Equilibrium and Kinetics of Rotamer Interconversion in Immunosuppressant Prodigiosin Derivatives in Solution

Abstract

The equilibrium and relative rate of rotamer interconversion around the bond joining the 2,2'-bipyrrolyl and pyrromethene moieties in a synthetic analogue of immunosuppressant prodigiosin are investigated as a function of pHapp in a water/acetonitrile mixture (1/1 by volume). Two chromatographically separable isomeric forms are obtained in acid solutions (pHapp < 4), whereas rapid interconversion occurs above neutrality. Furthermore, pH modulates the conformational preference of the molecule according to nitrogen protonation on the three pyrrole rings system (pKa = 7.2). At high pHapp (neutral form), the same conformer that is observed in pure acetonitrile prevails, whereas the other one is preferred by the protonated form. The nuclear magnetic resonance data indicate that the structures of the two conformers mainly differ in the value of the torsion angle around the aforementioned C-C bond. Kinetic and equilibrium data are quantitatively interpreted with a cyclic mechanism including two protonation (pKa1 = 8.23 +/- 0.03, pKa2 = 5. 4 +/- 0.2) and two conformational rearrangement steps. A molecular interpretation of the observed behavior includes, for the preferred conformer at low pH, formation of a new hydrogen bond between the exocyclic oxygen and the neighboring pyrrole NH upon protonation of the three pyrrole rings system.

Anti Cancer Compounds of Calappa calappa L. (1758)

“…The BMAP-28-treated U937 cell line revealed that some AMPs are endowed with cytotoxic mechanisms also involving triggering of cancer cell suicide by apoptosis (Rizzo et al, 1998). The results of the present study demonstrate.…”

Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products

“…While one solution would be to protect the amine as the hydrochloride salt, it was known that the protonated forms of prodiginines such as undecylprodigiosin and PNU-156804 ( 208 ) favored the trans- rotomeric configuration (Figure 27). 106 …”

Zinc and Copper Complexes of Prodigiosin: Implications for Copper-Mediated Double-Strand DNA Cleavage

“…The 1 H NMR spectrum of 8 in CDCl 3 ( Figure S3, Supporting Information) showed a single set of resonances, indicating the symmetrical nature of the Zn complex, with the NH proton of the A-pyrrole ring resonating at δ 9.27 ppm. This chemical shift is upfield by ∼3 ppm of the corresponding NH proton in protonated prodigiosin, 21 suggesting that the A-ring NH proton is shielded by the aromatic nucleus of the other Zn-bound prodigiosin molecule.…”