Microtubulin Binding Sites as Target for Developing Anticancer Agents

Abstract

Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made alpha-and beta-tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

Antiproliferative activity of yatein isolated fromAustrocedrus chilensisagainst murine myeloma cells: Cytological studies and chemical investigations

“…Lignans represent one of the most important and interesting classes of biologically active compounds, because lignan molecules can induce cancer cell apoptosis (Ayella et al, 2010;Chavez et al, 2011;Huong et al, 2011;Singh et al, 2007;Xu et al, 2006Xu et al, , 2011. Podophyllotoxin inhibits microtubule assembly of the mitotic apparatus, acting as a competitive inhibitor of the binding site for colchicine to tubulin (Loike et al, 1978); this process occurs during mitosis, where the microtubules are rearranged to form the mitotic spindle, which is essential for cell division (Ayres & Loik, 1990;Islam & Iskander, 2004;Schmidt & Bastians, 2007).…”

I-387, a Novel Antimitotic Indole, Displays a Potent In vitro and In vivo Antitumor Activity with Less Neurotoxicity

“…They interact physically with tubulin by binding to one of the three main binding sites: colchicine-, vinblastine-, or paclitaxel-binding site (3). Tubulin-binding agents alter the dynamic behaviors of microtubules and arrest mitotic cells in the M phase of the cell cycle, thus leading to apoptotic cell death.…”

Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

“…[1][2][3][4][5][6] Taxol (paclitaxel, Figure 1), a highly functionalized diterpenoid isolated from Taxus brevifolia (Pacific Yew tree), was the first compound recognized to interact specifically and reversibly with the β-subunit of the tubulin heterodimer, promoting microtubule stabilization and consequently, blocking cells in the mitotic phase of the cell cycle. The unique mechanism of action as a microtubule-stabilizing antimitotic agent (MSAA) is responsible by the extraordinary clinical success achieved by Taxol and related taxanes in the treatment of a variety of cancers.…”