期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 12, 期 15, 页码 2413-2422出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3ob42603c
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资金
- National Cancer Institute of the National Institutes of Health [R01-CA168365]
- University of Maryland
- NATIONAL CANCER INSTITUTE [R01CA168365] Funding Source: NIH RePORTER
We report the synthesis and X-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3-, OH, NH3+). The X-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by pi-pi interactions, H-bonds and ion-dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct H-1 NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pK(a) of 6-aminocoumarin 7 (pK(a) = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pK(a) = 4.9; 2h: pK(a) = 4.1; 2f, pK(a) = 3.4) which reflect in part the relevance of direct ion-ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17 alpha-ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents.
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