Cytotoxicity of enantiomers of gossypol Schiff’s bases and optical stability of gossypolone

doi:10.1016/j.ejmech.2004.04.001

European Journal of Medicinal Chemistry

Volume 39, Issue 7, July 2004, Pages 619-624

https://doi.org/10.1016/j.ejmech.2004.04.001 Get rights and content

Abstract

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.

Introduction

Gossypol (Fig. 1), a binaphthyl pigment present in the cotton plant and a number of other members of the Malvaceae family, is chiral because of steric hindrance to rotation about the internaphthyl bond [1]. Gossypol exhibits a number of interesting types of biological activity, including anti-fertility [2], [3], anti-malarial [4], [5], anti-HIV [6], [7] effects. More recently, gossypol has been shown to exhibit toxicity towards cancer cells [8], [9], [10], [11].

In a number of these studies, the (–)-enantiomer of gossypol has been shown to be substantially more active than the (+)-enantiomer [3], [9], [10], [12], [13], [14]. To date, most studies on gossypol derivatives have focused on the biological activities of racemic products. The cytotoxic potential of chiral gossypol derivatives has not been evaluated, despite the higher activities of (–)-gossypol.

In a previous paper, we showed that some Schiff’s bases of racemic gossypol exhibited higher toxicities than gossypol itself [15]. In this work, we report on the synthesis of Schiff’s bases of chiral gossypol and on the relative toxicities of these compounds against KB cells (mouth epidermoid carcinoma cells), MCF-7 cells (breast carcinoma cells), and MCF-7/ADR cells (doxorubicin resistant breast carcinoma cells).

Because gossypolone has also been shown to be active against cancer cell lines [15] we also attempted to extend the study to the gossypolone enantiomers and chiral derivatives. These compounds, however, racemized very quickly at room temperature, and it was not possible to test their activity.

Section snippets

Synthesis and cytotoxicity of Schiff’s bases of gossypol enantiomers

Gossypol enantiomers were prepared from racemic gossypol acetic acid by the low-temperature crystallization of the conglomerate gossypol/acetone (1:3) crystal form [16]. The final preparations were >99% chemically and optically pure and yielded CD curves (Fig. 2A) identical to those previously reported for (+)- and (–)-gossypol [17].

Schiff’s bases of both gossypol enantiomers were synthesized with ethylamine by previously described methods [15]. Ethylamine derivatives were used in this work

Conclusions

In a recent publication, the mechanism of gossypol-induced cell growth inhibition and cell death was investigated [25]. The action of gossypol on cancer cells is likely to be complex and involve multiple activities at various sites. These findings suggest that appropriate derivatives of gossypol could trigger apoptosis of cancer cells by targeting specific receptors.

The search for new anticancer compounds retaining the selective toxicity of gossypol without causing drug resistance remains a

Chemistry

Racemic gossypol (as gossypol / acetic acid (1:1)) was obtained as previously described [15]. Gossypol enantiomers were prepared by growing large enantiomorphic single crystals of gossypol/acetone (1:3) [16]. The chirality of each crystal was determined by HPLC separation of diastereomers formed with R-(–)-2-amino-1-propanol. Crystals containing the same enantiomer were combined, and the occluded acetone was removed by storing the preparations under vacuum for 4 days [16]. Reagents and solvent

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Short communicationCytotoxicity of enantiomers of gossypol Schiff’s bases and optical stability of gossypolone

Abstract

Introduction

Section snippets

Synthesis and cytotoxicity of Schiff’s bases of gossypol enantiomers

Conclusions

Chemistry

Contraception

Contraception

Gynecol. Oncol.

Cancer Lett.

Cancer Lett.

Eur. J. Med. Chem.

Biochem. Pharmacol.

Chirality

Int. J. Androl.

J. Med. Chem.

J. Med. Chem.

Antimicrob. Agents Chemother.

Short communication
Cytotoxicity of enantiomers of gossypol Schiff’s bases and optical stability of gossypolone