Diorganotin (IV) amino acid complexes as potential anticancer agents. Synthesis, structural characterization, and in vitro assays.

Nine new organotin (IV) derivatives from L-amino acids (l-lysine, L-ornithine, L-glutamic acid, and L-aspartic acid) were synthesized by one-pot ultrasound-assisted methodology. All compounds were characterized by ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared), LRMS (Low-Resolution Mass Spectrometry), and solution NMR (1H, 13C, 119Sn Nuclear Magnetic Resonance) spectroscopies. Complexes Bu2Sn(Lys) (1), Ph2Sn(Lys) (2), Bu2Sn(Orn) (3), and Ph2Sn (Glu-OMe) (6a) were crystallized, and the structures were established by single-crystal X-ray diffraction analysis. Diffraction results evidenced that complexes 1 to 3 were five-coordinated mononuclear species while the phenyl substituted derivative Ph2Sn (Glu-OMe) (6a) forms a polymeric network via Sn-O-Sn bridging whereby the tin atom is six-coordinated. In turn, 119Sn NMR results revealed that all tin complexes exist as mononuclear penta-coordinated species in solution. The tin derivatives were screened for ADME (Adsorption, Distribution, Metabolism, and Excretion) properties via the freely available tools SWISS ADME, and the results were analyzed hereafter. The antiproliferative activity of the complexes was tested against three human cancer cell lines: colorectal adenocarcinoma HT-29, breast adenocarcinoma MDA-MB-231, and chondrosarcoma SW-1353 using a non-tumoral cell line of human osteoblast as control, demonstrating selective inhibitory activities against cancer cells. Hence, these compounds could be a promising alternative to classical chemotherapy agents.

Exploring the self-assembly dynamics of novel steroid-coumarin conjugates: a comprehensive spectroscopic and solid-state investigation.

The design, synthesis, and characterization of seven novel steroid-coumarin conjugates with diverse steroidal nuclei as lipophilic fluorescent materials for bioimaging applications are presented. The conjugates were synthesized through amidation, characterized using spectroscopic and spectrometric methods, and their main photophysical properties were determined. Dioxane : water titration experiments revealed their ability to self-assemble, forming J-aggregates as evidenced by new spectral bands at higher wavelengths. Monocrystal X-ray diffraction analysis disclosed distinctive aggregation patterns exhibiting J- or H-aggregates for selected compounds. Bioimaging studies demonstrated cell membrane localization for most conjugates, with some of them displaying an interesting selectivity for lipid droplets. Notably, the presence of the steroid fragments significantly influenced both the self-assembly patterns and the cellular localization of the fluorescent probes.

Polymer Network Comprised of Steroidal Rotors as a Promising Storage Material.

The front cover artwork is provided by Dr habil. Izabella Jastrzebska's group from the University of Bialystok, Poland. The image shows a polymeric network with molecular rotors (MR) as crosslinks. The MR rotation is slowed or inhibited when a molecule of stored gas is placed inside the polymer material. Read the full text of the Research Article at 10.1002/cphc.202300793.

Molecular Dynamics of Steroidal Rotors Probed by Theoretical, Spectroscopic and Dielectric Methods.

Our study focuses on molecular rotors with fast-moving rotators and their potential applications in the development of new amphidynamic crystals. Steroidal molecular rotors with a dipolar fluorine-substituted phenyl group as the rotator were synthesized and characterized. Three different rotors were investigated with varying numbers of fluorine atoms. A comprehensive analysis was performed using vibrational spectroscopy (Raman, FT-IR), electronic circular dichroism (ECD), and dielectric response to understand the behavior of the investigated model rotors. The results were supported by theoretical calculations using Density Functional Theory (DFT) methods. The angle-dependent polarized Raman spectra confirmed the crystallinity of the samples. Nearly frequency and temperature-independent permittivity suggest low-frequency librational motion of stators. An in-depth analysis of ECD spectra revealed high conformational flexibility in solution, resulting in low ECD effects, while in the solid-state with restricted rotation, significant ECD effects were observed. These findings shed light on the conformational behavior and potential applications of the studied steroidal molecular rotors.

Polymer network comprised of steroidal rotors as promising storage material.

In this paper, we report a new generation of polymeric networks as potential functional material based on changes in molecular dynamics in the solid state. The material is obtained by free radical polymerization of a diacrylate derivative bearing a steroid (stator) and a 1,4-diethynyl-phenylene-d4 fragment (rotator). Polymer research using the PALS technique complements the knowledge about nanostructural changes occurring in the system in the temperature range -115 °C - +190 °C. It indicates the presence of two types of free nanovolumes in the system and the occurrence of phase transitions. The polymer is characterized using 1 H NMR, 2 H Solid Echo NMR, ATR-FTIR and Raman spectroscopies, thermal analysis, and porosimetry. It is proved that the applied procedure leads to the formation of a novel porous organic material containing multiple molecular rotors.

A Trojan horse approach for enhancing the cellular uptake of a ruthenium nitrosyl complex.

Ruthenium nitrosyl (RuNO) complexes continue to attract significant research interest due to several appealing features that make these photoactivatable nitric oxide (NO˙) donors attractive for applications in photoactivated chemotherapy. Interesting examples of molecular candidates capable of delivering cytotoxic concentrations of NO˙ in aqueous media have been discussed. Nevertheless, the question of whether most of these highly polar and relatively large molecules are efficiently incorporated by cells remains largely unanswered. In this paper, we present the synthesis and the chemical, photophysical and photochemical characterization of RuNO complexes functionalized with 17α-ethinylestradiol (EE), a semisynthetic steroidal hormone intended to act as a molecular Trojan horse for the targeted delivery of RuNO complexes. The discussion is centered around two main molecular targets, one containing EE (EE-Phtpy-RuNO) and a reference compound lacking this biological recognition fragment (Phtpy-RuNO). While both complexes displayed similar optical absorption profiles and NO˙ release efficiencies in aqueous media, important differences were found regarding their cellular uptake towards dermal fibroblasts, with EE-Phtpy-RuNO gratifyingly displaying a remarkable 10-fold increase in cellular uptake when compared to Phtpy-RuNO, thus demonstrating the potential drug-targeting capabilities of this biomimetic steroidal conjugate.

Halogen Bonding in Brominated BODIPY Crystals: a Crystallographic and Computational Study.

The study of halogen bonds (XBs) has been a subject of great interest in recent years due to its clear application in catalysis, liquid crystals, and crystal engineering. In this study, we analyzed the intermolecular interactions, in particular halogen bonds in BODIPYs with an increasing number of bromine atoms. The computational study included analyses through three different methods: the first approach of close contacts provided by mercury, then the expanded approach of the electron density partition of the molecules in the crystals provided by the analysis of Hirshfeld surfaces, and finally, the approach of the Quantum Theory of Atoms in Molecules (QT-AIM) to characterize the non-covalent interactions through finding electron density critical points between atoms and between neighboring molecules. The use of different computational methods allowed to gain insight into the interactions directing the crystal packing as the number of bromine atoms increased in the BODIPY moiety. Monocoordinated and bifurcated halogen bonds involving halide/halide were found. The penta-brominated BODIPY showed four-center cyclic nodes where each node is linked via XBs. This kind of motif can be useful in supramolecular chemistry and self-assembly.

Synthesis of a New Co Metal-Organic Framework Assembled from 5,10,15,20-Tetrakis((pyridin-4-yl) phenyl)porphyrin "Co-MTPhPyP" and Its Application to the Removal of Heavy Metal Ions.

The synthesis of a Co metal-organic framework assembled from 5,10,15,20-tetrakis((pyridin-4-yl)phenyl)porphyrin; TPhPyP) "Co-MTPhPyP" is reported. The TPhPyP ligand was synthesized via aldehyde condensation in 28% yield and characterized by 1H nuclear magnetic resonance (1H NMR), Fourier-transform infrared (FTIR), high-resolution mass spectrometry (HRMS), and UV-visible spectroscopy (UV-vis). Co-MTPhPyP was prepared by the solvothermal method from TPhPyP and CoCl2·H2O in 55% yield and characterized by X-ray powder diffraction (XRD), FTIR, thermogravimetric analysis (TGA), field-emission scanning electron microscopy with energy-dispersive X-ray (FESEM-EDS), X-ray photoelectron spectroscopy (XPS), and dynamic light scattering (DLS), showing a particle size distribution of 418 ± 58 nm. The sorption properties of the Co-MTPhPyP for the effective removal of Pb(II) and Cu(II) were evaluated in an aqueous medium and Cthe results showed uptake capacities of 383.4 and 168 mg of the metal g-1 after 2 h, respectively. Kinetic studies of Pb(II) adsorption by Co-MTPhPyP were adjusted to the pseudo-second-order model with a maximum adsorption capacity of 458.8 mg g-1 at 30 min of exposition.

BODIPY-Ethynylestradiol molecular rotors as fluorescent viscosity probes in endoplasmic reticulum.

Due to their capability for sensing changes in viscosity, fluorescent molecular rotors (FMRs) have emerged as potential tools to develop several promising viscosity probes; most of them, however, localize non-selectively within cells, precluding changes in the viscosity of specific cellular microdomains to be studied by these means. Following previous reports on enhanced fluorophore uptake efficiency and selectivity by incorporation of biological submolecular fragments, here we report two potential BODIPY FMRs based on an ethynylestradiol spindle, a non-cytotoxic semisynthetic estrogen well recognized by human cells. A critical evaluation of the potential of these fluorophores for being employed as FMRs is presented, including the photophysical characterization of the probes, SXRD studies and TD-DFT computations, as well as confocal microscopy imaging in MCF-7 (breast cancer) cells.

Bimetallic Ruthenium Nitrosyl Complexes with Enhanced Two-Photon Absorption Properties for Nitric Oxide Delivery.

One monometallic and three bimetallic ruthenium nitrosyl (RuNO) complexes are presented and fully characterized in reference to a parent monometallic complex of formula [FTRu(bpy)(NO)]3+ , where FT is a fluorenyl-substituted terpyridine ligand, and bpy the 2,2'-bipyridine. These new complexes are built with the new ligands FFT, TFT, TFFT, and TF-CC-TF (where an alkyne C≡C group is inserted between two fluorenes). The crystal structures of the bis-RuNO2 and bis-RuNO complexes built from the TFT ligand are presented. The evolution of the spectroscopic features (intensities and energies) along the series, at one-photon absorption (OPA) correlates well with the TD-DFT computations. A spectacular effect is observed at two-photon absorption (TPA) with a large enhancement of the molecular cross-section (σTPA ), in the bimetallic species. In the best case, σTPA is equal to 1523±98 GM at 700 nm, in the therapeutic window of transparency of biological tissues. All compounds are capable of releasing NO⋅ under irradiation, which leads to promising applications in TPA-based drug delivery.

Nanoemulsified Formulation of Cedrela odorata Essential Oil and Its Larvicidal Effect against Spodoptera frugiperda (J.E. Smith).

Cedrela odorata L. is a plant species from the Meliaceae family that is cultivated for timber production. Although the C. odorata essential oil (EO) contains mainly sesquiterpenes, its insecticidal potential is unknown. The lipophilic properties and high degradation capacity of EOs have limited their application for use in pest control. However, the currently available knowledge on the nanoemulsification of EOs, in addition to the possibility of improving their dispersion, would allow them to prolong their permanence in the field. The objective of the present work was to develop a nanoemulsion of the C. odorata EO and to evaluate its larvicidal activity against Spodoptera frugiperda. The EO was obtained by the hydrodistillation of C. odorata dehydrated leaves, and the nanoemulsion was prepared with non-ionic surfactants (Tween 80 and Span 80) using a combined method of agitation and dispersion with ultrasound. The stability of the nanoemulsion with a droplet diameter of <200 nm was verified in samples stored at 5 °C and 25 °C for 90 days. Both the C. odorata EO and its corresponding nanoemulsion presented lethal properties against S. frugiperda. The results obtained provide guidelines for the use of wood waste to produce sustainable and effective insecticides in the fight against S. frugiperda. In addition, considering that a phytochemical complex mixture allows the simultaneous activation of different action mechanisms, the development of resistance in insects is slower.

Effect of the π-bridge on the light absorption and emission in push-pull coumarins and on their supramolecular organization.

A family of eight π-extended push-pull coumarins with cross-conjugated (amide) and directly conjugated (p-phenylene, alkyne, alkene) bridges were synthesized through a convergent strategy. Using an experimentally calibrated computational protocol, their UV-Visible light absorption and emission spectra in solution were investigated. Remarkably, amide-, alkyne- and alkene-bridges undergo comparable vertical excitations. The different nature of these bridges manifests during excited-state relaxation and fluorescence. We predict that these molecules can serve as building blocks for p-type semiconductors with low reorganization energies, below 0.2 eV. Since solid-state self-assembly is crucial for this application, we examined the effect of the π-bridge over the supramolecular organization in this family of compounds to determine if stacking prevails in these π-extended coumarin derivatives. Amide and alkyne spacers allow coplanar conformations which crystallize readily; p-phenylene hinders planarity yet allows facile crystallization; alkene-bridged molecules eluded all crystallization attempts. All the crystals obtained feature dense face-to-face π-stacking with 3.5-3.7 Å interlayer distances, expected to facilitate charge transfer processes in the solid state.

Polymeric Encapsulate of Streptomyces Mycelium Resistant to Dehydration with Air Flow at Room Temperature.

Encapsulation is one of the technologies applied for the formulation of biological control agents. The function of the encapsulating matrix is to protect the biological material from environmental factors, while dehydration allows for its viability to be prolonged. An advantage of dehydrated encapsulation formulations is that they can be stored for long periods. However, vegetative cells require low-stress dehydration processes to prevent their loss of viability. Herein we describe the fabrication of a dehydrated encapsulate of the Streptomyces CDBB1232 mycelium using sodium alginate with a high concentration of mannuronic acid; sodium alginate was added with YGM medium for mycelium protection purposes. The encapsulation was carried out by extrusion, and its dehydration was carried out in a rotating drum fed with air at room temperature (2-10 L min-1). The drying of the capsules under air flows higher than 4 L min-1 led to viability loss of the mycelium. The viability loss can be decreased up to 13% by covering the alginate capsules with gum arabic. Compared to conventional dehydration processes, air moisture removal can be lengthy, but it is a low-cost method with the potential to be scaled.

In vitro, ex vivo and in vivo short-term screening of DHEA nitrate derivatives activity over Trypanosoma cruzi Ninoa and TH strains from Oaxaca State, México.

Chagas disease is a health problem that affects millions of persons, currently Nifurtimox (Nfx) and Benznidazole (Bz) are the unique drugs to treat it. However, these drugs produce adverse effects and high toxicity, which has motivated the search for new candidate drugs. Based on reports about the extensive biological activity of steroidal nitrate esters, in this study three nitrate esters steroids (1b, 2b and 4b) were synthetized and characterized from Dehydroepiandrosterone (DHEA, 1a), 19-hydroxy-DHEA (2a), and Androst-5-en-3ß,17ß-diol (4a), respectively. In addition, compounds 3a and 3b were obtained by introducing an α-ethynyl and a ß-hydroxyl groups at position 17 of 2b and further nitration of the hydroxyl group. The trypanocidal activity of these steroids was evaluated in vitro against the epimastigote stage of two T. cruzi strains, Ninoa and TH, and their cytotoxicity over J774.2 macrophage cell line was assayed. Compounds 3a, 3b, and 4a shown higher trypanocidal activity than Bz and Nfx against epimastigotes of Ninoa strain, whereas DHEA (1a) and its nitrate derivative 1b showed higher activity than the reference drugs against the TH strain epimastigote. None of the compounds showed activity in the ex vivo assays against the blood trypomastigote of both strains. Interestingly, the selectivity index of Androst-5-en-3ß,17ß-diol 4a was almost twice the value of Nfx and 50 times more than Bz, against Ninoa and TH strains, respectively. Therefore, compound 4a could represent a valuable starting point toward the optimization of steroid derivatives as trypanocidal agents.

Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes.

The dianionic aza crown ether-dtc N,N'-bis(dithiocarbamate)-1,10-diaza-18-crown-6 (L2-) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [µ-(κ2-S,-S'-L)M2(PPh3)4]Cl2 (M = Pd (1), Pt (2)), [µ-(κ2-S,-S'-L)M2(PPh3)4](BPh4)2 (M = Pd (3), Pt (4)), and µ-(κ-S,-S'-L)Ni2(PPh3)2Cl2 (5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC50 values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC50 = 2.3 ± 0.2 µM for 2 versus 3.6 ± 0.5 µM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC50 decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 µM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC50 improves by ca. 40% reaching 1.3 ± 0.1 µM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the X-ray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.

Steroidal Molecular Rotors with 1,4-Diethynylphenylene Rotators: Experimental and Theoretical Investigations Toward Seeking Efficient Properties.

Properly designed molecular rotors with sizable stators and a fast-moving rotator could provide efficient building blocks for amphidynamic crystals. Herein, we report the synthesis of steroidal compounds 1, 2, and 3 and their deuterated analogues 1D, 2D, and 3D envisioned to work as molecular rotors. The obtained compounds were characterized by attenuated total reflection-infrared, Raman, and circular dichroism (CD) spectroscopy measurements. The interpretation of spectra was supported by theoretical calculations using density functional theory methods. The analysis of the most characteristic bands confirmed different molecular dynamics of the rotors investigated. Angle-dependent polarized Raman spectra showed the crystallinity of some samples. Electronic CD (ECD) spectra of compounds 1-3 and their relevant deuterated analogues 1D-3D are identical. The increase of the band intensity with lowering the temperature shows that the equilibrium is shifted to the thermodynamically most stable conformer. ECD spectra simulated at the TDFFT level of theory for compound 3 were compared with experimental results. It was proved that conformer 3a, with a torsion angle of +50°, exhibits the best agreement with the experimental results. Simulated vibrational CD and IR spectra for conformer 3a and its deuterated analogue 3Da also display good agreement with experimental results. In light of our comprehensive investigations, we evidenced that steroidal compounds 1, 2, and 3 can work as molecular rotors.

Two-Photon-Triggered NO Release via a Ruthenium-Nitrosyl Complex with a Star-Shaped Architecture.

We report herein a molecular engineering strategy based on the design of a multipolar ruthenium-nitrosyl (Ru-NO) complex with a three-branched architecture. The three Ru-NO units are introduced at the periphery of a highly π-delocalized truxene core bearing three terpyridine ligands. The two-photon absorption capabilities of the complex were investigated by the Z-scan technique. The strong electronic coupling among the individual arms gives rise to a very strong two-photon absorption response (δ800 nm ∼ 1600 GM), which corresponds to a 16-fold enhancement of the capability of a single-arm reference, thereby promoting an efficient light-driven NO release process in aqueous media.

Tuning the Cell Uptake and Subcellular Distribution in BODIPY-Carboranyl Dyads: An Experimental and Theoretical Study.

A set of BODIPY-carboranyl dyads synthesized by a Sonogashira cross-coupling reaction, where different C-substituted ortho- and meta-carboranyl fragments have been linked to a BODIPY fluorophore is described. Chemical, photophysical and physicochemical analyses are presented, including NMR and single XRD experiments, optical absorption/emission studies and partition coefficient (log P) measurements. These studies, supported by DFT computations (M06-2X/6-31G**), provide an explanation to the largely divergent cell income that these fluorescent carboranyl-based fluorophores display, for which a structural or physicochemical explanation remains elusive. By studying the cell uptake efficiency and subcellular localization for our set of dyads on living HeLa cells, we tracked the origins of these differences to significant variations in their static dipole moments and partition coefficients, which tune their ability to interact with lipophilic microenvironments in cells. Remarkably, m-carboranyl-BODIPY derivatives with a higher lipophilicity are much better internalised by cells than their homologous with o-carborane, suggesting that m-isomers are potentially better theranostic agents for in vitro bioimaging and boron carriers for boron neutron capture therapy.

Synthesis, complete NMR assignment and structural study of a steroidal dimer of 17α-ethynyl-5α,10α-estran-17ß-ol with diethynylbenzene spacer.

A phenylene-bridged steroidal dimer derived from 17α-ethynyl-5α,10α-estran-17ß-ol with molecular rotor-like architecture was synthesized to investigate the supramolecular interactions directing the crystallization of these systems. Structures with varying importance in complementarity between H-bonding and hydrophobic interactions can be observed directing the packing of the obtained crystals, depending on the synthetic stage, though conserving the same space group for both systems. Such behavior clearly shows the versatility achievable using steroids as crystal packing directors. Alongside this structural study, the complete NMR assignment is presented for the dimer, and precursors, in which the steroids present an unconventional and noteworthy A-B ring fusion.

TiCl4 catalyzed cleavage of (25R)-22-oxo-23-spiroketals. Synthesis of sapogenins with furostanol and pyranone E rings on the side chain.

The regioselective opening of the F ring of 22-oxo-23-spiroketals 7a-d using TiCl4 in acetic anhydride yielded the novel furostanols 11a-d along with cholestanic derivatives 8a-d with pyranone E ring. The structures of the new derivatives thus obtained were established using one- (DEPT) and two-dimensional 1H, 13C NMR experiments (COSY, HSQC, HMBC, NOESY). The 22α-hydroxyl orientation in compounds 11a-d was proposed by comparison of the 13C chemical shifts with those of other aglycone members of this family, and confirmed by combined NOESY and X-ray diffraction analysis of compound 11a.