Hi, I have recently got a question on this topic. Decitabine (anticancer drug) has no charge throughout the entire pH region since high pKa value of hydroxyl group(~14) and extremely low pKa value of amine groups (-0.05); I referred the data from chemicalize.com. I was expecting it to have low hydrophilicity, however this molecule turned out to be hydrophilic. It dissolved very well in water even if there is no proto/deprotonation of the molecule in water. Now I got to know that I was wrong, since solvation of molecules in water is determined not by proto/deprotonation but, more precisely, by polarity. I can see that Decitiabine has ;Topological polar surface area
120.74 Å2, Polarizability 20.00 Å3. How can I actually transform this data to real world? What is the standard of polarizability or polar suface area that you can call the molecule hydrophilic?
Can anybody elaborate what is the role of protonation/deprotonation and polarity in terms of solvation of hydrophilic molecules in water?
Thanks
My answer is gonna be very simple and might be short for your question, anyway. In general any atom that has some asymmetry will be able to interact with water molecules: N and O are examples of this due to the free electrons. Moreover if a charge is present then water affinity greatly increases, which happens with N+ or O-. Thus a protonated amine or carboxylic acid are hydrophilic along with their unprotonated pairs, nonetheless NH3+ and COO- are way more hydrophilic. In your drug even though there is no possibility of having charges due to regular pH, the simple presence of amines, OH residues, and O in the ring will render the molecule hydrophilic. One more thing the NH2 group is the drug might have a "normal" pKa value around 9, if so it will be protonated a pH values below 8.
Dissolution of decitabine is a thermodynamic process
Decitabine ( сrystal)+ H2O (liquid) Decitabine... H2O (solution)
This thermodynamic process takes place in all cases when the gain in the Gibbs energy of dissolution occurs. Otherwise, when the change in Gibbs energy is negative. The gain can be due to increased chaos (disorder) or through hydration. A good solubility index is a large negative Gibbs solubility energy.
Decitabine is a complex molecule. It contains many functional groups that affect solubility. The polarizability is not related to the Gibbs energy. The dissociation constant or pK is related to the Gibbs dissociation energy, but not to the Gibbs solubility energy.
Thank you so much for a short but strong answer. Dr. Omar.
Dr. Yuri. Thanks for giving me a good intuition in the solubility of molecule. So, the conclusion is that, pK value of functional groups or polarizability of molecules are not related to the solubility but just physiochemistry of molecules in acqueous solution ( I guess it also applied to isoelectric point of molecules?). Thus, the solubility has to be decided by the Gibbs solubility energy? Am I understanding correct?
"So, the conclusion is that, pK value of functional groups or polarizability of molecules are not related to the solubility" I did not write like this.
Polarizability is a characteristic of a molecule. рK is the character of another process
DecitabineH (solution) Decitabine-(solution) + H+(solution)
Polarizability and pK affect solubility, but this effect is indirect, not proportional. Find these values and compare with the solubility of simple substances. Between them there will be no proportional dependence. And between the logarithm of solubility (activity) and the change in Gibbs energy of solubility there will be a proportional relationship.
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