Center for Computational Chemistry, CRD, PRIST University, Vallam, Thanjavur, Tamilnadu, 613403, India.
Department of Chemistry, Madras Christian College (Autonomous), Tambaram East, Chennai, 600 059, India.
J Biol Inorg Chem. 2018 May;23(3):413-423. doi: 10.1007/s00775-018-1547-7. Epub 2018 Mar 3.
Bent metallocenes (BM) have anti-tumor properties but they face a serious drug efficacy problem due to poor aqueous solubility and rapid hydrolysis under physiological conditions. These two problems can be fixed by encapsulating them in host molecules such as cyclodextrin (CD), cucurbituril (CB) etc. Experimentally, CD-BM, CB-BM host-guest complexes have been investigated to check the efficiency of the drug delivery and efficiency of the encapsulated drug. CB has been reported to be a better host than CD but the reasons for this has not been figured out. This can be done by finding out the mechanism of binding and the nature of the binding forces in both the inclusion complexes. This is exactly done here by performing a DFT study at BP86/TZP level on CB-BM host-guest systems. For comparison CD-BM with β-cyclodextrin as host have been studied. Four BMs (CpMCl, M=Ti, V, Nb, Mo) and their corresponding cations (CpMCl, CpM) are chosen as guests and they are encapsulated into cucurbit-[6]-uril (CB[6]) and cucurbit-[7]-uril(CB[7]) host systems. Computations reveal that CB[7] accommodates well the BMs over CB[6] due to their larger cavity size and also CB[7] is found to be a better host than β-cyclodextrin. BMs enter vertically rather than horizontally into the CB cavity. The reversible binding of BMs within CB[7] is controlled by various non-bonding interactions and mainly by hydrogen bonding between the portal oxygen atoms and Cp protons as revealed by QTAIM analysis. On the other hand, the interaction between the wall nitrogen atoms in CB[7] and chlorine atoms attached to the metal in BM strengthens the M-Cl bonds that prevents rapid hydrolysis of M-Cl and M-Cp bonds saving the drug. Comparatively, BMs experience less electrostatic attraction and more Pauli repulsion within β-cyclodextrin cavity and this affects the drug binding with CD. This makes β-cyclodextrin a less suitable drug carrier for BMs than CBs. Among the four BMs, niobocene binds strongly and titanocene binds weakly with CBs. EDA clearly shows that all the interactions between the guest and host are non-covalent in nature and electrostatic interactions outperform high-repulsion resulting in stable complexes. Cations form stronger complexes than neutral BMs. FMO analysis reveals that neutral BMs are less reactive compared to their cations and complexes are more reactive in CB[6] environment due to excess strain. QTAIM analysis helps to bring out the newer insights in these types of host-guest systems.
夹心配合物（BM）具有抗肿瘤特性，但由于其在生理条件下的水溶性差和快速水解，它们面临严重的药效问题。这两个问题可以通过将它们封装在主体分子如环糊精（CD）、葫芦脲（CB）等中来解决。实验上，已经研究了 CD-BM、CB-BM 主体-客体配合物，以检查药物输送的效率和封装药物的效率。已经报道 CB 比 CD 更适合作为主体，但原因尚未确定。通过在 BP86/TZP 水平上对 CB-BM 主体-客体体系进行密度泛函理论（DFT）研究，可以找到原因。为了进行比较，还研究了以β-环糊精作为主体的 CD-BM。选择了四种 BM（CpMCl，M=Ti、V、Nb、Mo）及其相应的阳离子（CpMCl、CpM）作为客体，并将它们封装到葫芦-[6]-脲（CB[6]）和葫芦-[7]-脲（CB[7]）主体系统中。计算表明，由于其较大的腔尺寸，CB[7]比 CB[6]更好地容纳 BM，并且 CB[7]被发现比β-环糊精更适合作为主体。BM 以垂直方式而不是水平方式进入 CB 腔。通过 QTAIM 分析揭示，BM 在 CB[7]中的可逆结合受各种非键相互作用控制，主要是通过门户氧原子和 Cp 质子之间的氢键控制。另一方面，CB[7]中壁氮原子与 BM 中金属相连的氯原子之间的相互作用增强了 M-Cl 键，防止了 M-Cl 和 M-Cp 键的快速水解，从而保存了药物。相比之下，BM 在β-环糊精腔中经历较少的静电吸引和更多的 Pauli 排斥，这影响了与 CD 的药物结合。这使得β-环糊精作为 BM 的药物载体不如 CB 合适。在四种 BM 中，铌烯与 CB 结合强烈，而钛烯与 CB 结合较弱。EDA 清楚地表明，客体与主体之间的所有相互作用都是非共价的，静电相互作用优于高排斥，从而形成稳定的配合物。阳离子形成的配合物比中性 BM 更强。FMO 分析表明，与阳离子相比，中性 BM 的反应性较低，并且由于过度应变，在 CB[6]环境中配合物的反应性更高。QTAIM 分析有助于揭示这些类型的主体-客体体系中的新见解。
