Tubulin Interactions

FIGURE 6.26 Compounds that affect microtubulin polymerization and depolymerization 

Why would the mole fraction of C and G influence duplex stability (Tm) differently than A and T  

What is the effect on Tm of lengthening a duplex strand from 10 base pairs to 15 15 to 20 95 to 100 Assume the C G and A T ratios are constant throughout all the strands, and use Equation 6.1 for your calculations. Is this trend reasonable Why or why not  

Nucleoside analogues do not always behave as expected. 5-Bromouracil (6.a) effectively forms base pairs with guanine nucleotides. This surprising observation has been explained by invoking a different tautomer of 6.a. Draw a different tautomer of 6.a and show how it can effectively base pair to a guanine nucleotide. (Tautomerization theory Topal, M. D., Fresco, J. R. Base Pairing and 

Fidelity in Codon-Anticodon Interaction. Nature. 1976, 263, 289-293. Opposing view Orozco, M., Hernandez, B., Luque, F. J. Tautomerization of 1-Methyl Derivatives of Uracil, Thymine, and 5-Bromouracil. Is Tautomerization the Basis for the Mutagenicity of 5-Bromouridine J. Phys. Chem. B. 1998,102, 5228-5233.) 

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Each category of chemotherapy drugs has similar side effects. Anthracyclines cause cardiac toxicity, which is related to the cumulative dose. Tubulin interactive agents are associated with neuropathy and ileus. Alkylating agents are associated with secondary malignancies. 

Niethammer, P., Bastiaens, P. and Karsenti, E. (2004). Stathmin-tubulin interaction gradients in motile and mitotic cells. Science 303, 1862-6. 

Catharanthus roseus) [9]. Maytansine (3) is an ansa macrolyde isolated from Maytenus ovatus [10], and rhizoxin (4) is an antitumor macrolide isolated from the fungus Rhizopus chinensis [11]. Another very important tubulin interactive anti-cancer agent is colchicine (6), and this compound binds to a different binding site of tubulin but is also used in anti-cancer therapy. 

That microtubules exhibit an intrinsic polarity (i.e., with protofilaments running parallel and tubulin protomers regularly arranged in a head-to-tail manner) is obvious from experiments other than those involving image reconstruction. This intrinsic polarity was observed by Rosenbaum and Child (1976) and Witman (1975), who demonstrated biased tubulin addition to microtubules in vitro. This biased addition is a consequence of the nature of tubule-tubulin interactions at the two ends of the microtubule ... 

Vyas DM and Kadow JF (1995) Paclitaxel a unique tubulin interacting anticancer agent. Prog Med Chem 32, 289-337. 

Before these investigations, most of the models of the paclitaxel-tubulin interaction had been directly extrapolated from the conformations of paclitaxel found either in polar [60] or non-polar media [61] and from the single crystal X-ray structure of docetaxel (Fig. 10a) [58],... 

Compound or class Residue Ligand-tubulin interaction References... 

Scheme 6.3 illustrates a few of the main structural classes of soft coral compounds. Included in this list are the tubulin interactive agents, eleutherobin 41 and sarcodictyin A 42, which show nanomolar potency against cancer cell lines. Also of interest are the pseudopterosin A 44 terpenoids which reduce inflammation. Two other terpenoids, sarcophytol A 43 and sinulodurin A 45, have shown micromolar activity against BALB/3T3 and mammary epithelial cells respectively. 

The seminal discoveries of taxol (tubulin-interactive) and camptothecin (topo I-interactive) by Wall and Wani (14—16) represent how natural products have influenced the additional development of natural product-derived and synthetic entities. The following discussion of the discovery and development of current important antineoplastic compounds will be organized by plant species. 

Kruczynski A, Barret JM, Erievant C, Colpaert F, Fahy J, Hill BT. Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem. Pharmacol. 1998 55 635-648. 

Walczak CE. 2000. Microtubule dynamics and tubulin interacting proteins. Curr. Opin. Cell Biol. 12 52-56... 

The importance of the tubulin-polymerization activity of taxol has led to numerous studies of the taxol— tubulin interaction. The nature of the binding site of taxol on tubulin could not be determined by X-ray crystallography because the complex cannot be crystallized, but stabilized zinc sheets of microtubules can be prejjtared and the structure of these sheets has been determined by electron crystallography at a resolution of... 

This molecule, like its parent, is a tubulin interactive agent with very potent activity at the nanomolar level in in vitro studies and binding at or close to the vinca site from recent modeling studies. Much fuller details of the synthetic and base biological information were published by the leaders of the studies in 2005, and recently a short article covering the basic details but including the latest clinical citations was published by Wang. These two articles should be read by the interested reader for fuller details of the evolution of this compound. 

Fig. (11). Structures of the non-benzimidazole fungicides, diethofencarb (15) and zarilamide (65a) which inhibit tubulin assembly, 5-hydroxy-7-methoxychromone (64), an antagonist of benzimidazole antidotes, and centaureidin (65), a tubulin-interactive flavone.

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