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We have recently developed a one-pot process for simultaneous extraction and chemical modification (SECheM) on Cienfuegosia digitata , a Mauritanian Malvaceae called locally "Izide". On the basis of this innovative methodology that consisted of using ground plant roots as starting material in gossypol Schiff base semisynthesis, we now report how this concept can be used to access enantiomerically pure Schiff base atropisomer derivatives of gossypol in only two steps. This study has been envisioned since enantiomerically pure Schiff base atropisomer derivatives of gossypol are generally more potent biologically when compared to racemic gossypol Schiff bases.

Di(phenylpropylamino)gossypol [systematic name: 2,2'-bis{1,6-dihydroxy-5-isopropyl-8-[(3-phenylpropylamino)methylidene]naphthalen-7-one}, C48H52N2O6, was formed by reaction of the dimeric natural product gossypol with 3-phenylpropylamine. The structure of this compound has its two naphthalene ring systems oriented approximately perpendicular to each other, and the two pendant phenylpropyl groups have different conformations. One of these side groups is considerably disordered at room temperature but less so at 120 K. The enantiomeric molecules form centrosymmetric dimers that are supported by intermolecular hydrogen bonds and by hydrophobic interactions between a pair of naphthalene rings. Two additional hydrogen bonds tie the dimer pairs into layers. Unlike gossypol and many gossypol Schiff base derivatives, the title compound crystallizes without the inclusion of solvent, which appears to occur because of the size and flexibility of its phenylpropyl pendent groups.

Stability constants of complexes formed by gossypol and by ten of its Schiff bases with Ag (+) cations were determined by the potentiometric method. The potentiometric and ESI MS experiments indicate the formation of AgL (+) and Ag 2L (2+) complexes between the Schiff bases G1-G7 and Ag (+) cations as well as the formation of AgL (+), Ag 2L (2+), AgL 2 (+) and Ag 3L 2 (3+) complexes between the Schiff bases G8-G10 and Ag (+) cations. The highest stability constant was found for the AgL (+) complex of G8 Schiff base and the lowest one for the AgL (+) complex of G molecule. The (13)C NMR spectra of mixtures between G and AgClO 4 as well as G1-G10 and AgClO 4 indicate that the complexation of the Ag (+) cations is exclusively realized by the aldehyde-aldehyde tautomer of gossypol and by the enamine-enamine form of gossypol Schiff bases, respectively. We show that the main coordination sites for the Ag (+) metal cations are either the oxygen or the nitrogen atoms of the amine parts of the Schiff bases of gossypol. The energetically most favorable structures of the Ag (+) complexes with gossypol (G) or with the gossypol Schiff bases (G1-G10) were calculated and visualized by the AM1d method at an semiempirical level of theory.

New Schiff bases and new hydrazones were synthesized and studied by (13)C and (15)N CP/MAS spectroscopy and by (1)H--(1)H COSY, (1)H--(13)C HMBC, (1)H--(13)C HSQC, (1)H--(15)N HMQC and (1)H--(15)N HSQC correlations. The CP/MAS investigation of gossypol has demonstrated that in the solid state it exists exclusively in the aldehyde-aldehyde tautomeric form. In contrast, CP/MAS studies of hydrazones and Schiff bases reveal that these compounds occur in the solid state in the N-imine-N-imine and enamine-enamine tautomeric forms, respectively. It is shown that the (13)C resonances of C-6, C-7 and C-11 carbon atoms are suitable for distinguishing between the tautomeric forms of aza-derivatives of gossypol in the solid state. Furthermore, we have proved that the (15)N CP/MAS spectra can be used to identify these tautomeric forms., (Copyright (c) 2008 John Wiley & Sons, Ltd)

A new Schiff base of gossypol with 5-methoxytryptamine (GSTR) and a new hydrazone of gossypol with dansylhydrazine (GHDH) have been synthesized and studied by Fourier transform infrared (FTIR), 1H and 13C nuclear magnetic resonance (NMR), ultraviolet-visible (UV-VIS), electrospray ionization-mass spectroscopy (ESI-MS) as well as the parametric method PM5. The spectroscopic methods have provided clear evidence that GSTR exists in chloroform solution as an enamine-enamine tautomer, whereas GHDH is present in chloroform as a N-imine-N-imine tautomer. The fluorescence spectra of both compounds indicate that their quantum yield of fluorescence is increased by one or two orders of magnitude compared to that of pure gossypol. The ESI-MS spectra of the 1:1 mixtures of GSTR or GHDH with formic acid have demonstrated that both compounds exist as protonated monomers in the gas phase, whereas GHDH can also exist in a stable protonated dimeric structure. The structures of the stable tautomers are calculated and visualized using the PM5 semiempirical method. The intra- and intermolecular hydrogen bonds within these structures are discussed., ((c) 2006 Wiley Periodicals, Inc.)

Schiff bases of gossypol with benzylamine, methylamine, 4-aminoacetophenone and 4-fluoroaniline have been synthesized and characterized by NMR spectroscopy. All the Schiff bases of gossypol are in the enamine form according to (3)J(HC,NH) and (1)J(N,H) coupling constants. The spectra are basically unchanged by change of solvent (CD(2)Cl(2), THF-d(8) and CD(3)OD) and by variation of temperature. For the derivative of benzylamine, deuterium isotope effects on (13)C chemical shifts are determined. They support strongly the enamine form and serve as a reference for other tautomeric Schiff bases. Structures and NMR nuclear shieldings of model compounds (the second monomer is replaced by a 2-hydroxybenzene ring) have been calculated by density functional theory (DFT) methods. A good correlation is observed between calculated (13)C nuclear shieldings of the enamine form and observed (13)C chemical shifts., (Copyright (c) 2005 John Wiley & Sons, Ltd)

Optical Schiff's bases of gossypol were prepared with chiral gossypol and ethylamine. As has been similarly observed among the gossypol enantiomers, the (-)-gossypol ethylimine was more active than either the (+)-gossypol ethylimine or the racemic gossypol ethylimine against KB and MCF7 cells. Gossypolone was also observed to be more toxic than gossypol against both cell lines. All of the gossypol products tested showed comparable toxicity toward MCF7/ADR (adriblastine-resistant) cells. Attempts at producing chiral gossypolone from chiral gossypol failed because of rapid racemization. In addition, the Schiff's base derivatives of gossypolone formed with R-(+)-2-amino-3-phenyl-1-propanol could only be separated at reduced temperature, indicating that gossypolone Schiff's bases are less optical stable than gossypol Schiff's bases.

A Schiff base of gossypol with 3,6,9,12,15,18,21,24-octaoxa-pentacosylamine (GSOB) forms stable complexes with monovalent cations. This process of complex formation was studied by electrospray ionization-mass spectrometry, (1)H-NMR and Fourier transform infrared spectroscopy as well as by the PM5 semiempirical method. It was found that GSOB forms 1:6 complexes with Li(+) and Na(+), and 1:4 complexes with K(+) as well as 1:2 complexes with Rb(+) or Cs(+) cations and exists in all these complexes in the enamine-enamine tautomeric form. Moreover, within these complexes only Li(+) cations can fluctuate between the oxygen atoms of the octaoxaalkyl chains. The interactions of Li(+) cations with hydroxyl groups of the gossypol part is also possible. All other cations are much more localized. In the complex of GSOB with protons, a 1:2 stoichiometry is realized. The two protons are localized on the N atoms of the Schiff base, and the complex exists in the imine-imine tautomeric form. The structures of the complexes are calculated by PM5 semiempirical methods and discussed., (Copyright 2004 Wiley Periodicals, Inc. Biopolymers, 2004)