Protein disulfide isomerases (PDIs) are multifunctional chaperones structurally related enzymes which catalyze disulfide bonds formation, reduction, or isomerization of newly synthesized proteins in the lumen of the endoplasmic reticulum (ER). In humans the PDI family, is composed of 21 members classified by sequence and structural homology.1 The first identified member of this protein family is PDIA1 and it is structurally characterized by two thioredoxin-like active domains (a, aʹ), two substrate-binding domains (b, bʹ) with a hydrophobic pocket in the bʹ domain, a linker sequence between the bʹ and the aʹ domains, and a C-terminal extended domain.2 Structure related with PDIA1, ERp57/PDIA3, shows considerable overlap in their entire protein structure. However notable differences concern their different cellular biochemical roles in cellular homeostasis. ERp57/PDIA3 is involved, as the other PDIs, in the proper folding and in the formation and reshuffling of the disulfide bridges of the proteins synthesized in the rough ER. Considering these functions, it is not surprising that PDIA3 has been associated with several human diseases, such as cancer, prion disorders, neurodegenerative diseases, hepatitis, metabolic diseases, musculoskeletal system conditions, airway inflammation, platelet aggregation , viral infection , and PDIA3 expression level has been evaluated as a useful biomarker for diagnosis and/or prognosis in several conditions. Therefore, PDIA3 may be an interesting pharmacological target. Previously, 16F16 was reported as an irreversible inhibitor of PDIA1 and PDIA3 proteins due the presence of a chloroacetyl group that covalently modifies free cysteine thiols.3 Starting from the chemical structure of 16F16, we designed and synthesized a small set of structural analogues, characterized by a tetrahydro-β-carbolines core endowed with a chloroacetyl group in 2-position as PDIA3 inhibitors, to further explore the structure activity relationship (SAR). The data coming from the biochemical assays will be shown and discussed.
Design and synthesis of tetrahydro-β-carbolines derivatives as PDIA inhibitors / Messore, A.; Madia, V. N.; Ialongo, D.; Patacchini, E.; Arpacioglu, M.; Scipione, L.; Altieri, F.; Paglia, G.; Meschiari, G.; Di Santo, R.; Costi, R.. - (2023). (Intervento presentato al convegno XXVIII edition of the National Meeting on Medicinal Chemistry tenutosi a Chieti; Italy).
Design and synthesis of tetrahydro-β-carbolines derivatives as PDIA inhibitors.
Messore, A.
;Madia, V. N.;Ialongo, D.;Patacchini, E.;Arpacioglu, M.;Scipione, L.;Altieri, F.;Paglia, G.;Meschiari, G.;Di Santo, R.;Costi, R.
2023
Abstract
Protein disulfide isomerases (PDIs) are multifunctional chaperones structurally related enzymes which catalyze disulfide bonds formation, reduction, or isomerization of newly synthesized proteins in the lumen of the endoplasmic reticulum (ER). In humans the PDI family, is composed of 21 members classified by sequence and structural homology.1 The first identified member of this protein family is PDIA1 and it is structurally characterized by two thioredoxin-like active domains (a, aʹ), two substrate-binding domains (b, bʹ) with a hydrophobic pocket in the bʹ domain, a linker sequence between the bʹ and the aʹ domains, and a C-terminal extended domain.2 Structure related with PDIA1, ERp57/PDIA3, shows considerable overlap in their entire protein structure. However notable differences concern their different cellular biochemical roles in cellular homeostasis. ERp57/PDIA3 is involved, as the other PDIs, in the proper folding and in the formation and reshuffling of the disulfide bridges of the proteins synthesized in the rough ER. Considering these functions, it is not surprising that PDIA3 has been associated with several human diseases, such as cancer, prion disorders, neurodegenerative diseases, hepatitis, metabolic diseases, musculoskeletal system conditions, airway inflammation, platelet aggregation , viral infection , and PDIA3 expression level has been evaluated as a useful biomarker for diagnosis and/or prognosis in several conditions. Therefore, PDIA3 may be an interesting pharmacological target. Previously, 16F16 was reported as an irreversible inhibitor of PDIA1 and PDIA3 proteins due the presence of a chloroacetyl group that covalently modifies free cysteine thiols.3 Starting from the chemical structure of 16F16, we designed and synthesized a small set of structural analogues, characterized by a tetrahydro-β-carbolines core endowed with a chloroacetyl group in 2-position as PDIA3 inhibitors, to further explore the structure activity relationship (SAR). The data coming from the biochemical assays will be shown and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
