Current Topics in Medicinal Chemistry - Volume 4, Issue 2, 2004

Transformation of a normal cell into a tumor cell results from six essential alterations in cell physiology. There is a complex relationship that exists between growth, differentiation, neoplastic transformation, and the expression of genes and tumor suppressor genes. The knowledge of these mechanisms demonstrates that it is possible to pharmacologically modulate the growth and differentiation of tumor cells. The differentiation therapy focuses on demonstrating that cancer is a reversible state with altered maturation in which the transformed phenotype may be suppressed by cytostatic agents and by the pharmacological differentiation towards benign forms with no proliferative potential. One of the mechanisms determining the activity of target genes is the post-translational modification of the Nterminal tails of core histones. Inappropriate repression of genes required for cell differentiation has been linked to several forms of cancer. Histone deacetylase inhibitors modulate transcription, and are endowed with cytodifferentiating, antiproliferative and apoptogenic properties. Retinoids modulate cell differentiation, proliferation, apoptosis and morphogenesis in vertebrates, and have proved to be clinically useful. Their biological effects are mediated by the activation of retinoic acid receptors, which are ligand-dependent gene transcription factors. Checkpoints during cell cycle allow the cell to respond to proliferation signals or decide between the alternate pathways leading to cytokinesis, differentiation, quiescence, and cell death. Abrogation of normal cell cycle controls in tumor cells contributes to their inability to differentiate and the restoration of such controls in G1 can lead to the resumption of differentiation and terminal cell division. Chemical inhibitors of cyclin-dependent kinases have been reported to stimulate differentiation of tumor-cell lines.

In the last two decades, paclitaxel (Taxol™, 1) has dominated the anticancer chemotherapy as one of the most important antimitotic agents. Despite its clinical success, it presents some limitations due to its low aqueous solubility or multidrug-resistance (MDR) susceptibility. Among new compounds sharing paclitaxel's mechanism of action, epothilones have emerged as very promising candidates and are currently under clinical trials. While the electron crystallography (EC) structure of tubulin with embedded paclitaxel is available, only hypotheses about epothilone binding upon the protein may be advanced. This review illustrates our efforts in the minireceptor modeling approach as the most recent advances in the field of three-dimensional quantitative structure-activity relationship (3D QSAR) studies involving taxanes, epothilones and the corresponding protein environment.

Aza-bioisosteres of anthracene-9,10-diones and of anthrapyrazoles comprise an innovative class of anticancer compounds. They are formally derived by introduction of one or more nitrogens into the carbocyclic ring system of the parent drugs. Bioisosteres exhibit extensive changes in the physico-chemical properties and in the interactions with the pharmacological targets, DNA and DNA-topoisomerase II, when compared to the carbocyclic analogues. A favourable spectrum of activity, reduced side effects and a unique tropism for solid tumors make the new derivatives a very interesting family of drugs. In particular, a 2-aza-anthracene-9,10-dione and a 9-aza-anthrapyrazole derivative are presently undergoing advanced clinical trials and appear to be promising in view of their approval as anticancer drugs.

Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researcher's attention not only for their biological activity, but also for its non intercalative binding to the minor groove of doublestranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicles for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself. In the last few years, several hybrid compounds, in which known antitumor derivatives or simple active moieties of known antitumor agents have been tethered to distamycin frames, have been designed, synthesized and tested. Several efforts have been made to modify DNA sequence selectivity and stability of the distamycin and the structural modifications have been based on replacement of pyrrole by other heterocycles and / or benzoheterocycles obtaining a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety, by means of the substitution with various groups, which includes ionizable, acid or basic, and non-ionizable groups, has been also studied. The synthesis of a hybrid deriving among the combination of the distamycin A and naturally occurring alkylating agent has been also reported. Several classes of distamycin derivatives that have been reported in the published literature have been described in this review article.

Cancer will be the major cause of death in the 21st century and natural products should provide novel and more effective anticancer agents. This review deals with new natural molecules liable to become anticancer drugs, as well as recent specific strategies for a selective treatment of cancer. The introduction presents the current state of the art on anticancer research. Beside, in the following subheadings we summarize our research on cytotoxic natural quinone methide-triperpenes and their analogues. We also discuss our results on the anti-tumour promoting activity of natural naphthoquinones and their derivatives.