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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) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) a. 47% HBr, NaNO2, −10 °C; b. Br2, −10 °C-RT; (iii) tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) TFA, CH2Cl2 (1:1), RT; (v) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C.
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f0020: Reagents and conditions: (i) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) a. 47% HBr, NaNO2, −10 °C; b. Br2, −10 °C-RT; (iii) tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) TFA, CH2Cl2 (1:1), RT; (v) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C.

Mentions: Unfortunately the isomeric thiazole 21 could not be prepared in this manner as the attempted coupling of the thiazole bromide 77 and the pyridyl-3-amine boronate failed. In order to circumvent this problem, the pyridine-sulphonamide 78 was introduced as a single subunit via a Suzuki reaction. Protection of the sulphonamide NH with an ethoxymethyl group was required for a successful coupling and this was removed under acidic conditions to furnish the desired thiazole 21. Finally, the pyridyl analogue 22 was prepared through reaction of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and 5-bromo-2-methylisoindolin-1-one to give the aminopyridine intermediate 79 (Scheme 3).


Benzenesulphonamide inhibitors of the cytolytic protein perforin
Reagents and conditions: (i) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) a. 47% HBr, NaNO2, −10 °C; b. Br2, −10 °C-RT; (iii) tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) TFA, CH2Cl2 (1:1), RT; (v) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

f0020: Reagents and conditions: (i) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (ii) a. 47% HBr, NaNO2, −10 °C; b. Br2, −10 °C-RT; (iii) tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate, Pd(dppf)Cl2, EtOH/toluene, 2 M Na2CO3, reflux; (iv) TFA, CH2Cl2 (1:1), RT; (v) 2,4-difluorobenzenesulfonyl chloride, pyridine, 0–45 °C.
Mentions: Unfortunately the isomeric thiazole 21 could not be prepared in this manner as the attempted coupling of the thiazole bromide 77 and the pyridyl-3-amine boronate failed. In order to circumvent this problem, the pyridine-sulphonamide 78 was introduced as a single subunit via a Suzuki reaction. Protection of the sulphonamide NH with an ethoxymethyl group was required for a successful coupling and this was removed under acidic conditions to furnish the desired thiazole 21. Finally, the pyridyl analogue 22 was prepared through reaction of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and 5-bromo-2-methylisoindolin-1-one to give the aminopyridine intermediate 79 (Scheme 3).

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