Synthesis of Combretastatin A-4 and 3'-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of Their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression.

Raül Agut,Juan Murga,Raquel Gil-Edo,Alberto Pla,J Alberto Marco,Miguel Carda,Eva Falomir,Celia Martín-Beltrán

doi:10.3390/molecules25030660

Raül Agut, Juan Murga + Show 6 more

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https://doi.org/10.3390/molecules25030660

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Abstract

Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549 cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the parent compound.

Highlights

Cancer is a disease characterized by the growth and spread by the body of aberrant cells
We have published several reports on the biological properties of combretastatin and aminocombretastatin A-4 derivatives [24,25,26,27,28,29]. In addition to their cytotoxicity, we have investigated their ability to inhibit the expression of certain genes related to the angiogenesis process and the telomerase activation, such as c-Myc, Vascular endothelial growth factor (VEGF)
Derivatives that incorporate d-amino acids, together with the derivative 4.9 (l-Met), exhibit, in general, the best therapeutic safety margins, with values higher than 1 for HT-29 and MCF-7 and close to this value on the A-549 line

Summary

Introduction

Cancer is a disease characterized by the growth and spread by the body of aberrant cells. Along with cardiovascular diseases, are the two leading causes of mortality in developed countries. The ageing of the populations in these countries cause an increase in cancer mortality so that there is considerable interest in the discovery of new anticancer agents. A range of natural products or direct derivatives are used in the treatment of cancer, and over the last 35 years, more than half of the new compounds indicated for the treatment of cancer are natural products or derivatives thereof [1]. Combretastatins are a class of natural phenolic stilbene compounds that have been isolated from the African willow tree Combretum caffrum. The most potent member of these natural stilbenes is combretastatin A-4 (CA-4, see Figure 1), whose antimitotic action is based on the inhibition of tubulin

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