**6. Conclusion**

782 Thermodynamics – Interaction Studies – Solids, Liquids and Gases

Fig. 4. Dependence of the IC50 of taxane analogs against A2780 non-resistant cells (black circles, solid line) and A2780AD resistant cells (white circles, dashed line) on their Ka to

Fig. 5. Dependence of the resistance index of the A2780AD MDR cells on the Ka of the

Log Ka (35ºC) M-1 3 4 5 6 7 8 9 10 11

Range of affinities for P-gp

taxanes to microtubules. Data from (Yang et al. 2007; Matesanz et al. 2008).

microtubules. Data from (Matesanz *et al.* 2008).

Log (resistance index)

0

1

2

3

We found a correlation between binding affinities of paclitaxel-like MSA to microtubules and their citotoxicities in tumoral cells both MDR and non-resistant. The results with taxanes further validate the binding affinity approach as a tool to be used in drug optimization as it was previously discuss for the case of epothilones. Moreover, from the thermodynamic data we could design novel high-affinity taxanes with the ability to overcome resistance in P-glycoprotein overexpressing cells. Anyway, there is a limit concentration below which MSA are not able to kill cells (discussed in (Matesanz *et al.* 2008)), the highest-affinity compounds studied have no dramatically better citotoxicities than paclitaxel or docetaxel have. Thus, the goal is not to find the drug with the highest cytotoxicity possible but rather to find one able to overcome resistances. The study of taxanes indicates that increased drug affinity could be an improvement in this direction. The extreme example of that come from the covalent binding of cyclostreptin (Buey *et al.* 2007) (that might be consider as infinite affinity) having a resistance index close to one.

However, in the case of chemically diverse paclitaxel-like MSA, the inhibition of cell proliferation correlates better with enthalpy change than with binding constants (Buey *et al.* 2005) suggesting that favourable enthalpic contributions to the binding are important to improve drug activity as it has been shown for statins and HIV protease inhibitors (Freire 2008).
