Non-peptidic cell-penetrating agents: synthesis of oligomeric chiral bicyclic guanidinium vectors.

Polycationic oligo(chiral bicyclic guanidines) constitute useful non-peptidic penetrating agents for cell uptake and protein surface recognition. We report herein improved and selective procedures for the preparation of oligoguanidinium scaffolds linked through thioether bonds, with similar or different groups and functions at both ends of the chain. Two synthetic strategies were developed to obtain these compounds in relatively good yields from a common thioacetate precursor: generation of a disulfide intermediate or thiolate formation.

A calixarene dendron with surface congestion at the first generation.

The X-ray structure of a dendrimeric receptor based on calixarenes showed a packed periphery in the first generation. The presence of urea groups as linkers between the calix[4]arene core and the calix[6]arene dendrons makes it a good model as an endo-receptor which is able to coordinate squarate dianions with a high association constant.

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes.

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process.

Synthesis and reactivity of functionalized bridged m-xylylenedioxycalix[6]arenes.

The synthesis of A,D-m-xylylene-bridged calix[6]arenes 1-8 functionalized at position 5 of the spacer arm is described. The cone conformation of the new bridged calix[6]arenes has been established by (1)H and (13)C NMR. The X-ray structure of compound 6 confirmed the cone conformation also in the solid state.

Nitric oxide binding and photodelivery based on ruthenium(II) complexes of 4-arylazo-3,5-dimethylpyrazole.

Two fluorescent ligands, 3,5-dimethyl-4-(6'-sulfonylammonium-1'-azonaphthyl)pyrazole (dmpzn, 1) and 3,5-dimethyl-4-(4'-N,N'-dimethylaminoazophenyl)pyrazole (dmpza, 2) were obtained by condensation of ketoenolic derivatives with hydrazine. 1 and 2 formed the novel dinuclear complexes [(H(2)O)(3)ClRu(micro-L)(2)RuCl(H(2)O)(3)] (3 or 4) and [(H(2)O)(NO)Cl(2)Ru(micro-L)(2)RuCl(2)(NO)(H(2)O)] (6 or 7) (where L 1 = 2 or , respectively) which were characterized by IR, NMR and elemental analysis. The nitrosyl complexes were prepared by bubbling purified nitric oxide through methanol solutions of the corresponding ruthenium(II) chloroderivative or by reaction of the appropriate ligands with Ru(NO)Cl(3).

Synthetic cation transporters incorporating crown ethers and calixarenes as headgroups and central relays: a comparison of sodium and chloride selectivity.

An earlier study showed that a calix[4]arene could function as a central relay unit to form an ion conductance pathway through a phospholipid bilayer membrane. The present study expands the range of compounds from calix[4]arene to calix[6]arene and incorporates them either as central units or as headgroups, substituting one or more diaza-18-crown-6 residues in functioning hydraphiles. Ion release was assayed by detecting either Na(+) or Cl(-) release from phospholipid vesicles.

Alkynyl expanded donor-acceptor calixarenes: geometry and second-order nonlinear optical properties.

A number of wide- and narrow-rimmed functionalized alkynylcalix[4]arenes have been synthesized by Sonogashira coupling. With respect to their optical properties, these donor-acceptor systems are treated as ensembles of covalently linked, electronically independent tolane subchromophores. Linear UV/visible and fluorescence spectroscopic investigations revealed that the charge-transfer character of the electronic transitions in calixarenes, and also the second-order nonlinear optical (NLO) properties depend on the electron-withdrawing nature of the terminal ethynylphenyl substituent (NO(2), CF(3), H).

Aryl-aryl linked bi-5,5'-p-tert-butylcalix[4]arene tweezer for fullerene complexation.

We report the synthesis and complexing properties of the new cavity-extended receptor 1, a C,C-linked bi-calix[4]arene that selectively binds [70]fullerene in a 2:1 tennis-ball fashion. [structure: see text]

Synthesis and conformational studies on hexa-O-alkyl p-unsubstituted calix[6]arenes.

[structure: see text] In this article we describe the selective O-benzylation of para-unsubstituted calix[6]arene 1 in rings 1 and 4 (2a-c) and the subsequent alkylation of phenol groups with alpha-haloesters (methyl esters 3a, 3c, and 3e; tert-butyl esters 3b, 3d, and 3f) to determine the effect of these groups on their conformational behavior. 2D NMR studies at 188 K reveal that compounds 2a-c, 3b, 3d, and 3f are less flexible, showing a 1,2,3-alternate conformation. The same conformation has been observed in the solid state.

Self-assembled pentamers and hexamers linked through quadruple-hydrogen-bonded 2-ureido-4[1H]-pyrimidinones.

The preorganization of bifunctional 2-ureido-4-pyrimidinones mediated by either 1,3-substituted adamantane or meta-substituted phenylene ring linkers leads to the preferred formation of stable pentameric (1)(5) and hexameric (2)(6) assemblies, respectively. Despite the high binding constant of the 2-ureido-4-pyrimidinone dimers and the highly preorganized structure of the monomer, the predominant formation of cycles (1)(5) and (2)(6) in solution occurs only within a specific concentration range.

Tetraalkynyl calix[4]arenes with advanced NLO properties.

Rigid, highly conjugated tetraalkynyl-calix[4]arenes synthesised via Sonogashira coupling give rise to improved second-order hyperpolarizability values as determined by hyper-Rayleigh scattering--a technique that in addition to X-ray crystallography also allows for the conformational analysis of the calixarene structures in solution.

Highly efficient, nonpeptidic oligoguanidinium vectors that selectively internalize into mitochondria.

Oligoguanidinium-based cell delivery systems have gained broad interest in the drug delivery field since one decade ago. Thus, arginine-containing peptides as Tat or Antp, oligoarginine peptides, and derived peptoids have been described as shuttles for delivering nonpermeant drugs inside cancer cells. Herein we report a new family of tetraguanidinium cell penetrating vectors efficiently internalized in human tumor cells.

Multinuclear calixarene synthons with covalently linked aryl-palladium(II) complexes.

New synthetic procedures have been developed for potentially useful metallacalixarene building blocks. The metal sites were covalently connected to calix[n]arenes (n = 4, 6) by oxidative addition of 4-iodobenzyl precursors to either Pd(PPh(3))(4) or Pd(2)(dba)(3)/tmeda (dba = dibenzylideneacetone) to furnish calixarene-modified aryl-Pd(II)I(L(n)()) complexes [L(n)() = bis-PPh(3) or N,N,N',N'-tetramethylethylenediamine (tmeda)]. Methods were explored for the selective preparation of mono-Pd(II)-calix[4]arene and di-Pd(II)-calix[n]arenes (n = 4 or 6) complexes and also for bifunctional calix[4]arene synthons with two Pd(II) complexes accompanied by 4-pyridylmethyl or 4-cyanobenzyl groups.

p-(1H-phenanthro[9,10-d]imidazol-2-yl)- substituted calix[4]arene, a deep cavity for guest inclusion.

The reaction of tetra-p-formyltetra-O-propylcalix[4]arene with phenanthrenequinone in the presence of NH(4)OAc affords compound 2, a new class of calixarene with an expanded aromatic cavity, that could be stabilized by hydrogen-bonded bridges and/or ion pairing, thus preventing collapse into fully stacked pinched cone conformations as depicted. Two partially protonated calixarenes interdigitate in the solid state to give rise to a self-assembled face-to-face dimer, stabilized by pi-pi stacking interactions.

Dimerization inhibitors of HIV-1 protease based on a bicyclic guanidinium subunit.

Original inhibitors of HIV-1 protease based on a chiral bicyclic guanidinium scaffold linked to short peptidic mimics of the terminal protease sequences and to a lipophilic group were designed. These inhibitors prevent dimerization of the native protease by an interfacial structure at the highly conserved antiparallel beta-strand involving both the N and C termini that substantially account for dimerization. The preorganized guanidinium spacer introduces additional electrostatic hydrogen-bonding interactions with the C-terminal Phe-99 carboxylate.

Unexpected single-step formation of 1,2-anti-heterodisubstituted calix[4]arenes upon alkylation of a tribenzoyl precursor.

The selective preparation and complete structural characterization of a small series of 1,2-anti-heterodisubstituted calix[4]arenes has been accomplished. These compounds were obtained in two steps from unsubstituted p-tert-butylcalix[4]arene by tribenzoylation and a subsequent one-pot, two-step sequence involving alkylation with simultaneous partial deacylation, resulting in heterodisubstituted calixarenes carrying an alkyl and an aroyl group. The monoalkyl-tribenzoyl intermediate, prior to in situ deprotection, could also be isolated.

Guanidinium receptors as enantioselective amino acid membrane carriers.

A number of artificial carriers for the transport of zwitterionic aromatic amino acids across bulk model membranes (U-tube type) have been prepared and evaluated. 1,2-Dichloroethane and dichloromethane were employed in the organic phase. All compounds are based on a bicyclic chiral guanidinium scaffold that ideally complements the carboxylate function.

Enantioselective transport by a steroidal guanidinium receptor.

The cationic steroidal receptors 9 and 11 have been synthesized from cholic acid 3. Receptor 9 extracts N-acetyl-alpha-amino acids from aqueous media into chloroform with enantioselectivities (L:D) of 7-10:1. The lipophilic variant 11 has been employed for the enantioselective transport of N-acetylphenylalanine, a) through dichloromethane (DCM) and dichloroethane (DCE) bulk liquid membranes (U-tube apparatus), and b) through 2.

Resorcinarenes with 2-benzimidazolone bridges: self-aggregation, self-assembled dimeric capsules, and guest encapsulation.

The synthesis and spectroscopic characterization of self-assembled dimeric resorcinarenes 1a-d containing four 2-benzimidazolone (cyclic urea) bridges are reported. The nanometer-size capsules are held together by a cyclic array of complementary hydrogen bonds. Unlike the related imide-bridged resorcinarenes reported by Rebek and coworkers [Heinz, T.

A Self-Assembled Calix[4]arene Dimer Linked through Hydrogen-Bonded 2-Ureidopyrimidin-4(1H)-one Groups.

Tightly linked! A linear array of complementary hydrogen bonds forms between two 2-ureidopyrimidin-4(1H)-one rings attached to the upper rims of facing 1,3-alternate calix[4]arenes (shown schematically). The strength of the binding (K >10  M in chloroform) and the efficiency of the self-assembly open up interesting perspectives in the design of highly ordered multicomponent cages.

A Synthetic Cation-Transporting Calix[4]arene Derivative Active in Phospholipid Bilayers.

One order of magnitude: The transport of Na and K ions through a phospholipid bilayer occurs with much higher conductance levels with 1 and 2 than with typical Na -transporting proteins or gramicidin. However, the cations do not appear to pass through the calix[4]arene ring, which has a rigid 1,3-alternate conformation. diazacrown=10-benyzl-1,10-diaza[18]crown-6 group.