A bioconjugate approach toward squalamine mimics: Insight into the mechanism of biological action.

A short and efficient synthesis has been devised for a family of squalamine mimics, based on the use of cholic acid, deoxycholic acid, lithocholic acid, putrescine, and spermine as starting materials. Those mimics that contain two facially amphiphilic sterol-spermidine conjugates show strong antibacterial activity against a broad spectrum of Gram-positive bacteria; their corresponding activities against a broad spectrum of Gram-negative bacteria are relatively moderate. Larger mimics, containing four such sterol-spermidine conjugates, exhibit very weak activities. Reversal of the pendent spermidine moiety and a putrescine linkage on the A- and D-rings had little consequence on the antibacterial activity for the most active of the squalamine mimics, which contained two sterol-polyamine units; similar results were obtained with squalamine mimics made from only one sterol unit. Detailed structure-activity measurements, in combination with kinetic studies carried out using liposomes as model membranes, support a mechanism of action involving noncovalent dimers as ion transporting species, most probably via the formation of pores or channels.

Hydrogen-bonding-mediated anthranilamide homoduplexes. Increasing stability through preorganization and iterative arrangement of a simple amide binding site.

This paper describes the assembly of two new series of self-complementary duplexes by making use of amide units, the simplest assembling units of hydrogen bonding, as binding sites. All the new monomers possess a rigidified anthranilamide skeleton, which is stabilized by intramolecular hydrogen bonding. Amide units are iteratively introduced to one side of the preorganized skeletons to facilitate the formation of intermolecular hydrogen bonding. Compounds 2 and 3 bear two and three CONH(2) units, respectively, while 4, 6, and 7 are incorporated with two, three, and four AcNH units, respectively. For comparison, compound 5, which is similar to 4 but contains one AcNH and one CF(3)CONH unit, is also prepared. X-ray diffraction analysis of 2, 4, and 5 revealed homodimeric motifs in the solid state which are stabilized by two or more intermolecular hydrogen bonds. (1)H NMR investigations in CDCl(3) indicated that all the compounds form hydrogen-bonded homoduplexes. Duplexes 3.3, 6.6, and 7.7 are highly stable in CDCl(3), with a lower K(assoc) limit of 2.3 x 10(5) M(-1). The K(assoc) values of the three duplexes in more polar CDCl(3)/CD(3)CN (9:1, v/v) were determined with the (1)H NMR dilution method. The result opens the way for the development of new polymeric duplexes of well-ordered structures.

Hydrogen-bonding-driven preorganized zinc porphyrin receptors for efficient complexation of C60, C70, and C60 derivatives.

This paper describes the self-assembly of a new class of foldamer-based molecular tweezers, whose rigid folded conformations are stabilized by intramolecular hydrogen bonding. Two zinc porphyrin units are introduced to the ends of molecular tweezers Zn(2)1 and Zn(2)2, while three zinc porphyrin units are incorporated to the S-shaped bi-tweezers Zn(3)3, which may be regarded as a combination of two Zn(2)1 molecules. Due to the preorganized U-shaped feature, Zn(2)1 and Zn(2)2 are able to strongly complex C60, C70, and C60 derivative 25 in chloroform or toluene in a 1:1 binding stoichiometry, whereas Zn(3)3, which possesses two tweezer units, complexes the guests in a 1:2 stoichiometry. More stable complex Zn(3)3.24 is formed between Zn(3)3 and 24, a linear molecule bearing two C60 moieties at the ends, as a result of the cooperative interaction of two binding sites. Chiral induction is observed for all the three receptors upon complexation with C60-incoporated chiral phenylalanine derivative 29, although the complexation of 29 by the folding receptors is pronouncedly weaker than that of C60 and 25 due to increased steric hindrance. The driving force for the formation of the complexes is the well established pi-pi stacking between the zinc porphyrin and fullerene units. The 1H and 13C NMR, UV-vis, fluorescent, and circular dichroism spectroscopy have been used to investigate the complexing behavior of the folding receptors and the fullerene guests. The association constants of the corresponding complexes in toluene and chloroform (if possible) have been evaluated with the UV-vis and fluorescent titration experiments.

Poly(choloyl)-based amphiphiles as pore-forming agents: transport-active monomers by design.

This paper describes the design and synthesis of a family of pore-forming amphiphiles. Two of these amphiphiles, which are derived from cholic acid, lysine, and p-phenylenediamine, can produce pores in lipid bilayers as individual molecules. In sharp contrast, analogous amphiphiles that do not contain a rigid 1,4-phenylenediamide moiety favor the formation of dimer-based pores. Kinetic evidence in support of monomer- and dimer-based pores has been obtained from Na+ transport measurements across bilayers made from 1-palmitoyl-2-oleoyl-2-sn-glycero-3-phosphocholine (POPC). Structure-activity studies that have been carried out with pore-forming, dimer-based amphiphiles have also revealed a significant activity dependence on their overall compactness. The practical potential of pore-forming amphiphiles with controllable supramolecular properties is briefly discussed.

Hydrogen bonded oligohydrazide foldamers and their recognition for saccharides.

This paper describes the synthesis and characterization of the first series of hydrogen bonding-driven hydrazide foldamers and their recognition for alkyl saccharides in chloroform. Oligomers 1, 2-4, 5, 6, and 7, which contain one, two, four, six, or twelve repeated dibenzoyl hydrazide residues, respectively, have been prepared. The rigid and planar conformations of 1 and 2 or 4 have been established with X-ray analysis and (1)H NMR spectroscopy, whereas the folding and helical conformations of 5-7 have been evidenced by the 1D and 2D (1)H NMR and IR spectroscopy and molecular mechanics calculations. Molecular mechanics calculations also revealed that 5, 6, and 7 possess a rigid cavity with size of ca. 10.6 to 11.1 A, and half of the carbonyl groups in the folding conformations are orientated inwardly inside the cavity. (1)H NMR and CD experiments revealed that 5-7 efficiently complex alkylated mono- and disaccharides 32-35 in chloroform. The association constants (K(assoc)) of the complexes have been determined with the (1)H NMR and fluorescent titration methods. The energy-minimized conformation of 6.34 has been obtained with molecular mechanics calculation. The hydrazide-based folding structures described here represent novel examples of hydrogen bonding-driven foldamers that act as artificial receptors for selective molecular recognition.

Recognition through self-assembly. A quadruply-hydrogen-bonded, strapped porphyrin cleft that binds dipyridyl molecules and a [2]rotaxane.

Quadruply-hydrogen-bonded porphyrin homodimer Zn1.Zn1 has been designed, assembled, and evaluated as a supramolecular cleft-featured receptor for its ability to bind dipyridyl guests in chloroform-d. Monomer Zn1 consists of a 2-ureidopyrimidin-4(1H)-one unit, which was initially reported by Meijer et al., and a zinc porphyrin unit. The zinc porphyrin is strapped with an additional aliphatic chain for controlling the atropisomerization of porphyrin. The 2-ureidopyrimidin-4(1H)-one unit dimerizes exclusively in chloroform even at the dilute concentration of 10(-)(4) M, while the two "strapped" zinc porphyrin units of the homodimer provide additional binding sites for selective guest recognition. (1)H NMR studies indicate that the new homodimer Zn1.Zn1 adopts an S-type conformation due to strong donor-acceptor interaction between the electron-rich porphyrin units and the electron-deficient 2-ureidopyrimidin-4(1H)-one unit. (1)H NMR, UV-vis, and vapor pressure osmometry investigations reveal that Zn1.Zn1 could function as a new generation of assembled supramolecular cleft, to be able to not only efficiently bind linear dipyridyl molecules 14-17, resulting in the formation of stable termolecular complexes, with K(aasoc) values ranging from 3.8 x 10(6) to 8.9 x 10(7) M(-)(1), but also strongly complex a hydrogen-bond-assembled [2]rotaxane, 18, which consists of a rigid fumaramide thread and a pyridine-incorporated tetraamide cyclophane, with K(aasoc) = 1.2 x 10(4) M(-)(1). (1)H NMR competition experiments reveal that complexation to the dipyriyl guests also promotes the stability of the quadruply-hydrogen-bonded dimeric receptor.

Selective rearrangements of quadruply hydrogen-bonded dimer driven by donor-acceptor interaction.

A general method has been developed to control the selective rearrangement of Meijer's AADD quadruply hydrogen-bonded homodimers by introducing an additional donor-acceptor interaction. Therefore, one donor-assembling monomer, 1, in which the electron-rich bis(p-phenylene)-34-crown-10 moiety is connected to the hydrogen-bonding moiety, and two acceptor-assembling monomers, 2 and 3, in which the electron-deficient pyromellitic diimide or naphthalene diimide group is incorporated, respectively, are synthesized and characterized. 1H NMR and 2D-NOESY studies show that all these compounds exist as stable homodimers in chloroform. Mixing 1 equiv of 1 with 1 equiv of 2 in chloroform leads to the formation of heterodimers 1.2 in approximately 60 % yield, as a result of the electrostatic interaction between the bis(p-phenylene)-34-crown-10 moiety of 1 and the pyromellitic diimide group of 2. Selective formation of heterodimer 1.3 (>97 %) was achieved by mixing 1 equiv of 1 with 1 equiv of 3 in chloroform which resulted in a strengthened electrostatic interaction between the bis(p-phenylene)-[34]crown-10 moiety of 1 and the naphthalene diimide group of 3. The structures of heterodimers 1.2 and 1.3, which have been characterized by 1H NMR and UV/Vis experiments, reveal a remarkable promoting effect between the donor-acceptor interaction and intermolecular hydrogen-bonding. 1H NMR studies also reveal that heterodimers 1.2 and 1.3 can be fully and partially dissociated by addition of heterocycle 29, leading to the formation of new more robust heterodimers 1.29 and 2.29, or 3.29,respectively, and partially regenerated by subsequent addition of heterocyclic compound 30 through the formation of a new heterodimer 29.30. Heterodimers 1.2 and 1.3 represent a novel class of pseudo[2]rotaxanes constructed by two different noncovalent interactions.

First zipper-featured molecular duplexes driven by cooperative donor-acceptor interaction.

[structure: see text] The first class of zipper-shaped artificial duplexes, which are driven by multiple donor-acceptor interactions between electron-rich 1,5-dioxynaphthalene or 1,4-dioxybenzene and electron-deficient pyromellitic dimide units, have been studied in organic media by (1)H NMR, UV-vis, and vapor pressure osmometry. (1)H NMR binding investigations reveal substantial cooperativity of the donor-acceptor interaction in the duplexes.