title: Acyclic Cucurbit[n]uril-Type Molecular Containers: Influence of Linker Length on Their Function as Solubilizing Agents.
abstract: Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue with a (CH2 )3 linker (M2, 14 mm) studied previously. (1) H NMR dilution experiments show that M2C2 and M2C4 do not self-associate in water, which enables their use as solubilizing excipients. We used phase solubility diagrams (PSDs) to compare the solubilizing capacities of M2, M2C2, M2C4, hydroxypropyl-β-cyclodextrin (HP-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD) toward 15 insoluble drugs. We found that M2C2 and M2C4-as gauged by the slope of their PSDs-are less potent solubilizing agents than M2. However, the higher inherent solubility of M2C2 allows higher concentrations of drug to be formulated using M2C2 than with M2 in several cases. The solubilizing ability of M2C2 and SBE-β-CD were similar in many cases, with Krel values averaging 23 and 12, respectively, relative to HP-β-CD. In vitro cytotoxicity and in vivo maximum tolerated dose studies document the biocompatibility of M2C2.
authors.affiliation: Department of Chemistry, University of Maryland, College Park, MD, 20742, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sigwalt
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, 20742, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Moncelet
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, 20742, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Falcinelli
authors.affiliation: Department of Chemistry, University of New South Wales Canberra, Australian Defence Force Academy, Canberra,ACT, 2600, Australia.
authors.forename: Vijaybabu
authors.initials: V
authors.lastname: Mandadapu
authors.affiliation: Department of Chemistry, University of Maryland, College Park, MD, 20742, USA.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Zavalij
authors.affiliation: Department of Chemistry, University of New South Wales Canberra, Australian Defence Force Academy, Canberra,ACT, 2600, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Day
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, 20742, USA. vbriken@umd.edu.
authors.forename: Volker
authors.initials: V
authors.lastname: Briken
authors.affiliation: Department of Chemistry, University of Maryland, College Park, MD, 20742, USA. LIsaacs@umd.edu.
authors.forename: Lyle
authors.identifier: 0000-0002-4079-332X
authors.initials: L
authors.lastname: Isaacs
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000633:toxicity; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry; D000099246:Cucurbit(n)urils
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D001952:Bridged-Ring Compounds; D007093:Imidazoles; D047392:beta-Cyclodextrins; C000616451:cucurbit(2)uril; D000099246:Cucurbit(n)urils; C000616452:cucurbit(4)uril
keywords: cucurbiturils; cyclodextrins; host-guest chemistry; molecular recognition; solubilizing excipients