Red-light photosensitized cleavage of DNA by (l-lysine)(phenanthroline base)copper(II) complexes

Ternary copper(II) complexes [Cu(l-lys)B(ClO4)](ClO4)(1-4), where B is a heterocyclic base, viz. 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazene (dppz, 4), are prepared and their DNA binding and photo-induced DNA cleavage activity studied (l-lys =l-lysine). Complex 2, structurally characterized by X-ray crystallography, shows a square-pyramidal (4 + 1) coordination geometry in which the N,O-donor l-lysine and N,N-donor heterocyclic base bind at the basal plane and the perchlorate ligand is bonded at the elongated axial site. The crystal structure shows the presence of a pendant cationic amine moiety -(CH2)4NH3+ of l-lysine. The one-electron paramagnetic complexes display a d-d band in the range of 598-762 nm in DMF and exhibit cyclic voltammetric response due to Cu(II)/Cu(I) couple in the range of 0.07 to -0.20 V vs. SCE in DMF-Tris-HCl buffer. The complexes having phenanthroline bases display good binding propensity to the calf thymus DNA giving an order: 4 (dppz) > 3 (dpq) > 2 (phen)> 1 (bpy). Control cleavage experiments using pUC19 supercoiled DNA and distamycin suggest major groove binding for the dppz and minor groove binding for the other complexes. Complexes 2-4 show efficient DNA cleavage activity on UV (365 nm) or visible light (694 nm ruby laser) irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The amino acid l-lysine bound to the metal shows photosensitizing effect at red light, while the heterocyclic bases are primarily DNA groove binders. The dpq and dppz ligands display red light-induced photosensitizing effects in copper-bound form.     

Covalent linkage of the type-2 and type-3 structural mimics to model the active site structure of multicopper oxidases: synthesis and magneto- structural properties of two angular trinuclear copper(II) complexes

Two new angular trinuclear copper(II) complexes of formulation [Cu(3)(HL)LL'](ClO(4)), where L' is imidazole (Him, 1) or 1-methylimidazole (1-MeIm, 2) and H(3)L is a Schiff base obtained from the condensation of salicylaldehyde and 1,3-diaminopropan-2-ol (2:1 mole ratio), are prepared from a reaction of [Cu(2)L(mu-Br)] and [Cu(HL)] in the presence of L' and isolated as perchlorate salts. The crystal structures of 1 and 2 consist of a trinuclear copper(II) unit formed by the covalent linkage of monomeric type-2 mimic and dimeric type-3 mimic precursor complexes to give an angular arrangement of the metal atoms in the core which is a model for the active site structure of blue multicopper oxidases. In 1 and 2, the coordination geometry of two terminal copper atoms is distorted square-planar. The central copper has a distorted square-pyramidal (4 + 1) geometry. The mean Cu...Cu distance is approximately 3.3 A. The complex has a diphenoxo-bridged dicopper(II) unit with the phenoxo oxygen atoms showing a planar geometry. In addition, the complex has an endogenous alkoxo-bridged dicopper(II) unit showing a pyramidal geometry for the oxygen atom. The 1:1 electrolytic complexes show a d-d band at 607 nm. Cyclic voltammetry of the complexes in MeCN containing 0.1 M TBAP using a glassy carbon working electrode displays a Cu(3)(II)/Cu(2)(II)Cu(I) couple near -1.0 V (vs SCE). The variable temperature magnetic susceptibility measurements in the range 300-18 K show antiferromagnetic coupling in the complexes giving magnetic moments of approximately 3.0 mu(B) at 300 K and approximately 2.1 mu(B) at 18 K for the tricopper(II) unit. The experimental susceptibility data are theoretically fitted using a model with Heisenberg spin-(1)/(2) Hamiltonian for a trimer of spin-(1)/(2) copper(II) ions having two exchange parameters involving the alkoxo-bridged dicopper(II) (J1) and the diphenoxo-bridged dicopper(II) (J2) units, giving J1 and J2 values of -82.7, -73 cm(-1) for 1 and -98.3, -46.1 cm(-1) for 2, respectively. The structural features indicate a higher magnitude of anitiferromagnetic coupling in the alkoxo-bridged unit based on the greater value of the Cu-O-Cu angle in comparison to the diphenoxo-bridged unit. The core structures of 1 and 2 compare well with the first generation model complexes for the active site structure of multicopper oxidases in the oxidized form. The crystal structure of 1 exhibits a lamellar structure with a gap of approximately 7 A containing water molecules in the interlamellar space. Complex 2 forms a hexanuclear species due to intermolecular hydrogen bonding interactions involving two trimeric units. The crystal packing diagram of 2 displays formation of a three-dimensional framework with cavities containing the perchlorate anions.     

Simple aromatic amines from justicia gendarussa. 13C NMR spectra of the bases and their analogues

Four simple 0-disubstituted aromatic amines have been isolated from the leaves of Justicia gendarussa Burm and characterized as 2-amino benzyl alcohol (3), 2-(2′-amino-benzylamino) benzyl alcohol (4) and their respective 0-methyl ethers 1 and 2 from ¹H NMR and mass spectral analyses of the bases and their acetates. Structures 3 and 4 have also been confirmed by synthesis. Intramolecular hydrogen bonding (cf. 9, 13 and 14) has been envisaged to explain the unexpected shielding of -CH₂-OH carbon signals of 34 on acetylation and upfield displacement of -CH₂-N signal of 2a vs 4a in their ¹³C NMR spectra in CDCl₃ solution ₁J_CH values have been found to be useful for the assignment of aromatic methine carbon signals in o-disubstituted compounds. Part 68 of the series Studies on Indian medicinal plants. For Part 67, see P. K. Dutta, D. Bagchi and S.C. Pakrashi, Indian J. Chem. in press.     

Multiple time scale behaviors and network dynamics in liquid methanol

Canonical ensemble molecular dynamics simulations of liquid methanol, modeled using a rigid-body, pair-additive potential, are used to compute static distributions and temporal correlations of tagged molecule potential energies as a means of characterizing the liquid state dynamics. The static distribution of tagged molecule potential energies shows a clear multimodal structure with three distinct peaks, similar to those observed previously in water and liquid silica. The multimodality is shown to originate from electrostatic effects, but not from local, hydrogen bond interactions. An interesting outcome of this study is the remarkable similarity in the tagged potential energy power spectra of methanol, water, and silica, despite the differences in the underlying interactions and the dimensionality of the network. All three liquids show a distinct multiple time scale (MTS) regime with a 1/ f (alpha) dependence with a clear positive correlation between the scaling exponent alpha and the diffusivity. The low-frequency limit of the MTS regime is determined by the frequency of crossover to white noise behavior which occurs at approximately 0.1 cm (-1) in the case of methanol under standard temperature and pressure conditions. The power spectral regime above 200 cm (-1) in all three systems is dominated by resonances due to localized vibrations, such as librations. The correlation between alpha and the diffusivity in all three liquids appears to be related to the strength of the coupling between the localized motions and the larger length/time scale network reorganizations. Thus, the time scales associated with network reorganization dynamics appear to be qualitatively similar in these systems, despite the fact that water and silica both display diffusional anomalies but methanol does not.     

Molecularly nonstoichiometric crystals in phosphorus compounds

Molecularly nonstoichiometric crystals obtained as a result of differential occupation of sites with oxygen atom/phosphorus lone pair of electrons or with sulfur/selenium in three sets of phosphorus compounds are described. These are formed by a combination of (a) [CH2(6-t-Bu-4-MeC6H2O)2]PNMe2 (11) and [CH2(6-t-Bu-4-MeC6H2O)2]P(O)NMe2 (13), (b) [CH2(6-t-Bu-4-MeC6H2O)2]P(S)NMe2 (14) and [CH2(6-t-Bu-4-MeC6H2O)2]P(Se)NMe2 (15), and (c) [(2,6-Me2C6H3O)(O)P-micro-N-t-Bu]2 (16) and (2,6-Me2C6H3O)(O)P(micro-N-t-Bu)2P(O-2,6-Me2C6H3) (17). In the case of c, three different types of crystals with varying stoichiometry of 16 and 17 (1:9, 1:1.5, and 1:0.43) are obtained. The results are substantiated by the combined use of 31P NMR spectroscopy and X-ray crystallography. These observations suggest that we should be cautious with regards to the purity of samples when syntheses involving the oxidation of P(III) systems are reported. It is also emphasized that the apparent P-X distances in some of these crystals cannot actually be taken as true bond lengths.     

Waterlike structural and excess entropy anomalies in liquid beryllium fluoride

The relationship between structural order metrics and the excess entropy is studied using the transferable rigid ion model (TRIM) of beryllium fluoride melt, which is known to display waterlike thermodynamic anomalies. The order map for liquid BeF2, plotted between translational and tetrahedral order metrics, shows a structurally anomalous regime, similar to that seen in water and silica melt, corresponding to a band of state points for which average tetrahedral (q(tet)) and translational (tau) order are strongly correlated. The tetrahedral order parameter distributions further substantiate the analogous structural properties of BeF2, SiO2, and H2O. A region of excess entropy anomaly can be defined within which the pair correlation contribution to the excess entropy (S2) shows an anomalous rise with isothermal compression. Within this region of anomalous entropy behavior, q(tet) and S2 display a strong negative correlation, indicating the connection between the thermodynamic and the structural anomalies. The existence of this region of excess entropy anomaly must play an important role in determining the existence of diffusional and mobility anomalies, given the excess entropy scaling of transport properties observed in many liquids.     

Simultaneous determination of mercury and organic carbon in sediment and soils using a direct mercury analyzer based on thermal decomposition–atomic absorption spectrophotometry

The purpose of this work was to study the feasibility of using a direct mercury analyzer (DMA) to simultaneously determine mercury (Hg) and organic matter content in sediment and soils. Organic carbon was estimated by re-weighing the sample boats post analysis to obtain loss-on-ignition (LOI) data. The DMA-LOI results were statistically similar (p < 0.05) to the conventional muffle furnace approach. A regression equation was developed to convert DMA-LOI data to total organic carbon (TOC), which varied between 0.2% and 13.0%. Thus, mercury analyzers based on combustion can provide accurate estimates of organic carbon content in non-calcareous sediment and soils; however, weight gain from moisture (post-analysis), measurement uncertainty, and sample representativeness should all be taken into account. Sediment cores from seasonal wetland and open water areas from six oxbow lakes in the Mississippi River alluvial flood plain were analyzed. Wetland sediments generally had higher levels of Hg than open water areas owing to a greater fraction of fine particles and higher levels of organic matter. Annual loading of Hg in open water areas was estimated at 4.3, 13.4, 19.2, 20.7, 129, and 135 ng cm⁻² yr⁻¹ for Beasley, Roundaway, Hampton, Washington, Wolf and Sky Lakes, respectively. Generally, the interval with the highest Hg flux was dated to the 1960s and 1970s.     

The cis‐Diammineplatinum(II) Complex of Curcumin: A Dual Action DNA Crosslinking and Photochemotherapeutic Agent

[Pt(cur)(NH₃)₂](NO₃) ( 1 ), a curcumin‐bound cis‐diammineplatinum(II) complex, nicknamed Platicur, as a novel photoactivated chemotherapeutic agent releases photoactive curcumin and an active platinum(II) species upon irradiation with visible light. The hydrolytic instability of free curcumin reduces upon binding to platinum(II). Interactions of 1 with 5′‐GMP and ct‐DNA indicated formation of platinum‐bound DNA adducts upon exposure to visible light (λ=400–700 nm). It showed apoptotic photocytotoxicity in cancer cells (IC₅₀≈15 μM ), thus forming ^?OH, while remaining passive in the darkness (IC₅₀>200 μM ). A comet assay and platinum estimation suggest Pt–DNA crosslink formation. The fluorescence microscopic images showed cytosolic localization of curcumin, thus implying possibility of dual action as a chemo‐ and phototherapeutic agent.     

Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca²⁺-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.