Conformational analysis of geometric isomers of pitavastatin together with their lactonized analogues

Abstract

Super-statins are synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme responsible for the biosynthesis of cholesterol. All of the super-statins with a C=C double bond spacer between the heterocyclic and the dihydroxycarboxylic moiety that are currently on the market exist as E-isomers. To extend the understanding of conformational and thermodynamic preferences of Z-isomeric super-statin analogues, this study focused on analyzing pitavastatin and its lactonized derivatives via NMR spectroscopy and ab initio calculations. Z-isomeric pitavastatin analogues exist in solution as a pair of interconverting rotamers, where the Gibbs free energies between the major and minor rotamers are within 0.12 and 0.25 kcal mol-1 and the rotational energy barriers are between 15.0 and 15.9 kcal mol-1. The analysis of long-range coupling constants and ab initio calculations revealed that rotation across the C5'-C7 single bond is essential for generating a pair of atropisomers. The overall comparison of the results between Z-isomeric pitavastatin and rosuvastatin analogues demonstrated that the former are to some extent more flexible to attain numerous conformations. Demonstrating how structural differences between super-statin analogues induce distinctive conformational preferences provides important insight into the super-statins' conformational variability and may well improve future drug design.

Figure 1

Chemical structures of Z-isomeric pitavastatin (P-1, P-2, P-3) and rosuvastatin analogues (R-1, R-2, R-3), together with atom numbering for 4-O-TBS protected lactone 1, deprotected lactone 2, and calcium salt 3 of the corresponding super-statin analogue (R = 4-F–C₆H₄).

Scheme 1

Synthesis of Z-isomers of pitavastatin analogues.

Figure 2

¹H-NMR (600 MHz) spectra of (a) P-1 in acetone-d₆ in the range from 223 to 323 K; (b) P-2 in acetone-d₆ in the range from 223 to 303 K; (c) P-3 in methanol-d₄ in the range from 223 to 303 K.

Figure 3

Van’t Hoff plots for dynamic conformational equilibrium M ⇄ m of P-1 (▲), P-2 (■), and P-3 (●) in the temperature range from 223 K to 253 K. The straight lines are the best fits to the experimental data using least-square method. Pearson correlation coefficient R² was 0.9918, 0.9965, and 0.9941 for P-1, P-2, and P-3, respectively.

Figure 4

Relative potential energy profile of P-1 as a function of the torsion angles $\varphi$ [C6'–C5'–C7–H7] ($●$) and θ [H5–C5–C6–H6] ($■$) at the B3LYP/6-311+G(d,p) level of theory.

Figure 5

The energetically minimized preferred conformations of P-1 at the B3LYP/6-311+G(d,p) level of theory. For clarity, the tert-butyldimethylsilyl group attached to C3 is not presented (although it was included in calculations).