Harnessing the Reactivity of Duclauxin toward Obtaining hPTP1B1-400 Inhibitors
Por:
Aguilar-Ramírez, E, Reyes-Pérez, V, Fajardo-Hernández, CA, Quezada-Suaste, CD, Carreón-Escalante, M, Merlin-Lucas, V, Quiroz-García, B, Granados-Soto, V, Rivera-Chávez, J
Publicada:
5 dic 2023
Resumen:
Duclauxin (1) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) (hPTP1B(1-400)), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a, 6, and 7. Moreover, a one-/two-step semisynthetic approach guided by docking toward hPTP1B(1-400) produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 (8a-15a, 36a, and 37a) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 (5b, 11b-37b). In vitro evaluation and structure-activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin (1) and 36b were assessed for their potential acute toxicity, estimating their LD50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.
Filiaciones:
Aguilar-Ramírez, E:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Reyes-Pérez, V:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Fajardo-Hernández, CA:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Quezada-Suaste, CD:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Carreón-Escalante, M:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Merlin-Lucas, V:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Quiroz-García, B:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
Granados-Soto, V:
Ctr Invest & Estudios Avanzados, Pharmacobiol Dept, Sede Sur, Mexico City 14330, Mexico
Rivera-Chávez, J:
Univ Nacl Autonoma Mexico, Inst Chem, Dept Nat Prod, Mexico City 04510, Mexico
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