The influence of protonation on molecular structure and physico-chemical properties of gossypol Schiff bases

Abstract

Protonation of gossypol Schiff bases (S1 and S2), possessing different numbers of basic N-atoms, was studied using potentiometric, spectroscopic, ESI MS and PM5 methods. Titration of S1 and S2 with HClO(4), monitored by the FT-IR and (1)H NMR, indicated that the change from the enamine-enamine into the protonated imine-imine tautomeric form occurs at different Schiff base-H(+) ratio. The FT-IR and PM5 results show that for S1 the first protonation step occurs at Schiff base moiety whereas for S2 it is realised at N-atom of the morpholine. The formation of N(+)-HO hydrogen bond between morpholine moieties within S2 contributes to high pK(a(ACN)) = 22.65.

Intriguing roles of reactive intermediates in dissociation chemistry of N-phenylcinnamides

“…Protonation has long been recognized as a fundamental process that plays an important role in many chemical and biological reactions. [1][2][3][4][5] For molecules with multiple functional groups, protonation may take place at different sites, resulting in different forms of protonated molecules. The thermodynamically favored site of protonation is mainly dependent on the proton affinity (PA) 6 at each local functionality of the molecule.…”

Cancer‐Cell‐Specific Drug Delivery by a Tumor‐Homing CPP‐Gossypol Conjugate Employing a Tracelessly Cleavable Linker

“…Furthermore its structure was confirmed by HSQC ( 1 H‐ 13 C heteronuclear single quantum coherence spectroscopy, Figure S7, Supporting Information). As mentioned above, the unusual stability of such Schiff's bases resulting from nucleophilic addition of Gossypol with amines has been described before and can be attributed to stabilization through intramolecular hydrogen bonds as indicated in Figure . The question remained, whether it was the thiazolidine conjugate 1 a or its imine congener 1 b , which was responsible for the encouraging selective cell toxicity observed in the initial experiments.…”

“…An imine‐based linkage through an Ala‐modified homing peptide was also explored ( 1 b ). Gossypol is known to form comparably stable conjugates with amines as well as small peptides, as the resulting Schiff's base is stabilized by two cooperative intramolecular hydrogen bonds formed by the ortho ‐ and meta ‐hydroxyl groups …”

“…Gossypol is known to form comparably stable conjugates with amines as well as small peptides, [25] as the resultingS chiff's base is stabilized by two cooperative intramolecular hydrogen bonds formed by the ortho-and meta-hydroxyl groups. [26] For this work the tumor homing peptides pecific to MCF-7 cells was synthesized by Fmoc-based solid-phase peptides ynthesis with ac ysteine residue attached at the N-terminus (Figure 2A). The methionine residue was substituted by its analogue,n orleucine, to avoid oxidation.…”

“…As mentioned above, the unusual stabilityo fs uch Schiff's bases resultingf rom nucleophilic addition of Gossypol with amines has been described before and can be attributed to stabilization through intramolecular hydrogen bonds as indicated in Figure 3. [25,26] The question remained, whether it was the thiazolidine conjugate 1a or its iminec ongener 1b,w hich was responsible for the encouraging selectivec ell toxicity observed in the initial experiments. To preventd esulfurization of the Cys residue during ligation of gossypolt op eptide 2a,t he reaction was repeated under an argon atmosphere at lower temperature (37 8C), which yielded ac lean sample of 1a after purification by HPLC (Figure 3c).…”