pironetin and Neoplasms

Molecules that bind to tubulin and disrupt tubulin dynamics are known as microtubule targeting agents. Treatment with a microtubule targeting agent leads to cell cycle arrest followed by apoptosis. Tubulin inhibitors have been highly effective in the clinical treatment of a variety of tumors and are being investigated for treatment of several other diseases. Currently, all FDA approved microtubule inhibitors bind to β-tubulin. Given the overall success of tubulin-binding agents in anticancer chemotherapy, α-tubulin is an attractive and unexplored target. Herein, we will discuss pironetin, the only compound known to bind α-tubulin, with particular focus on the known biological properties, the total syntheses, exploration of its structure-activity relationship, and future directions.

Topics: Binding Sites; Humans; Microtubules; Neoplasms; Pyrones; Tubulin Modulators

The preparation of several new analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the nature of the side chain and the lactone ring. Their cytotoxic activity has been measured. In addition, their interaction with tubulin, their ability to inhibit the secretion of the vascular endothelial growth factor (VEGF) and the expression of angiogenesis and telomerase-related genes have been determined. Unexpectedly, and unlike pironetin, the lactones studied in this work do not interact with tubulin. Two of the compounds have been found to downregulate the expression of the hTERT and VEGF genes. Furthermore, one of them causes an appreciably decrease in the secretion of the VEGF protein.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Humans; Lactones; Microtubules; Neoplasms; Pyrones; Telomerase; Tubulin; Vascular Endothelial Growth Factor A

We here describe the preparation of a series of hybrid molecules containing a combretastatin A-4 moiety and a pironetin analogue fragment connected through a spacer of variable length which includes a 1,2,3-triazole ring. The cytotoxic activities of these compounds have been measured. Relations between structure and cytotoxicity are discussed. Some of the tested compounds showed cytotoxicity values of the same order of magnitude as combretastatin A-4 and were less toxic than the latter compound for normal cells.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Proliferation; Cells, Cultured; Drug Design; Drug Screening Assays, Antitumor; Flow Cytometry; HEK293 Cells; Humans; Molecular Structure; Neoplasms; Pyrones; Structure-Activity Relationship; Triazoles

We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an ester-amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated. Relations between the structure and activity are discussed. Since the spacer is not long enough to permit a simultaneous binding of the hybrid molecules to the colchicine and pironetin sites on tubulin, a further feature investigated was whether these molecules would interact with the latter through the pironetin end (irreversible covalent binding) or through the colchicine end (reversible noncovalent binding). It has been found that binding to tubulin may take place preferentially at either of these ends depending on the length of the connecting spacer.

Topics: Antineoplastic Agents; Binding Sites; Cell Proliferation; Colchicine; Drug Design; Fluorescent Antibody Technique; Humans; Microtubules; Molecular Structure; Neoplasms; Pyrones; Structure-Activity Relationship; Tubulin; Tumor Cells, Cultured

The preparation of several new truncated analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the suppression of some of the alkyl pendants in either the side chain or the dihydropyrone ring. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that all analogues are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, thus strongly suggesting that, like natural pironetin, they also display a covalent mechanism of action. Their cytotoxicity is, however, lower than that of the parent compound. This indicates that all alkyl pendants are necessary for the full biological activity, with the ethyl group at C-4 seemingly being particularly relevant. Most likely, the alkyl groups cause a restriction in the conformational mobility of the molecule and reduce the number of available conformations. This makes it more probable that the molecule preferentially adopts a shape which fits better into the binding point in α-tubulin.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Humans; Neoplasms; Pyrones; Tubulin; Tubulin Modulators