We have designed, synthesized, and crystallized 36 compounds,e ach containing an azide group and an oxygen atom separated by three bonds.C rystal structure analysis revealed that each of these molecules adopts aconformation in which the azide and oxygen groups orient syn to each other with as hort O•••N b contact. Geometry-optimized structures [using M06-2X/6-311G(d,p) level of theory] also showed the syn conformation in all 36 of these cases,suggesting that this is not merely ac rystal packinge ffect. Quantum topological analysis using BadersA toms in Molecules (AIM) theory revealed bond paths and bond critical points (BCP) in these structures suggesting its nature and energetics to be similar to weak hydrogen bonding.The NCI-RDG plot clearly revealed the attractive interaction consisting of electrostatic or dispersive components in all the 36 systems.N BO analysis suggested aw eak orbital-relaxation (charge-transfer) contribution of energy for af ew (sp2) O-donor systems.N atural population analysis (NPA) and molecular electrostatic potential mapping (MESP) of these crystal structures further revealed the existence of favorable azide-oxygen interaction. ACSD search indicated the frequent and consistent occurrence of this interaction and its role dictating the syn conformation of azide and oxygen in molecules where these groups are separated by 2-4 bonds.
We have designed, synthesized, and crystallized 36 compounds, each containing an azide group and an oxygen atom separated by three bonds. Crystal structure analysis revealed that each of these molecules adopts a conformation in which the azide and oxygen groups orient syn to each other with a short O⋅⋅⋅Nβ contact. Geometry‐optimized structures [using M06‐2X/6–311G(d,p) level of theory] also showed the syn conformation in all 36 of these cases, suggesting that this is not merely a crystal packing effect. Quantum topological analysis using Bader's Atoms in Molecules (AIM) theory revealed bond paths and bond critical points (BCP) in these structures suggesting its nature and energetics to be similar to weak hydrogen bonding. The NCI‐RDG plot clearly revealed the attractive interaction consisting of electrostatic or dispersive components in all the 36 systems. NBO analysis suggested a weak orbital‐relaxation (charge‐transfer) contribution of energy for a few (sp2)O‐donor systems. Natural population analysis (NPA) and molecular electrostatic potential mapping (MESP) of these crystal structures further revealed the existence of favorable azide‐oxygen interaction. A CSD search indicated the frequent and consistent occurrence of this interaction and its role dictating the syn conformation of azide and oxygen in molecules where these groups are separated by 2–4 bonds.
There is huge demand for developing guests that bind β‐CD and can conjugate multiple cargos for cellular delivery. We synthesized trioxaadamantane derivatives, which can conjugate up to three cargos per guest. 1H NMR titration and isothermal titration calorimetry revealed these guests form 1 : 1 inclusion complexes with β‐CD with association constants in the order of 103 M−1. Co‐crystallization of β‐CD with guests yielded crystals of their 1 : 1 inclusion complexes as determined by single‐crystal X‐ray diffraction. In all cases, trioxaadamantane core is buried within the hydrophobic cavity of β‐CD and three hydroxyl groups are exposed outside. We established biocompatibility using representative candidate G4 and its inclusion complex with β‐CD (β‐CD⊂G4), by MTT assay using HeLa cells. We incubated HeLa cells with rhodamine‐conjugated G4 and established cellular cargo delivery using confocal laser scanning microscopy (CLSM) and fluorescence‐activated cell sorting (FACS) analysis. For functional assay, we incubated HeLa cells with β‐CD‐inclusion complexes of G4‐derived prodrugs G6 and G7, containing one and three units of the antitumor drug (S)‐(+)‐camptothecin, respectively. Cells incubated with β‐CD⊂G7 displayed the highest internalization and uniform distribution of camptothecin. β‐CD⊂G7 showed higher cytotoxicity than G7, camptothecin, G6 and β‐CD⊂G6, affirming the efficiency of adamantoid derivatives in high‐density loading and cargo delivery.
There is huge demand for developing guests that bind β‐CD and can conjugate multiple cargos for cellular delivery. We synthesized trioxaadamantane derivatives, which can conjugate up to three cargos per guest. 1H NMR titration and isothermal titration calorimetry revealed these guests form 1 : 1 inclusion complexes with β‐CD with association constants in the order of 103 M−1. Co‐crystallization of β‐CD with guests yielded crystals of their 1 : 1 inclusion complexes as determined by single‐crystal X‐ray diffraction. In all cases, trioxaadamantane core is buried within the hydrophobic cavity of β‐CD and three hydroxyl groups are exposed outside. We established biocompatibility using representative candidate G4 and its inclusion complex with β‐CD (β‐CD⊂G4), by MTT assay using HeLa cells. We incubated HeLa cells with rhodamine‐conjugated G4 and established cellular cargo delivery using confocal laser scanning microscopy (CLSM) and fluorescence‐activated cell sorting (FACS) analysis. For functional assay, we incubated HeLa cells with β‐CD‐inclusion complexes of G4‐derived prodrugs G6 and G7, containing one and three units of the antitumor drug (S)‐(+)‐camptothecin, respectively. Cells incubated with β‐CD⊂G7 displayed the highest internalization and uniform distribution of camptothecin. β‐CD⊂G7 showed higher cytotoxicity than G7, camptothecin, G6 and β‐CD⊂G6, affirming the efficiency of adamantoid derivatives in high‐density loading and cargo delivery.
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