Tricarbonyl rhenium(i) complexes with 8-hydroxyquinolines: structural, chemical, antibacterial, and anticancer characteristics.

Twelve tricarbonyl rhenium(i) complexes in the '2 + 1' system with the anionic bidentate N,O-donor ligand (deprotonated 8-hydroxyquinoline (HQ) or its 2-methyl (MeHQ) or 5-chloro (ClHQ) derivative) and neutral N-donor diazoles (imidazole (Him), 2-methylimidazole (MeHim), 3,5-dimethylpyrazole (Hdmpz), and 3-phenylpyrazole (HPhpz)) were synthesized: [Re(CO)3(LN,O)LN] (LN,O = Q-, MeQ-, ClQ-; LN = Him, MeHim, Hdmpz, HPhpz). Their crystal structures were determined by the scXRD method, compared with the DFT-calculated ones, and characterized by analytical (EA) and spectroscopic techniques (FT-IR, NMR, and UV-Vis) interpreted with DFT and TD-DFT calculations. Most of the Re(i) complexes did not show relevant antibacterial activity against Gram-negative and Gram-positive bacterial strains. Only [Re(CO)3(MeQ)Him] demonstrated significant action 4-fold better against Gram-negative Pseudomonas aeruginosa than the free MeHQ ligand. The cytotoxicity of the compounds was estimated using human acute promyelocytic leukemia (HL-60), ovarian (SKOV-3), prostate (PC-3), and breast (MCF-7) cancer, and breast non-cancerous (MCF-10A) cell lines. Only HQ and ClHQ ligands and [Re(CO)3(Q)Hdmpz] complex had good selectivity toward MCF-7 cell line. HL-60 cells were sensitive to all complexes (IC50 = 1.5-14 µM). Still, pure HQ and ClHQ ligands were slightly more active than the complexes.

VCD spectra of chiral naphthalene-1-carboxamides in the solid-state.

The VCD spectra of chiral 2,3-dihydro-1H-benzo[de]isoquinolin-1-one (8-substituted naphthalene-1-carboxamide, BIQ) were studied in KBr pellets. The X-ray diffractometry revealed that the Me, Ph, and pClPh BIQs crystalize in the monoclinic P21, while nBu, pMePh, and oMeOPh BIQs in the orthorhombic P212121 space group. Only the Me-BIQ crystal exhibits the presence of cyclic amide dimers, while the others contain chains of the amid group hydrogen bonds. For all BIQs, except pMePh, the most intense IR band in the 1750-1550 cm-1 region is located at ca. 1680 cm-1 and is accompanied by two weak ones at ca. 1618 and 1590 cm-1. For the pMePh derivative, four almost equally intense IR bands at 1662, 1639, 1614, and 1588 cm-1 are observed. This region of the IR spectra of BIQs, but pMePh, is well reproduced by calculations based on BIQ monomers. On the other hand, the complex IR pattern of pMePh is computationally reproduced when larger crystal fragments, like octamers, are considered. Registration of the VCD spectra enabled recognizing the complexity of IR contours at ca. 1680 cm-1 by the corresponding VCD motives. For (i) Me, Ph and pClPh (R)-enantiomers, two (+)(-) bands were distinguished and for (ii) nBu and pMePh ones, one VCD band with right-side asymmetry was found. For (iii) oMeOPh the VCD pattern cannot be unambiguously assigned. Thus, the VCD spectra in the ν(C=O) range diverse the studied compounds. Among the set of molecules, pMePh has exceptional crystal geometry. Therefore, its most intense ν(C=O) band position and shape can be connected with the geometry of the hydrogen bonds, interactions, and crystal packing. Interpretation of the VCD spectra is based on linear and packed BIQ octamers. This cluster model can reproduce the main features of the solid-state VCD of BIQs.

UV-vis and ECD spectroelectrochemistry of atropisomeric naphthalenediimide derivative.

The UV-vis and ECD spectroelectrochemistry (SEC) of a chiral binaphthalenylamine derivative of the N-butyl naphthalenediimide (NDIB-NH2) enantiomers were applied to measure UV-vis and ECD spectra of NDIB-NH2 radicals and dianion formed in the reduction and oxidation processes observed in cyclic voltammetry (CV). The CV curves and EPR spectroelectrochemistry enabled us to establish conditions at which a radical-anion [NDIB-NH2]̇.-, a dianion [NDIB-NH2]2-, and a radical-cation [NDIB-NH2]̇.+ are formed. The DFT restricted open-shell CAM-B3LYP-D3/def2TZVP/PCM calculations demonstrated that in the radical-anion [NDIB-NH2]̇.-, spin is spread over the NDI system while in the radical-cation [NDIB-NH2]̇+ it is spread over the aminonaphthalene moiety. The UV-vis spectra of radical-anion and dianion show the most significant changes in the 400-800 nm range. In that range, the ECD spectra varied with the change of electrode potential more than the UV-vis did and enabled the identification of a new ECD band of [NDIB-NH2]̇.- at ca. 400 nm hidden in the background in the UV spectra at -1000 mV. A broad structured ECD pattern with a maximum at ca. 530 nm was observed for [NDIB-NH2]̇.- (-1000 mV), while a single smooth ECD band of [NDIB-NH2]2- was located at 520 nm (-1750 mV). For the first time, an isosbestic point (455 nm) was found in ECD spectroelectrochemical measurements for the radical-cation [NDIB-NH2]̇.+ in equilibrium with the NDIB-NH2 neutral form. The TD-DFT CAM-B3LYP-D3/6-31G** calculations combined with the hybrid (explicit combined with implicit) solvation model fairly well reproduced the UV-vis and ECD SEC of neutral and redox forms of NDIB-NH2 but the ECD spectrum of [NDIB-NH2]̇.+ above 390 nm.

New chiral ECD-Raman spectroscopy of atropisomeric naphthalenediimides.

In this study, we found that a recently discovered ECD-Raman effect dominated over the natural Raman optical activity in a series of atropisomeric naphthalenediimides, and we investigated the kind of information about the molecular structure that could be obtained from the spectra. The ECD-Raman effect is polarised Raman scattering modulated by electronic circular dichroism. We showed that the spectra significantly depended on the substitution of the solute and/or the change of the solvent. Moreover, the spectra could be well-predicted by the theory, thus providing an interesting tool to monitor the chirality of the binaphthyl compounds.

Enantioselective sensing of (S)-Thalidomide in blood plasma with a chiral naphthalene diimide derivative.

Fast, simple in use and highly effective voltammetric enantiosensor dedicated for determination of thalidomide (TD) enantiomers (especially towards the toxic (S)-enantiomer) in blood plasma is still desirable. Here we have proven that newly synthesized chiral naphthalene diimide (NDI) derivatives are excellent electroactive materials for TD enantiosensors. The recognition process relies on the specific interaction between the chiral NDI receptor and the thalidomide enantiomer of the opposite configuration. This unique specific interaction between (S)-thalidomide and (R)-NDI derivative counterparts, evident in the DPV voltammograms, was confirmed by molecular modeling. The demonstrated voltammetric enantiosensors are characterized by the low detection limit at the level of µg·L-1, wide analytical range from 5·10-4 - 10 mg·L-1, high selectivity and long lifetime. The results of the recovery rates showed a very good degree of accuracy towards the determination of (S)-thalidomide in the blood samples, so it can be successfully used in the analysis of clinical samples.

On Raman optical activity sign-switching between the ground and excited states leading to an unusual resonance ROA induced chirality.

Raman optical activity (ROA) spectra recorded for a chiral naphthalene diimide derivative (nBu-NDI-BINAM) dissolved in a series of solvents exhibit strong solute to solvent induced chirality with: (1) dominating bands of solvents, (2) nBu-NDI-BINAM resonance ROA (RROA) bands which are barely visible, (3) monosignate RROA Solvent spectra with an unexpected sign concordant with that of the ECD band of the resonant electronic state, (4) bisignate RROA bands for a few solvents, and (5) superposition of non-resonant and resonant ROA bands of the chiral solvents. The unusual ROA enhancement was explained in terms of resonance energy transfer with resonant Raman emission. The surprising RROA sign-switching was found to be due to specific conformational equilibria where one solute conformer dominates in the ground and the other in the first excited singlet state, and, the signs of the related ECD bands of these two conformers are opposite.

The Vibrational Circular Dichroism Pattern of the ν(C=O) Bands in Isoindolinones.

The IR and vibrational circular dichroism (VCD) spectra of both enantiomers of Me-, iPr-, nBu-, Ph-, and CH2 Ph-substituted isoindolinones in solution and KBr pellets were measured and interpreted by DFT calculations. The spectra in solution revealed no important differences in the C=O stretching vibration region while the interpretation of very distinct spectra taken in pellets required determining the crystal structures. The studied compounds crystallized in the P21 21 21 (Me, iPr, CH2 Ph), P31 (nBu), and P21 (Ph) space groups. We found that the quality of simulated spectra strongly depends on the substituent, the structure of the molecular cluster assumed, basis set, and use of the dispersion correction. The IR spectra can be reproduced well based on the simplest linear arrangement of hydrogen-bonded chains mimicking the molecular arrangement in the crystals. We found no common approach to reproduce all the registered VCD spectra in the crystal phase. For the Me and nBu isoindolinones, the VCD pattern was the best reproduced by full optimization of the selected large molecular clusters. For iPr, Ph and CH2 Ph derivatives optimizing only the position of H-atoms in a fragment frozen as in the crystal provides the best results. Such an approach can reduce the computation time from months to one week.

Cyclo(Pro-DOPA), a third identified bioactive metabolite produced by Streptomyces sp. 8812.

A new metabolite, cyclic dipeptide, cis-(3S,8aS)-3-(3,4-dihydroxybenzyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, named JS-3 was isolated from Streptomyces sp. 8812 fermentation broth. Its chemical structure was established by means of spectroscopic analysis. A wide-range-screening study, which included inhibition assay of DD-carboxypeptidase/transpeptidase activity, determination of antibacterial, antifungal, and antiproliferative activities as well as free-radical scavenging was performed. To authors knowledge, this is the first isolation of such compound from natural sources and the first one from bacteria, Streptomyces.

Chiral Thiophene Sulfonamide-A Challenge for VOA Calculations.

Two enantiomers of 2-methyl-N-(1-thien-2-ylethyl)propane-2-sulfonamide (TSA) were synthesized, and their VCD, ROA, IR, and Raman spectra were registered. The solved (S)-TSA X-ray structure shows a disorder connected to the presence of two TSA conformers differing by a slight rotation of the thiophene ring. Two molecules in the unit cell of the monoclinic P21 crystal form a net of NH···OS and C*H···OS hydrogen bonds. Out of a series of computational levels tested to interpret the spectra, the B3LYP functional combined with the def2TZVP basis set satisfactorily reproduces the experimental VCD and ROA spectra. To simulate the VCD spectra of TSA enantiomers in KBr pellets, dimers and tetramers, with two different positions of the thiophene ring, were considered. The VCD spectra measured in CDCl3 are completely different from those taken in KBr due to the conformational freedom of TSA in chloroform. Seven TSA conformers fall into two groups of opposite configurations at the pyramidal N atom forming the additional stereogenic center. However, the barriers between conformers in each group are lower than the energy of thermal motions at 300 K. Thus, all conformers, but the most stable in each group, are likely to be metastable states. The calculated IR, VCD, Raman, and ROA spectra of the conformers depend not only on the type of stereogenic N atom but also on the thiophene ring rotation. Yet, they are likely to coexist because of low barriers between them. Three approaches were tested to reproduce the chiroptical spectra in solution using PCM and hybrid solvation models. As a consequence, it was found that a model in which all conformers contribute to the spectra with equal population factors seems to best reproduce the experimental data. Such a result suggests that in a dissolved state in 300 K TSA occurs in a very shallow potential well and all of its conformers coexist.

Preliminary study of mechanism of action of SN38 derivatives. Physicochemical data, evidence of interaction and alkylation of DNA octamer d(GCGATCGC)2.

The synthesis of water-soluble SN38 derivatives is presented, and their stability in solutions used during drug development studies has been investigated. A preliminary study of mechanism of action of 9-aminomethyl SN38 is presented. Using NMR techniques, the interaction of the oligomer d(GCGATCGC)2 is studied, showing that the terminal GC base pairs are the main site of interaction. Using pulsed field gradient spin echo and mass spectroscopy, evidence of a spontaneous alkylation reaction of the DNA oligomer with SN38 derivatives is presented. A proposed mechanism of reaction is suggested. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular docking studies, biological and toxicity evaluation of dihydroisoquinoline derivatives as potential anticancer agents.

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt's lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.

INTRACELLULAR ANTIOXIDANT ACTIVITY OF A STREPTOMYCES SP. 8812 SECONDARY METABOLITE, 6,7-DIHYDROXY-3,4-DIHYDROISOQINO- LINE-3-CARBOXYLIC ACID, AND ITS SYNTHETIC DERIVATIVES.

The aim of this study was to determine the antioxidant properties of 6,7-dihydroxy-3,4-dihydroiso- quinoline-3-carboxylic acid (1) and its derivatives in living cells against reactive forms of oxygen and nitrogen, i.e., hydrogen peroxide and nitric oxide. Four of tested compounds scavenged the reactive form of nitrogen more efficiently or similarly to Trolox (EC50 = 55.80 µM). Two compounds exhibited antioxidant activity against reactive oxygen species better than Trolox (EC50 = 51.88 µM). The most active derivative of 1 was the compound containing an iodine atom at position 8 (6,7-dihydroxy-8-iodo-3,4-dihydroisoquinoline-3-carboxylic acid). Our studies showed that some of the derivatives had the ability to cross the cell membrane and scavenge free radicals inside living cells. Thus, they are able to protect DNA and other cellular structures from the dam- aging effects of reactive oxygen and nitrogen species. In addition, some molecular descriptors of the tested compounds were determined with the use of ICM Pro (Molsoft L.L.C.).

DOSY NMR and MALDI-TOF evidence of covalent binding the DNA duplex by trimethylammonium salts of topotecan upon near UV irradiation.

Using DOSY NMR and MALDI-TOF MS techniques, we present evidence that quaternary trimethylammonium salts of topotecan, [TPT-NMe3 ](+) X(-) (X = CF3SO3, HCOO), bind covalently the natural DNA oligomer upon near UV irradiation in water under physiological conditions. It is shown that formate salt is very reactive at pH 7 and requires short irradiation time. This weak irradiation at 365 nm paves the way for a new application of TPT derivatives in clinical use, which can dramatically increase the therapeutic effects of a medicine.

New derivatives of 3,4-dihydroisoquinoline-3-carboxylic acid with free-radical scavenging, D-amino acid oxidase, acetylcholinesterase and butyrylcholinesterase inhibitory activity.

A series of 3,4-dihydroisoquinoline-3-carboxylic acid derivatives were synthesised and tested for their free-radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS·+), superoxide anion radical (O2·-) and nitric oxide radical (·NO) assays. We also studied d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Almost each of newly synthesised compounds exhibited radical scavenging capabilities. Moreover, several compounds showed moderate inhibitory activities against DAAO, AChE and BuChE. Compounds with significant free-radical scavenging activity may be potential candidates for therapeutics used in oxidative-stress-related diseases.

Genistein binding mode to doubly nicked dumbbell DNA. Dynamic and diffusion ordered NMR study.

New genistein derivatives were synthesized, which are fairly well soluble in water, with respect to parent genistein, and thus facilitate study of the interaction with dumbbell DNA dodecamer, mimicking the biological target for topoisomerase II inhibitors. A pulsed field gradient spin echo NMR experiment was used to check the binding and to estimate the association constants and its pH dependence of genistein with dumbbell DNA. Experimental restraints based on nuclear Overhauser spectroscopy spectra were used to calculate the NMR structure in solution in case of 6,8-disubstituted genistein with dimethylaminomethyl groups and were used in molecular modeling calculations. The structure is dynamic, and 10 molecular dynamics runs yield a family of conformations that essentially differ in a depth of inclusion of genistein into a nick. The paper experimentally shows evidence for binding, intercalation in the nick is proposed as a mode of genistein binding, and a model of the event is provided.

A dumbbell double nicked duplex dodecamer DNA with a PEG6 tether.

A hairpin dodecamer DNA motif with a dangling end composed of four bases was studied in order to find conditions which promote a dumbbell structure as the sole form in solution. It could be used as a model of a DNA duplex with two nicks on opposite strands, mimicking a target for topo II poisons. We have established two alternative means of obtaining a dumbbell in solution as the only form present at 0 °C. The first one is to use a relatively high concentration of a hairpin motif, ca. 3.5 mM, at low ionic strength, and second is to use a moderate hairpin motif concentration of ca. 2 mM at high ionic strength, 200 mM and 15% of methanol. An NMR-derived structure in a buffered water solution is presented. A representative structure ensemble of 10 structures was obtained from MD calculations utilizing the AMBER protocol and using NOESY-derived experiment cross peak volumes transferred to experimental restraints by the MARDIGRAS algorithm.

Topotecan dynamics, tautomerism and reactivity--1H/13C NMR and ESI MS study.

Topotecan (TPT) is in clinical use as an antitumor agent, hycamtin. Because of this, it requires both biologically and chemically useful information to be available. TPT acts by binding to the covalent complex formed by nicked DNA and topoisomerase I. This has a poisonous effect since inserted into the single-strand nick and TPT inhibits its religation. We used NMR to trace TPT dynamics, tautomerism and solvolysis products in various solvents and conditions. Chemical stability was assessed in methanol and DMSO as compared to water, and the regioselectivity of the N- and O-methylation was studied using various alkylating agents. The reaction products of quaternization of the nitrogen atom and methylation of the oxygen atom were characterized by means of ESI MS, (1)H/(13)C-HMBC and -HSQCAD NMR. We have focused on the NMR characterization of TPT with an anticipation that its aggregation, tumbling properties and the intramolecular dipolar interactions will be a common feature for other compounds described in this article. These features can also be useful in tracing the interactions of this class of topoisomerase I (TopoI) poisons with DNA. Moreover, the results explained shed light on the recently disclosed problem of lack of stability of TPT in the heart tissue homogenate samples using the analytical assays developed for this class of compounds carried out in the presence of methanol.

A novel isoquinoline alkaloid, DD-carboxypeptidase inhibitor, with antibacterial activity isolated from Streptomyces sp. 8812. Part II: Physicochemical properties and structure elucidation.

A novel antimicrobial agent labeled JS-1, being a member of isoquinoline alkaloids, of molecular formula C10H9NO4 was isolated from the culture broth of Streptomyces sp. 8812. In this study, we present the structure based on physicochemical and spectroscopic NMR investigations and on quantum chemical structure modeling. The structure of a molecule suggests the biosynthetic path starting from 3'-hydroxy tyrosine. The synthesis was undertaken and it resulted in NMR data that fully agree with the presented analysis.

Structure and dynamics of methyl cis-3,4-diamino-2,3,4,6-tetradeoxy-alpha-L-lyxo-hexopyranoside complexes with PtCl(2) and PdCl(2), by (1)H, (2)H, (13)C, (15)N and (195)Pt NMR spectroscopy in DMSO, CD(3)CN and H(2)O.

Pd(II) and Pt(II) chloride complexes with LL = methyl cis-3,4-diamino-2,3,4,6-tetradeoxy-alpha-l-lyxo-hexopyranoside of the formulae [Pd(LL)Cl(2)] and [Pt(LL)Cl(2)], 1, were studied by (1)H, (2)H, (13)C, (15)N and (195)Pt NMR spectroscopy. These techniques were applied for characterization of the structure and ligand exchange dynamics, in case of diastereomeric species formed from 1 in DMSO-d(6), DMSO-h(6) and H(2)O; their general formula was [Pt(LL)XY](+) (X = Cl, Y = DMSO-d(6), 2a; X = DMSO-d(6), Y = Cl, 2b; X = Cl, Y = DMSO-h(6), 2a'; X = DMSO-h(6), Y = Cl, 2b'; X = Cl, Y = H(2)O, 3a; X = H(2)O, Y = Cl, 3b). Their theoretical structures and NMR parameters, calculated at the level of DFT approach, were also presented and compared to the experimental data. The model complex [Pt(trans-diaminocyclohexane)Cl(2)], 4, was studied as well. To the best of our knowledge, this work is the first account dealing with the detailed analysis of structure and dynamics of ligand exchange processes in organic solvents and water, performed for a PtCl(2) complex containing a diaminosugar moiety. The kinetic behavior of the studied coordination compounds suggests that some of them may be potentially active in bioassays against cancer cells. Compound 1 exhibits noticeable versatile ligand exchange possibilities in DMSO and H(2)O. Particularly, it undergoes solvolysis in DMSO-d(6), exchanging one chloride atom and yielding two diastereomers 2a and 2b; the former, being the kinetically favored species, has the DMSO-d(6) ligand syn to the N(3) atom. The lyophilisate of the respective 2a + 2b mixture, earlier equilibrated in DMSO-d(6), after dissolving in H(2)O yields only the latter isomer, which is thermodynamically favored. The solvolysis of 1 in H(2)O yields instantaneously two diastereomeric monoaquated species, 3a and 3b, amounting to 10% of each.