Ishikawa Minoru
Graduate School of Life Sciences, Tohoku University.
Yakugaku Zasshi. 2022;142(4):365-379. doi: 10.1248/yakushi.21-00185-3.
Sufficient aqueous solubility is a key requirement for small molecular drug candidates, and improvement of the aqueous solubility of bioactive compounds is often a major issue for medicinal chemists. Decreasing the partition coefficient (Log P) by the introduction of a hydrophilic group is the conventional approach for improving the aqueous solubility of drug candidates, but is not always effective. On the other hand, the solubility of a solid solute in water is also dependent on the crystal packing of the solute suggesting the existence of another principle of solvation. We have developed alternative strategies to improve solubility by means of chemical modification to weaken intermolecular interaction in the solid state, thereby lowering the melting point and increasing the solubility. In this review, we summarize the strategies for improving solubility, that is, modification of molecules in ways that would disrupt molecular planarity by increasing the dihedral angle, that would bend the molecular structure, that would disrupt molecular symmetry, or that introduce a non-flat substituent at the meta position of a benzene substructure. We showed that these strategies can increase the aqueous solubility of molecules even if their hydrophobicity is concomitantly increased. Furthermore, we found that disruption of intermolecular interaction resulted in better aqueous solubility than a decrease of hydrophobicity in some cases.
对于小分子候选药物而言，足够的水溶性是一项关键要求，而提高生物活性化合物的水溶性往往是药物化学家面临的一个主要问题。通过引入亲水性基团来降低分配系数（Log P）是提高候选药物水溶性的传统方法，但并非总是有效。另一方面，固体溶质在水中的溶解度还取决于溶质的晶体堆积，这表明存在另一种溶剂化原理。我们已经开发出了替代策略，通过化学修饰来削弱固态下的分子间相互作用，从而降低熔点并提高溶解度。在这篇综述中，我们总结了提高溶解度的策略，即通过增加二面角、弯曲分子结构、破坏分子对称性或在苯亚结构的间位引入非平面取代基等方式对分子进行修饰，从而破坏分子的平面性。我们表明，即使分子的疏水性同时增加，这些策略也可以提高其水溶性。此外，我们发现，在某些情况下，破坏分子间相互作用比降低疏水性能带来更好的水溶性。
