Function-Oriented Synthesis of Marine Phidianidine Derivatives as Potential PTP1B Inhibitors with Specific Selectivity

Abstract

Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP) were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure-activity relationship (SAR) and molecular docking analyses are also described.

Keywords: Function Oriented Synthesis; PTP1B inhibitor; docking analysis; marine natural products; phidianidine; specific selectivity; structure-activity relationship.

Figure 1

Structures of phidianidines (1 and 2) and their protein tyrosine phosphatase 1B (PTP1B) inhibitory analog 3.

Scheme 1

Reagent and conditions: (a) NH₂OH·HCl, NaOH, 50% EtOH, r.t., overnight; (b) Dichloro(p-cymene)ruthenium(II) dimer, CH₃CN, 80 °C, 4 h; (c) NH₂OH·HCl, NaHCO₃, EtOH, r.t., 4 h; (d) HATU, DIPEA, CH₂Cl₂, r.t., 2 h; (e) NaOAc, 30% EtOH, reflux, overnight.

Scheme 2

Reagent and conditions: (a) NH₂OH·HCl, NaHCO₃, EtOH, 65 °C, 4 h; (b) for 14a–14k, and 14p–14u: i, carboxylic acid, HATU, DIPEA, CH₂Cl₂, r.t., 2 h; ii, NaOAc, 30% EtOH, reflux, overnight. (c) For 14l–14o, acyl chloride, K₂CO₃, toluene, reflux, 4 h.

Figure 2

Docking results for compounds 14c, 14p, and 14l–14n on PTP1B, respectively (upper row: without showing surface of PTP1B, lower row: showing surface of PTP1B).