 2-furanboronic acid or 2-bromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) NIS, AcOH, CHCl3, RT; (iii) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C; (v) 2,4-dibromothiazole, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (vi) a. Pyridine, 0–45 °C, b. (chloromethoxy)ethane, NaH, DMF, RT; (vii) a. 78, bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DMSO, 90 °C, 3 h; b. 77, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; c. 1:1 3 M HCl and 1,4-dioxane, reflux, 1 h, followed by 2 M NaOH to precipitate the sodium salt.
Mentions: A small set of analogues where the thiophene of compound 5 was replaced with other heterocycles was also prepared (compounds 19–22, Table 2 and Scheme 2).

View Article: PubMed Central - PubMed

ABSTRACT

The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility.

No MeSH data available.


Related in: MedlinePlus