Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.

Tricyclic Triazoles as σ1 Receptor Antagonists for Treating Pain.

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.

Intramolecular azide-alkyne cycloaddition for the fast assembly of structurally diverse, tricyclic 1,2,3-triazoles.

The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported. Some of these compounds exhibit significant affinity for the sigma-1 receptor.

Aminopyridine-benzoxanthene enantioselective receptor for sulfonylamino acids.

Combination of a cis-tetrahydrobenzoxanthene skeleton with a benzoxazole and an amidopyridine provides an enantioselective receptor for sulfonylamino acids with chiral recognitions of up to 18. The structure of the complex between receptor 1 and the leucine triflate is known by X-ray analysis. The receptor racemic mixture can be suitably resolved through crystalization in the presence of leucine triflate as guest. Receptor 1 can be used for the enantioselective extraction of sulfonylamino acids from aqueous solutions of their salts.

A trans-tetrahydrobenzoxanthene receptor for the resolution of racemic mixtures of sulfonylamino acids.

An enantioselective cleft-type receptor for sulfonylamino acids has been prepared and its use for the resolution of the amino acid racemic mixture is shown.

Self-assembly of double-decker cages induced by coordination of perylene bisimide with a trimeric Zn porphyrin: study of the electron transfer dynamics between the two photoactive components.

We describe the thermodynamic characterization of the assembly process of a covalently connected trimeric Zn porphyrin induced by coordination to a bispyridyl functionalized perylene bisimide . The perylene bisimide ligands act as pillars via two axial coordination bonds with the porphyrinic Zn(ii) ions fixing the planes of the porphyrin units in a nearly co-facial orientation and inducing the formation of trigonal prism-like structures. The fully assembled (2).(3) aggregate and the partially assembled one, (2).(2), in which only two zinc porphyrin sites of trimeric are axially coordinated to , are present in solution in equilibrium with freely diffusing species and . The strong quenching observed in the mixture for the luminescence of the components and is ascribed to an efficient photoinduced electron transfer from the Zn porphyrin units of to coordinated occurring upon excitation of both components within the assemblies. In the formed assemblies, the Zn porphyrin units of the trimer behave independently. Thus, the porphyrin units that are not coordinated with in the partially assembled complex, (2).(2), display the same photophysical behaviour registered for freely diffusing . The rate of charge separation within the cage is nearly independent on the polarity of the solvent (ca. 10(10) s(-1)) whereas the charge recombination process, leading to the ground state, has a lifetime of 110 ps in dichloromethane and ca. 6 ns in toluene, in agreement with a Marcus inverted behaviour.

Energy migration in a self-assembled nonameric porphyrinic molecular box.

We describe the construction of self-assembled double-decker porphyrin arrays built up from two covalently connected trimeric Zn-porphyrin units that are joined together by metal-coordination bonds with diamine ligands. We used three different types of diamine ligands: 1,4-diaza[2.2.2]bicyclooctane (DABCO), 4,4'-bipyridine (BIPY), and 5,15-bis(4-pyridyl)-10,20-diphenylporphyrin (DPYP). The ligands act as pillars, through two axial coordination bonds with the porphyrinic Zn(II) ions, to block the planes of the porphyrin units in an almost cofacial orientation and inducing the formation of a trigonal prismatic structure. The spectroscopic and photophysical properties of the Zn-trisporphyrin component were determined as well as those of the resulting multimolecular cagelike assemblies. The double-decker assembly with DPYP as the pillars constitutes a nonameric porphyrin aggregate. Although this assembly is thermodynamically less stable than those containing DABCO or BIPY, efficient photoinduced energy transfer occurs (96% yield) from the trisporphyrin base units to the DPYP side walls. The rate of the energy-transfer process is in good agreement with that calculated for a dipole-dipole (Förster) mechanism corrected for the unfavorable orientation geometry of the donor and the axially bound acceptor.

DABCO-Induced self-assembly of a trisporphyrin double-decker cage: thermodynamic characterization and guest recognition.

This paper describes the thermodynamic characterization of the self-assembly of a Zn trisporphyrin induced by coordination with 1,4-diazabicyclo[2.2.2]octane (DABCO) to form a stable 2:3 double-decker molecular coordination cage that recognizes benzene-1,3,5-tricarboxamides. The self-assembly process has been studied using UV-vis and (1)H NMR spectroscopy and quantitatively characterized in terms of a single stability constant that describes the strength of the individual coordination interactions and two effective molarities (EM) that describe the additional stability imparted by intramolecular cyclization. The EM values of the two consecutive cyclic intramolecular interactions are very similar. At micromolar concentrations, the formation of the fully assembled coordination cage is highly favored over the formation of intermediate species stabilized by fewer interactions, and so self-assembly is an all-or-nothing process. In contrast, at millimolar concentrations, the relative stability of intermediate species increases, leading to a stepwise self-assembly process, and a 2:2 intermediate can be clearly identified using (1)H NMR spectroscopy. The molecular recognition of benzene-1,3,5-tricarboxamides by the cage was investigated using (1)H NMR spectroscopy. The tricarboxamides bind inside the central cavity of the cage complex, and isothermal titration calorimetry (ITC) allowed the quantification of the stoichiometry and binding affinities.

Self-assembly, binding, and dynamic properties of heterodimeric porphyrin macrocycles.

A series of heterodimeric tetralactam macrocycles have been self-assembled using two kinetically labile zinc porphyrin-pyridine interactions. The stability constants have been determined by UV-vis titrations in CHCl3. The stability constants depend on the degree of preorganization of the linker units connecting the interacting groups. The ability of the self-assembled macrocycles to bind a terephthalamide guest was also investigated. One of the macrocycles was used for the construction of a [2]rotaxane. The dynamic properties of this system provide insight into the exchange mechanisms that operate in complex noncovalent assemblies.

Chromogenic charge transfer cleft-type tetrahydrobenzoxanthene enantioselective receptors for dinitrobenzoylamino acids.

A combination of a benzoxanthene cleft-type receptor with an electron-rich aromatic ring capable of establishing charge-tranfer interactions provides enantioselective receptors for dinitrobenzoylamino acids. Racemic mixtures of the receptor can be resolved with TLCs impregnated with the guest. The structure of the complexes has been established in an X-ray study. Enantiomeric amino acids provide complexes with different colors.

Enantioselective chromenone benzoxazole receptor for glutamic acid and its derivatives.

Combination of a binaphthyl unit with chromenone benzoxazole fragments provided a chiral receptor that is enantioselective for glutamic acid and its derivatives. The receptor racemic mixture was resolved by TLCs impregnated with (R,R)-thiodilactic acid. High association constants were measured for dansylglutamic acid, using a fluorescent method. This receptor can be used for the resolution of the tosylglutamic acid racemic mixture.