The first series of 4,11-bis[(2-aminoethyl)amino]anthra[2,3-b]furan-5,10- diones: Synthesis and anti-proliferative characteristics

European Journal of Medicinal Chemistry, France. 2011. Vol. 46. No. 1. P. 423–428.

Shchekotikhin A. E., Glazunova V.A., Dezhenkova L. G., Shevtsova E. K., Traven' V. F., Balzarini J., Huang H. -., Shtil A. A., Preobrazhenskaya M. N.

We developed the synthesis of a series of furan-fused tetracyclic analogues of the antitumor agent ametantrone. The reactions included nucleophilic substitution of propoxy groups in 4,11-dipropoxyanthra[2,3-b]furan-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b] furan-5,10-dione in good yields. Studies of anti-proliferative activity on a panel of mammalian tumor cell lines demonstrated that anthra[2,3-b]furan-5,10- diones were the most potent derivatives among heteroarene-fused ametantrone analogues with one heteroatom. We identified several compounds that evoked a growth inhibitory effect at submicromolar concentrations. The anthra[2,3-b]furan-5,10-dione 9 with distal methylamino groups was markedly potent against drug-resistant cell lines with P-glycoprotein overexpression or p53 gene deletion. Furthermore, this derivative attenuated in vitro topoisomerase I-mediated DNA uncoiling at low micromolar concentrations. These results demonstrate that anthrafurandiones are a new class of heterocyclic anthraquinone derivatives with the properties potentially valuable for anticancer therapy.

 

 

Keywords: Tumor cells, Drug resistance, Cytotoxicity, topoisomerase I