Synthesis and medicinal chemical characterisation of antiproliferative O, N-functionalised isopulegol derivatives

Abstract

Benzylation of isopulegol furnished O-benzyl-protected isopulegol, which was transformed into aminodiols via epoxidation followed by ring opening of the corresponding epoxides and subsequent hydrogenolysis. On the other hand, (-)-isopulegol was oxidised to a diol, which was then converted into dibenzyl-protected diol derivatives. The products were then transformed into aminotriols by using a similar method. The antiproliferative activity of aminodiol and aminotriol derivatives was examined. In addition, structure-activity relationships were also explored from the aspects of substituent effects and stereochemistry on the aminodiol and aminotriol systems. The drug-likeness of the compounds was assessed by in silico and experimental physicochemical characterisations, completed by kinetic aqueous solubility and in vitro intestinal-specific parallel artificial membrane permeability assay (PAMPA-GI) measurements.

Scheme 1. Isopulegol-based chiral aminodiol derivatives. Reagents and conditions: (i) NaH (1.0 eq.), substituted BnBr (1.5 eq.), KI (1.0 eq.), dry THF, 60 °C, 12 h, 70–88%; (ii) m-CPBA (2 eq.), Na₂HPO₄·12H₂O (3 eq.), CH₂Cl₂, 25 °C, 2 h, 25–47%; (iii) R¹NH₂ (2 eq.), LiClO₄ (1 eq.), CH₃CN, 70–80 °C, 20 h, 55–92%; (iv) imidazole or benzimidazole (3 eq.), K₂CO₃ (5 eq.), dry DMF, 70–80 °C, 96 h, 25–71%; (v) 5% Pd/C, H₂ (1 atm), CH₃OH, 25 °C, 24 h, 67–87%.

Scheme 2. Isopulegol-based chiral aminotriol derivatives. Reagents and conditions: (i) (a) (CH₃CO)₂O (2 eq.), dry pyridine (1 eq.), 25 °C, 24 h, 95%, (b) SeO₂ (0.24 eq.), 70% t-BuOOH (4 eq.), CHCl₃, 60 °C, 20 h, (c) LiAlH₄ (3 eq.), dry (CH₃CH₂)₂O, 0 °C, 6 h, 60%; (ii) NaH (1.0 eq.), substituted BnBr (1.5 eq.), KI (1.0 eq.), dry THF, 60 °C, 24–72 h, 60–88%; (iii) m-CPBA (2 eq.), Na₂HPO₄·12H₂O (3 eq.), CH₂Cl₂, 25 °C, 2 h, 28–48%; (iv) R¹NH₂ (2 eq.), LiClO₄ (1 eq.), CH₃CN, 70–80 °C, 8 h, 60–92%; (v) imidazole or benzimidazole (3 eq.), K₂CO₃ (5 eq.), dry DMF, 70–80 °C, 48 h, 45–84%; (vi) 5% Pd/C, H₂ (1 atm), CH₃OH, 25 °C, 24 h, 75–93%.

Fig. 1. Antiproliferative activities of the O,N-functionalised (−)-isopulegol analogues against cancer cells. *: data from reference.