Design, Synthesis And Biological Evaluation Of Benzosultams As Novel Tubulin Inhibitors

Cancer is a common and frequently-occurring disease that threatens the human life seriously and causes mortality only second to cardiovascular vessel diseases. Tumor cells proliferate rapidly, and the cell cycle is obviously shorter than normal cell. The tubulin/microtubule system is an integral component of the cytoskeleton. Microtubules are highly dynamic structures that play a critical role in orchestrating the separation and segregation of chromosomes during mitosis. This makes microtubules highly valued as anticancer drug targets.Antimitotic agents that target the dynamic equilibrium between the microtubule polymer and tubulin heterodimers are key components of chemotherapeutic regimens for various solid tumors. These agents can be divided into two major classes based on their effect on microtubule polymerization and the mass of microtubule polymers: those that inhibit polymerization, such as the vinca alkaloids and those that stabilize microtubules, such as the taxanes and epothilones. The agents that inhibit tubulin polymerization bind toβ-tubulin, and make cells in G₂/M arrest. The microtubule-stabilizing agents bind to two classes of sites on tubulin: the colchicine, and Vinca domains. But their mechanism of action are similar. They bind toβ-tubulin to form "drug-proteinum" complex reversibly, so they can prevent other protein to bind, resulting in inhibition of tubulin polymerization. At the same time they inhibit the formation of spindles through inducing the depolymerization of microtubule. These actions make cells in M arrest. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first antimicrotubule agents approved for use in solid tumors, but their usefulness is often limited by development of drug resistance. In recent years, small-molecule antimitotic agents have been a focus in the development of effective anticancer drugs. Among them, ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization and currently undergoing clinical evaluation for the treatment of many kinds of tumors.On the other hand, the polyphenolic pharmacophore are widely existed in the molecules of many antimitotic agents like colchicines, podophyllotoxin, Combretastatin A4, among others.Fragment-based drug design has become an important and powerful tool for the discovery and optimization of new drug leads. Base on the binding models of colchicine site in tubulin, making use of the fragment-based drug design approach, with the help of computer-assisted drug design, we designed a series of five-membered benzosultams in order to discover novel antimitotic agents. These compounds have the key features that combine the sulfonamide fragment and the important polyphenolic pharmacophore in one molecule.We have developed a novel method for the synthesis of 3-monosubstitued five-membered benzosultams. Based on our new method, 23 compounds with different substituens at A-ring or C-ring have been synthesized. All of them have been characterized by IR, MS and ¹H-NMR spectral analysis.Some of the synthesized benzosultam analogues have been analyzed for tubulin destabilization activity using commercial reagents with fluorescence detection. The preliminary results showed that these analogs appears capable of inhibiting tubulin polymerization to some extent, but the levels of activity measured in these assays does not appear to demonstrate meaningful activity that can be expected to significantly impact cancer cell proliferation. Some of the synthesized benzosultams have also been analyzed for growth inhibition activity using breast cancer cells. The results indicate these compounds have much lower growth inhibition activity than podophyllotoxin or colchicine. The poor solubility in water and the racemic properties may attribute, in part, to the low activities in the bioassay tests.In summary, based on the sulfonamide fragment and the polyphenolic pharmacophore, with the aid of computer-assisted drug design, we have designed and synthesized novel benzosultams as antimitotic agents. The tubulin destabilization activity and the cell growth inhibition activity have been also studied. Our researches may provide useful information for further design of small-molecule antimitotic drugs.