A novel calix[4]pyrrole derivative as a potential anticancer agent that forms genotoxic adducts with DNA.

meso-(p-acetamidophenyl)-calix[4]pyrrole 3 was found to exhibit remarkable cytotoxicity towards A549 cancer cells. A comparative study including the isomer of 3 meso-(m-acetamidophenyl)-calix[4]pyrrole 5, as well as molecules containing 'fragments' of these structures, demonstrated that both the calix[4]pyrrole and the acetamidophenyl units are essential for high cytotoxicity. Although calix[4]pyrroles and other anion-complexing ionophores have recently been reported to induce apoptosis by perturbing cellular chloride concentrations, in our study an alternative mechanism has emerged, as proven by the isolation of covalent DNA adducts revealed by the 32P postlabelling technique. Preliminary pharmacokinetic studies indicate that 3 is able to cross the Blood-Brain-Barrier, therefore being a potential drug that could kill primary and brain metastatic cancer cells simultaneously.

A calixpyrrole derivative acts as an antagonist to GPER, a G-protein coupled receptor: mechanisms and models.

Estrogens regulate numerous pathophysiological processes, mainly by binding to and activating estrogen receptor (ER)α and ERß. Increasing amounts of evidence have recently demonstrated that G-protein coupled receptor 30 (GPR30; also known as GPER) is also involved in diverse biological responses to estrogens both in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds; nevertheless, some ligands exhibit opposed activity through these receptors. It is worth noting that, owing to the availability of selective agonists and antagonists of GPER for research, certain differential roles elicited by GPER compared with ER have been identified. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, such as breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data might open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives could be considered in future anticancer strategies targeting GPER in cancer cells.

Host-guest chemistry of a bis-calix[4]pyrrole derivative containing a trans/cis-switchable azobenzene unit with several aliphatic bis-carboxylates.

The azobenzene unit used as a photochemically and thermally switchable linker in the assembly of a bis-calix[4]pyrrole receptor provides a means to modulate the binding of bis-carboxylates of significant biological importance in cancer research. Conversely, the complexation of different bis-anionic guests has significant kinetic effects on both the photochemical and thermal trans/cis isomerization of the azobenzene unit.

Host-guest chemistry of aromatic-amide-linked bis- and tris-calix[4]pyrroles with bis-carboxylates and citrate anion.

A small library of polytopic receptors has been synthesized from meso-p- and meso-m-aminophenylcalix[4]pyrroles and p- or m-phthaloyl or trimesic chloride. Selected bis-carboxylates and the citrate anion, which either exhibit altered distribution profiles in cancerous tissues in comparison with healthy tissues or are metabolites of carcinogenic substances (for example, trans,trans-muconic acid from benzene exposure in humans) were tested as ligands. Varied affinities and binding modes were observed as a function of the number of calix[4]pyrroles and the topology of amide units present in each of the polytopic receptors. The structures of the 1:1 complexes derived by molecular modeling are in excellent agreement with the results of (1)H NMR complexation studies.

Drug delivery with a calixpyrrole--trans-Pt(II) complex.

A meso-p-nitroaniline-calix[4]pyrrole derivative trans-coordinated to a Pt(II) center was synthesized and its structure solved by X-ray analysis. Adenosine monophosphate (AMP) was used as a model compound to evaluate the potential for the assisted delivery of the metal to the DNA nucleobases via the phosphate anion-binding properties of the calix[4]pyrrole unit. An NMR investigation of the kinetics of AMP complexation in the absence of an H-bonding competing solvent (dry CD(3)CN) was consistent with this hypothesis, but we could not detect the interaction of the calix[4]pyrrole with phosphate in the presence of water. However, in vitro tests of the new trans-calixpyrrole-Pt(II) complex on different cancer cell lines indicate a cytotoxic activity that is unquestionably derived from the coexistence of both the trans-Pt(II) fragment and the calix[4]pyrrole unit.

The absolute configuration of palladium(II) and ruthenium(II) pseudochiral centers in either chiral or achiral environments.

The meso-dithioxamide H-((R)-1-(1-phenyl)ethyl)-NSC-CSN-((S)-1-(1-phenyl)ethyl)-H (H(2)-mesoDTO) bonds [(η(6)-p-cymene)chlorido-ruthenium(II)](+) or [(η(3)-allyl)-palladium(II)](+) fragment and provides the C(s) symmetrical complexes [(η(6)-p-cymene)ClRu(H-mesoDTO κ-S,S Ru)] (1) and [(η(3)-allyl)palladium(H-mesoDTO κ-S,S Pd)] (2). These complexes are pseudochiral, and each of them exists as a mixture of two symmetrical meso forms. The improper symmetry of [(η(3)-allyl)palladium(H-mesoDTO κ-S,S Pd)] has been broken in two different ways: (i) by changing the symmetrical allyl moiety with a η(3)-crotyl frame or (ii) by substituting the residual amidic hydrogen in the dithiooxamidate ligand with a M(PR(3))Cl(+) fragment (M = Pd or Pt and PR(3) = triorganophosphine). As a consequence, a chiral plane is added to the pseudochiral palladium center, and two pairs of enantiomers are formed in each case. Furthermore, [(η(6)-p-cymene)chlorido-ruthenium(II)](+) and [(η(3)-allyl)-palladium(II)](+) fragments have been joined by means of the binucleating meso-dithiooxamidate ligand in a κ-S,S Ru κ-N,N Pd coordination mode. The resulting C(s)-symmetrical complex [(η(6)-p-cymene)ClRu(µ-mesoDTO κ-S,S Ru κ-N,N Pd)Pd(η(3)-allyl)] (8) possesses two pseudochiral metal centers, and it is therefore a mixture of four isomeric meso forms. All of these isomers in a chloroform solution interconvert in that both palladium and ruthenium invert their configurations. A mechanism of epimerization for both palladium and ruthenium is proposed. The absolute configurations of pseudochiral palladium in [(η(3)-allyl)(c)-Pd(µ-((R)-1-(1-phenyl)ethyl)-NSC-CSN-((S)-1-(1-phenyl)ethyl) κ-N,N (c)-Pd κ-S,S (A,C)-Pd)(A,C)-Pd(tri(n)propyl-phosphine)Cl] (6) and of pseudochiral palladium and ruthenium in [(η(3)-allyl)(c)-Pd(µ-((R)-1-(1-phenyl)ethyl)-NSC-CSN-((S)-1-(1-phenyl)ethyl) κ-N,N (c)-Pd κ-S,S(s)-Ru)(s)-Ru(η(6)-isopropyltoluene)Cl] (8) are provided. A suitable stereochemical notation is proposed for bimetallic complexes containing pseudochiral centers in either a chiral or an achiral environment.

Synthesis, X-ray structure, and anion-binding properties of a cryptand-like hybrid calixpyrrole.

The novel cryptand in/out-3, containing two tripyrrolemethane units bridged by three 1,3- diisopropylidenbenzene arms, was readily synthesized by a convergent three-step synthesis. It binds fluoride by inclusion with excellent selectivity with respect to a number of other tested anions. The structure of the free receptor and that of its fluoride complex were investigated in solution by NMR spectroscopy. The solid-state X-ray structure of the free cryptand 3 was also determined.

Calixpyrrole derivatives: "multi hydrogen bond" catalysts for gamma-butenolide synthesis.

Calix[4]pyrrole (1), calix[2]m-benzo[4]pyrrole (2), 10alpha,20beta- and 10alpha,20alpha- bis(4-nitrophenyl)-calix[4]pyrroles 3 and 4, respectively, were found to exhibit various organocatalytic activities in the diastereoselective vinylogous addition reaction of 2-trimethylsilyloxyfuran (TMSOF, 7) to aldehydes. The gamma-hydroxybutenolide products are obtained in fairly good yields and with moderate diastereoselectivity. The structures of the catalysts, as well as the reaction conditions, strongly influence the efficiency of the reaction.

pH-Controlled molecular switches and the substrate-directed self-assembly of molecular capsules with a calix[4]pyrrole derivative.

10alpha,20alpha-Bis(4-nitrophenyl)calix[4]pyrrole (1) forms 1:1 complexes with anions of selected aromatic hydroxy acids in which the host orientation within the guest is controlled by a change in the pH value. Some bis-anionic guests, including those obtained from 4-hydroxybenzoic acid, 1,4- and 1,3-benzenedicarboxylic acids, induce the self-assembly of molecular capsules involving two molecules of the receptor. (1)H NMR data and solid-state structures of the 1:1 complex of 1 with p-C(6)H(4)(COOH)(COO(-))(+)NMe(4) and the 2:1 capsule [(1)(2)m-C(6)H(4)(COO(-))(2)((+)NMe(4))(2)] provide structural details in solution and in the solid state.

Syntheses, structures, and anion-binding properties of two novel calix[2]benzo[4]pyrroles.

Calix[2]benzo[4]pyrrole m-6 and p-6, each containing two dipyrromethane moieties and two m-phenylene or p-phenylene units, respectively, were readily synthesised from pyrrole, 1,3- and 1,4-bis(1,1'-dimethylhydroxymethyl)benzene, (m-4 and p-4, respectively) and acetone. Macrocycles m-6 and p-6 were tested as receptors for a selection of anions, such as acetate, dihydrogenphosphate and fluoride. The X-ray structures of m-6 and p-6 and those of the complexes m-6F(-), m-6Cl(-) and m-6CH(3)COO(-) (with an nBu(4)N(+) counterion) were also determined.

Calix[6]pyrrole and hybrid calix[n]furan[m]pyrroles (n+m=6): syntheses and host-guest chemistry.

Calix[6]pyrrole 2 and the "hybrid systems" calix[3]furan[3]pyrrole 12, calix[2]furan[4]pyrrole 13, and calix[1]furan[5]pyrrole 14, have been synthesized by increasing conversion of the furan units present in the readily accessible calix[6]furan 3 to pyrroles. The host-guest chemistry of these novel macrocycles towards a number of anions, including halogen ions, dihydrogen phosphate, hydrogen sulfate, nitrate, and cyanide has been investigated in solution by (1)H NMR titration techniques and/or phase transfer experiments. The solid-state structures of the free receptors 2, 12, and 13, the 1:1 complexes of calix[6]pyrrole 2 with chloride and bromide, and the 1:1 complex of 14 with chloride are also reported.

The Elusive beta-unsubstituted calix[5]pyrrole finally captured.

[reaction: see text] The meso-decamethyl-calix[5]pyrrole 2b was synthesized from the furan-based analogue 1b via the homologation of the furan rings to pyrrole, and its solid-state structure was determined by X-ray crystallography: surprisingly, the binding constant of 2b toward chloride is found to be lower than that of the tetrameric analogue 2a.