Synthesis of gossypol atropisomers and derivatives and evaluation of their anti-proliferative and anti-oxidant activity

Dodou, Kalliopi; Anderson, Rosaleen J.; Lough, W. J.; Small, David A.; Shelley, Mike; Groundwater, Paul W.

doi:10.1016/j.bmc.2005.04.026

Cited by 59 publications

(40 citation statements)

References 35 publications

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“…For instance, earlier studies of the structures of Schiff bases of gossypol have demonstrated that these compounds are present in the solutions in the enamine-enamine tautomeric forms. These tautomeric forms were also conserved in the complexes of these Schiff bases with metal cations [15][16][17][18]. The ability of complex formation with monovalent cations, especially Na ?…”

Section: Introductionmentioning

confidence: 95%

X-ray, FT-IR, ESI MS and PM5 studies of Schiff base of gossypol with allylamine and its complexes with alkali metal cations and perchlorate anion

et al. 2008

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Crystals of the Schiff base derivative of gossypol with allylamine (GSBAL) were grown and subsequently examined by X-ray diffraction and FT-IR methods. The crystal space group is C2/c with a = 16.057(1) Å , b = 14.112(1) Å , c = 27.185(2) Å , b = 99.371(5) and Z = 8. In the crystal, GSBAL exists in the enamineenamine tautomeric form. The FT-IR spectral features of the crystals are in agreement with the X-ray data indicating that both parts of the molecule are similarly intramolecular hydrogen-bonded but different intermolecular hydrogenbonded, although the molecule is symmetrically substituted. On the basis of the electrospray ionization mass spectrometry (ESI MS) experiments, it has been shown for the first time that Schiff base of gossypol forms complexes with the perchlorate anion and metal cations simultaneously. The ESI MS spectra of the 1:1:1 mixtures of GSBAL:GOS:M ? , in the positive and negative ion detection mode, have indicated the preferential formation of the 1:1 complexes of GSBAL with M ? (Li, Na or K) and ClO 4 -over the respective complexes forming between GOS and the metal cation or the anion. The PM5 semiempirical calculations have allowed visualization of the most energetically favourable structures of these two types of GSBAL complexes.

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Section: Introductionmentioning

confidence: 95%

X-ray, FT-IR, ESI MS and PM5 studies of Schiff base of gossypol with allylamine and its complexes with alkali metal cations and perchlorate anion

et al. 2008

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“…For this reason the syntheses and tests of gossypol derivatives, in which both aldehyde groups are blocked, are desired to enable their application as drugs. Up to now many gossypol derivatives including its Schiff bases, periacetylated gossylic nitriles, periacetylated gossylic imino-lactones, azo-derivatives, hydrazones, thioderivatives of gossypol have been obtained [13][14][15][16][17][18][19] and tested for their antipsoriatic [20], antimalarial [21], anticancer [22,23], interferon-inducing [24] as well as anti-HIV [25] activity. Earlier studies have shown that the activity of gossypol is rather bacteriostatic than antibacterial [26][27][28] although gossypol structural analogues like hemigossypol, 2,7-dihydroxycadalene, lacinilene and their respective 7-methyl esters have shown very promising antibacterial activity [29,30].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, crystal structures and antibacterial activity studies of aza-derivatives of phytoalexin from cotton plant – gossypol

Przybylski¹,

Pyta²,

Stefańska³

et al. 2009

European Journal of Medicinal Chemistry

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“…2 To reduce toxicity, structural modifications in the (Ϫ)-gossypol isomer led to the analog apogossypol, which lacks the reactive aldehydic groups and displays proapoptotic activity comparable with that of gossypol 3 ; another derivative, gossypolone, demonstrates lower cytotoxicity than the parent compound. 4 The success of these agents resulted in the development of additional analogs, such as the l-isomer of gossypol, AT-101, 5 and ABT-737, which was designed on the basis of structure activity-based studies. 6,7 The gossypol isomers and analogs exhibited inhibitory activity against a wide range of human carcinoma cell lines and in tumor xenograft models.…”

Section: Introductionmentioning

confidence: 99%

Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells

Balakrishnan¹,

Wierda

Keating

et al. 2008

Blood

119

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Gossypol, a cottonseed extract derivative, acts as a BH3-mimetic, binding to the BH3 pocket of antiapoptotic proteins and displacing pro-death partners to induce apoptosis. However, knowledge on the molecular underpinnings of its downstream effects is limited. Since chronic lymphocytic leukemia (CLL) cells express high levels of antiapoptotic proteins that act as a survival mechanism for these replicationally quiescent lymphocytes, we investigated whether gossypol induces apoptosis in these cells and what mechanism underlies gossypol-mediated cytotoxicity. Gossypol induced cell death in a concentration-and time-dependent manner; 24-hour incubation with 30 M gossypol resulted in 50% cell death (median; range, 10%-80%; n ‫؍‬ 47) that was not abrogated by pan-specific caspase inhibitor. Starting at 4 hours, the mitochondrial outer membrane was significantly permeabilized (median, 77%; range, 54%-93%; n ‫؍‬ 15). Mitochondrial outer membrane permeabiliztaion (MOMP) was concurrent with increased production of reactive oxygen species (ROS); however, antioxidants did not abrogate gossypolinduced cell death. Mitochondrial membrane permeabilization was also associated with loss of intracellular adenosine triphosphate (ATP), activation of BAX, and release of cytochrome c and apoptosisinducing factor (AIF), which was translocated to the nucleus. Blocking AIF translocation resulted in a decreased apoptosis, suggesting that AIF contributes to gossypol-mediated cytotoxicity in CLL lymphocytes. (Blood. 2008;112:1971-1980 Introduction Gossypol, a natural product derived from cottonseed extracts, was originally extensively investigated in China as a male contraceptive agent. 1 It exhibits a type of enantiomerism that arises from restricted rotation: the (Ϫ)-gossypol isomer showed greater cytotoxicity than the (ϩ)-isomer in several human cancer cell lines. 2 To reduce toxicity, structural modifications in the (Ϫ)-gossypol isomer led to the analog apogossypol, which lacks the reactive aldehydic groups and displays proapoptotic activity comparable with that of gossypol 3 ; another derivative, gossypolone, demonstrates lower cytotoxicity than the parent compound. 4 The success of these agents resulted in the development of additional analogs, such as the l-isomer of gossypol, AT-101, 5 and ABT-737, which was designed on the basis of structure activity-based studies. 6,7 The gossypol isomers and analogs exhibited inhibitory activity against a wide range of human carcinoma cell lines and in tumor xenograft models. [8][9][10][11] However, these and other investigations illustrated different actions of this agent, and knowledge on the molecular underpinnings of its biologic effects is still limited.Early studies in HeLa cells demonstrated that the cytotoxicity of gossypol was based on its inhibitory activity on DNA synthesis through DNA polymerases alpha and beta 12 or on topoisomerases. 13 Gossypol's effect on DNA synthesis, leading to S-phase arrest, was specific: no effects on RNA and protein syntheses were observed. 14 In concordance...

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Synthesis of gossypol atropisomers and derivatives and evaluation of their anti-proliferative and anti-oxidant activity

Cited by 59 publications

References 35 publications

X-ray, FT-IR, ESI MS and PM5 studies of Schiff base of gossypol with allylamine and its complexes with alkali metal cations and perchlorate anion

X-ray, FT-IR, ESI MS and PM5 studies of Schiff base of gossypol with allylamine and its complexes with alkali metal cations and perchlorate anion

Synthesis, crystal structures and antibacterial activity studies of aza-derivatives of phytoalexin from cotton plant – gossypol

Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells

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