Kumar Dileep, Poša Mihalj
Laboratory for Chemical Computation and Modeling, Institute for Computational Science and Artificial Intelligence, Van Lang University, Ho Chi Minh City 70000, Vietnam.
Faculty of Applied Technology, School of Technology, Van Lang University, Ho Chi Minh City 70000, Vietnam.
Int J Mol Sci. 2024 Dec 4;25(23):13055. doi: 10.3390/ijms252313055.
Bile acid salts are steroid biosurfactants that build relatively small micelles compared to surfactants with an alkyl chain due to the rigid conformation of the steroid skeleton. In order to increase the capacity of micellar solubilization of the hydrophobic molecular guest, certain C7 alkyl derivatives were synthesized. Namely, introducing an alkyl group in the C7 position of the steroid skeleton results in a more effective increase in the micelle's hydrophobic domain (core) than the introduction in the C3 position. In comparison, fewer synthetic steps are required than if alkyl groups are introduced into the C12 position of cholic acid in the Grignard reaction. Here, the thermodynamic parameters of micellization (demicellization) of C7 alkyl (number of C atoms in the alkyl group: 2, 3, 4, and 8) derivatives of cholic acid anion in an aqueous solution without additives are examined (which have not yet been determined) in the temperature interval (10-40) °C. The critical micellar concentration and the change in the standard molar enthalpy of demicellization (∆hdemic0) are determined by isothermal calorimetric titration (ICT). From the temperature dependence of ∆hdemic0, the change in the standard molar heat capacity of demicellization is obtained (∆Cdemic0), the value of which is proportional to the hydrophobic surface of the monomer, which in the micellar state is protected from hydrophobic hydration. The values of ∆Cdemic0 indicate that in the case of C7-alkyl derivatives of cholic acid anion with butyl and octyl chains, parts of the steroid skeleton and alkyl chain remain shielded from hydration after disintegration of the micelle. Conformational analysis can show that starting from the C7 butyl chain in the alkyl chain, sequences with gauche conformation are also possible without the formation of steric repulsive strain between the alkyl chain and the steroid skeleton so that the C7 alkyl chain takes an orientation above the convex surface of the steroid skeleton instead of an elongated conformation toward the aqueous solution. This is a significant observation, namely, if the micelle is used as a carrier of a hydrophobic drug and after the breakdown of the micelle in the biological system, the released drug has a lower tendency to associate with the monomer if its hydrophobic surface is smaller, i.e., the alkyl chain is oriented towards the angular methyl groups of the steroid skeleton (the ideal monomer increases the hydrophobic domain of the micelle, but in aqueous solution, it adopts a conformation with the as small hydrophobic surface as possible oriented towards the aqueous solution)-which then does not disturb the passage of the drug through the cell membrane.
胆汁酸盐是类固醇生物表面活性剂，由于类固醇骨架的刚性构象，与具有烷基链的表面活性剂相比，它们形成的胶束相对较小。为了提高胶束对疏水性分子客体的增溶能力，合成了某些C7烷基衍生物。也就是说，在类固醇骨架的C7位引入烷基比在C3位引入能更有效地增加胶束的疏水区域（核心）。相比之下，与在格氏反应中把烷基引入胆酸的C12位相比，所需的合成步骤更少。在此，研究了在无添加剂的水溶液中，胆酸阴离子的C7烷基（烷基中碳原子数：2、3、4和8）衍生物在（10 - 40）℃温度区间内的胶束化（去胶束化）热力学参数（尚未确定）。通过等温滴定量热法（ICT）测定临界胶束浓度和去胶束化的标准摩尔焓变（∆hdemic0）。根据∆hdemic0对温度的依赖性，得到去胶束化的标准摩尔热容变化（∆Cdemic0），其值与单体的疏水表面成正比，在胶束状态下，该疏水表面受到保护不发生疏水水合作用。∆Cdemic0的值表明，对于具有丁基和辛基链的胆酸阴离子的C7 - 烷基衍生物，在胶束解体后，类固醇骨架和烷基链的部分仍能免受水合作用。构象分析表明，从烷基链中的C7丁基链开始，gauche构象的序列也是可能的，烷基链与类固醇骨架之间不会形成空间排斥应变，这样C7烷基链会取向于类固醇骨架凸面上方，而不是向水溶液方向呈伸长构象。这是一个重要的观察结果，即如果将胶束用作疏水性药物的载体，并且在生物系统中胶束分解后，如果释放的药物疏水表面较小，即烷基链取向于类固醇骨架的角甲基（理想的单体增加胶束的疏水区域，但在水溶液中，它会采取疏水表面尽可能小的构象取向于水溶液），那么其与单体缔合的倾向就较低，这不会干扰药物通过细胞膜。
