DDQ/Fe(NO3)3-Catalyzed Aerobic Synthesis of 3-Acyl Indoles and an In Silico Study for the Binding Affinity of N-Tosyl-3-acyl Indoles toward RdRp against SARS-CoV-2.

In the present study, we herein report a DDQ-catalyzed new protocol for the synthesis of substituted 3-acylindoles. Being a potential system for virtual hydrogen storage, introduction of catalytic DDQ in combination with Fe(NO3)3·9H2O and molecular oxygen as co-catalysts offers a regioselective oxo-functionalization of C-3 alkyl-/aryllidine indolines even with scale-up investigations. Intermediate isolation, their spectroscopic characterization, and the density functional theory calculations indicate that the method involves dehydrogenative allylic hydroxylation and 1,3-functional group isomerization/aromatization followed by terminal oxidation to afford 3-acylindoles quantitatively with very high regioselectivity. This method is very general for a large number of substrates with varieties of functional groups tolerance emerging high-yield outcome. Moreover, molecular docking studies were performed for some selected ligands with an RNA-dependent RNA polymerase complex (RdRp complex) of SARS-CoV-2 to illustrate the binding potential of those ligands. The docking results revealed that few of the ligands possess the potential to inhibit the RdRp of SARS-Cov-2 with binding energies (-6.7 to -8.19 kcal/mol), which are comparably higher with respect to the reported binding energies of the conventional re-purposed drugs such as Remdesivir, Ribavirin, and so forth (-4 to -7 kcal/mol).

Practical Access to meta-Substituted Anilines by Amination of Quinone Imine Ketals Derived from Anisidines: Efficient Synthesis of Anti-Psychotic Drugs.

Reversing the conventional site-selectivity of C-H activation provides efficient retrosynthetic disconnections to otherwise unreactive bonds. Described herein is the Brønsted acid-catalyzed reaction that selectively performs meta-amination of anisidines with aliphatic-, heterocyclic- and aromatic amines in a one-pot procedure. In addition to dramatically simplifying the synthesis of meta-substituted anilines, our approach has the advantage of the scalability and remarkable functional group tolerance, including late-stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed computational analysis provide insight into the reaction mechanism and the origin of meta-selectivity. The protocol extended to the synthesis of challenging tri-aminated arenes and successfully applied for the efficient synthesis of 5-HT6 receptor antagonists, the anti-psychotic drugs viz.. SB-214111, SB-258510, and specifically, anti-schizophrenic drug SB-271046.

Transition-Metal-Free Transfer Hydrogenative Cascade Reaction of Nitroarenes with Amines/Alcohols: Redox-Economical Access to Benzimidazoles.

This report describes an efficient transition-metal-free process toward the transfer hydrogenative cascade reaction between nitroarenes and amines or alcohols. The developed redox-economical approach was realized using a combination of KOtBu and Et3SiH as reagents, which allows the synthesis of benzimidazole derivatives via σ-bond metathesis. The reaction conditions hold well over a wide range of substrates embedded with diverse functional groups to deliver the desired products in good to excellent yields. The mechanistic proposal has been depicted on the basis of a series of control experiments, mass spectroscopic evidence which is well supported by density functional theory (DFT) calculations with a feasible energy profile.

Iron(III) Complex-Functionalized Gold Nanocomposite as a Strategic Tool for Targeted Photochemotherapy in Red Light.

Iron(III)-phenolate/carboxylate complexes exhibiting photoredox chemistry and photoactivated reactive oxygen species (ROS) generation at their ligand-to-metal charge-transfer (LMCT) bands have emerged as potential strategic tools for photoactivated chemotherapy. Herein, the synthesis, in-depth characterization, photochemical assays, and remarkable red light-induced photocytotoxicities in adenocarcinomic human immortalized human keratinocytes (HaCaT) and alveolar basal epithelial (A549) cells of iron(III)-phenolate/carboxylate complex of molecular formula, [Fe(L1)(L2)] (1), where L1 is bis(3,5 di-tert-butyl-2-hydroxybenzyl)glycine and L2 is 5-(1,2-dithiolan-3-yl)-N-(1,10-phenanthroline-5-yl)pentanamide, and the gold nanocomposite functionalized with complex 1 (1-AuNPs) are reported. There was a significant red shift in the UV-visible absorption band on functionalization of complex 1 to the gold nanoparticles (λmax: 573 nm, 1; λmax: 660 nm, 1-AuNPs), rendering the nanocomposite an ideal candidate for photochemotherapeutic applications. The notable findings in our present studies are (i) the remarkable cytotoxicity of the nanocomposite (1-AuNPs) to A549 (IC50: 0.006 µM) and HaCaT (IC50: 0.0075 µM) cells in red light (600-720 nm, 30 J/cm2) while almost nontoxic (IC50 > 500 µg/mL, 0.053 µM) in the dark, (ii) the nontoxicity of 1-AuNPs to normal human diploid fibroblasts (WI-38) or human peripheral lung epithelial (HPL1D) cells (IC50 > 500 µg/mL, 0.053 µM) both in the dark and red light signifying the target-specific anticancer activity of the nanocomposite, (iii) localization of 1-AuNPs in mitochondria and partly nucleus, (iv) remarkable red light-induced generation of reactive oxygen species (ROS: 1O2, •OH) in vitro, (v) disruption of the mitochondrial membrane due to enhanced oxidative stress, and (vi) caspase 3/7-dependent apoptosis. A similar cytotoxic profile of complex 1 was another key finding of our studies. Overall, our current investigations show a new red light-absorbing iron(III)-phenolate/carboxylate complex-functionalized gold nanocomposite (1-AuNPs) as the emerging next-generation iron-based photochemotherapeutic agent for targeted cancer treatment modality.

A noncovalent hybrid of [Pd(phen)(OAc)2] and st-DNA for the enantioselective hydroamination of ß-nitrostyrene with methoxyamine.

We developed a novel Pd-catalysed enantioselective synthesis of C-N bonds using the chiral scaffold of DNA. The non-covalently linked [Pd(phen)(OAc)2] with st-DNA catalysed the Markonicov hydroamination of ß-nitrostyrene with methoxyamine for the first time with >75% enantiomeric excess (ee) in an aqueous buffer (pH 7.4) at room temperature.

Strategic design and development of a siderophore mimic: pioneering anticancer therapy via ROS generation and ferroptosis.

We designed a tris-catecholate-based siderophore mimic, H6-T-CATL, to selectively chelate iron(III) from mitochondrial cytochromes and other iron-containing proteins within cellular matrices. This strategic sequestration aims to trigger apoptosis or ferroptosis in cancer cells through the glutathione (GSH)-dependent release of reduced iron and subsequent ROS-mediated cytotoxicity. Synthesis of H6-T-CATL involved precise peptide coupling reactions. Using the Fe(III)-porphyrin model (Fe-TPP-Cl), akin to cytochrome c, we studied H6-T-CATL's ability to extract iron(III), yielding a binding constant (Krel) of 1014 for the resulting iron(III) complex (FeIII-T-CATL)3-. This complex readily underwent GSH-mediated reduction to release bioavailable iron(II), which catalyzed Fenton-like reactions generating hydroxyl radicals (˙OH), confirmed by spectroscopic analyses. Our research underscores the potential of H6-T-CATL to induce cancer cell death by depleting iron(III) from cellular metalloproteins, releasing pro-apoptotic iron(II). Evaluation across various cancer types, including normal cells, demonstrated H6-T-CATL's cytotoxicity through ROS production, mitochondrial dysfunction, and activation of ferroptosis and DNA damage pathways. These findings propose a novel mechanism for cancer therapy, leveraging endogenous iron stores within cells. H6-T-CATL emerges as a promising next-generation anticancer agent, exploiting iron metabolism vulnerabilities to induce selective cancer cell death through ferroptosis induction.

Nondirected, Site-Selective Arylation of Quinone Imine Ketals Derived from Arylamines: One-Pot Access to meta-Substituted Anilines.

Herein, we develop a metal-free, nondirected, site-selective, one-pot approach to meta-arylation of arylamines. This Brønsted acid-catalyzed, direct C-C bond formation offers a broad substrate scope and scalability and creates the ideal conditions for overriding the conventional site-selectivity to furnish meta-substituted anilines. Additionally, the protocol applies to the meta-allylation of anilines and has been extended to afford late-stage functionalization and synthesis of medicinally privileged arylated diamines and densely functionalized anilines. The control experiments and density functional theory studies provide evidence for the proposed mechanism and selectivity.

Red light-activable biotinylated copper(II) complex-functionalized gold nanocomposite (Biotin-Cu@AuNP) towards targeted photodynamic therapy.

We report the synthesis and characterization of red-light activable gold nanoparticle functionalized with biotinylated copper(II) complex of general molecular formula, [Cu(L3)(L6)]-AuNPs (Biotin-Cu@AuNP), where L3 = N-(3-((E)-3,5-di-tert-butyl-2-hydroxybenzylideneamino)-4-hydroxyphenyl)-5-((3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide, L6 = 5-(1,2-dithiolan-3-yl)-N-(1,10-phenanthrolin-5-yl)pentanamide, which was explored for their photophysical, theoretical and photo-cytotoxic potentials. The nanoconjugate exhibits differential uptake in biotin positive and biotin negative cancer cells as well as normal cells. The nanoconjugate also shows remarkable photodynamic activity against biotin positive A549 (IC50: 13 µg/mL in red light; >150 µg/mL in dark) and HaCaT (IC50: 23 µg/mL in red light; >150 µg/mL in dark) cells under red light (600-720 nm, 30 Jcm-2) irradiation, with significantly high photo-indices (PI>15). The nanoconjugate is less toxic to HEK293T (biotin negative) and HPL1D (normal) cells. Confocal microscopy confirms preferential mitochondrial and partly cytoplasmic localization of Biotin-Cu@AuNP in A549 cells. Several photo-physical and theoretical studies reveal the red light-assisted generation of singlet oxygen (1O2) (Ф (1O2) =0.68) as a reactive oxygen species (ROS) which results in remarkable oxidative stress and mitochondrial membrane damage, leading to caspase 3/7-dependent apoptosis of A549 cells. Overall, the nanocomposite (Biotin-Cu@AuNP) exhibiting red light-assisted targeted photodynamic activity has emerged as the ideal next generation PDT agents.

Computational Studies of Selected Transition Metal Complexes as Potential Drug Candidates against the SARS-CoV-2 Virus.

The earth has witnessed the greatest global health crisis due to the outbreak of the SARS-CoV-2 virus in late 2019, resulting in the pandemic COVID-19 with 3.38 million mortality and 163 million infections across 222 nations. Therefore, there is an urgent need for an effective therapeutic option against the SARS-CoV-2 virus. Transition metal complexes with unique chemical, kinetic and thermodynamic properties have recently emerged as the viable alternative for medicinal applications. Herein, the potential application of selected antiviral transition metal-based compounds against the SARS-CoV-2 virus was explored in silico. Initially, the transition metal-based antiviral compounds (1-5) were identified based on the structural similarity of the viral proteins (proteases, reverse transcriptase, envelop glycoproteins, etc.) of HIV, HCV, or Influenza virus with the proteins (S-protein, RNA-dependent RNA polymerase, proteases, etc) of SARS-CoV-2 virus. Hence the complexes (1-5) were subjected to ADME analysis for toxicology and pharmacokinetics report and further for the molecular docking calculations, selectively with the viral proteins of the SARS-CoV-2 virus. The molecular docking studies revealed that the iron-porphyrin complex (1) and antimalarial drug, ferroquine (2) could be the potential inhibitors of Main protease (Mpro) and spike proteins respectively of SARS-CoV-2 virus. The complex 1 exhibited high binding energy of -11.74 kcal/mol with the Mpro of SARS-CoV-2. Similarly ferroquine exhibitred binding energy of -7.43 kcal/mol against spike protein of SARS-CoV-2. The complex 5 also exhibited good binding constants values of -7.67, -8.68 and -7.82 kcal/mol with the spike protein, Mpro and RNA dependent RNA polymerase (RdRp) proteins respectively. Overall, transition metal complexes could provide an alternative and viable therapeutic solution for COVID-19.

New Selenonapthaquinone-Based Copper (II) Complexes as the Next-Generation Photochemotherapeutic Agents.

BACKGROUND AND OBJECTIVE: Photoactive transition metal complexes like copper complexes find great interest in promoting metal-based photochemotherapeutic agents. In the present study, we explored the photocytotoxic efficacy of new selenylnaphthoquinone-based copper (II) complexes that provide a phenomenal platform in making an effective photo-chemotherapeutic agent via PDT in the clinical field of cancer therapy. METHODS: Three new copper(II) complexes (1-3) were synthesized in 40-60% yield and characterized analytically/ spectroscopically. ATCC® Normal Adult Human Primary Epidermal Keratinocytes were grown in Dermal Cell Basal Media supplemented with Keratinocyte Growth Kit components, to propagate keratinocytes in serum- free (not animal free) conditions. Anticancer activity of the complexes was studied using MTT (3- [4,5- dimethyltiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay. The intracellular ROS (1O2) generation was studied by using Flow Cytometric Analysis (FACS) on HaCaT cells using cell accessible non-polar 2',7'- Dichlorofluorescein Diacetate (DCFH-DA) dye. The Acridine Orange/Ethidium Bromide (AO/EB) dual staining assay was performed for detecting apoptosis in HaCaT cells. Several photophysical studies probing the generation of singlet oxygen was also carried out. We have performed Time-Dependent Density Functional Theory (TD-DFT) calculations using unrestricted B3LYP to understand the mechanism of type-II process. RESULTS: All the complexes were remarkably cytotoxic in HaCaT cells with IC50, 1-4µM under visible light with comparing lower dark toxicity. The presence of low-lying and long-lived triplet excited state allowed effective intersystem crossing and subsequent generation of singlet oxygen, which was the primary cytotoxic species responsible for oxidative stress and apoptosis. The experimental findings are in good agrrement with the computational analysis (TD-DFT). CONCLUSION: The remarkably enhanced cytotoxicity of the new selenyl copper (II) complexes under the visible light probed the role of Se in photosensitized generation of singlet oxygen which was responsible for apoptosis in HaCaT cells. The results in the present work are of paramount importance in developing next generation copper(II)-based PDT agents.

Interfacial and Aggregation Behaviour of Sodium Dodecyl Sulphate Induced by Ionic Liquids.

Aggregation studies of anionic surfactant sodium dodecyl sulphate (SDS) was investigated in aqueous 1-butyl-3-methylimidazolium chloride [bmim]Cl and N-butyl-N-methyl pyrrolidinium tetrafluoroborate [bmp]BF4 ionic liquid (IL) solutions respectively. Systems were studied by surface tension, conductance, UV-VIS absorption/emission spectroscopy and dynamic light scattering. Critical micelle concentration (CMC) values gradually decreased with increasing IL concentration which indicates synergistic interaction between ILs and SDS. Gibbs free energy change results demonstrated spontaneous micellization induced by ILs; however the effect of ILs were not similar to the corresponding regular salts (NaCl and NaBF4). Aggregation number (n) of micelles, determined by fluorescence quenching method, indicate that the 'n' values increase with increasing ILs concentration, induced by the oppositely charged IL cation. Size of the micelles, determined by dynamic light scattering studies, increased with increasing ILs concentration, which were due to the formation of larger aggregates; the aggregates are considered to be comprised of the anionic surfactant with a substantial proportion of ILs cation as the bound counter ions. Such studies are considered to shed further light in the fundamentals of IL induced micellization as well as in different practical applications.

Photo-physical, theoretical and photo-cytotoxic evaluation of a new class of lanthanide(iii)-curcumin/diketone complexes for PDT application.

Herein we report the synthesis, characterization, photophysical and photocytotoxicity studies of a new class of curcumin-based lanthanide(iii) complexes of general molecular formula [La(1,10-phen)2(L)(NO3)2] (1-4), where L = 1-phenylbutane-1,3-dione (L1, 1), 1-(anthracen-9-yl)butane-1,3-dione (L2, 2), 1-(3a1,5a1-dihydropyren-1-yl)butane-1,3-dione (L3, 3) and curcumin (L4, 4). Complex 1 was characterized by single-crystal X-ray crystallography and it exhibited the N4O6 coordination of La(iii). The presence of the low-lying and long-lived triplet excited state enabled the luminescent complexes (2-4) to generate singlet oxygen (1O2) in high yield when the complex was activated with visible light (400-700 nm, 10 J cm-2), which could be responsible for the photo-ablation of cancer cells. Complexes (2-4) exhibited remarkable photocytotoxicity in HeLa and MCF-7 cells with photocytotoxicity index 4-50 in the presence of visible light (400-700 nm, 10 J cm-2), while they were non-toxic in the dark with an IC50 value of >100 µM. The significantly lower toxicity (IC50 > 100 µM in the dark; IC50 in visible light ∼60 µM) of the complexes in MCF-10A (normal cells) in the dark and in visible light suggested their potential for targeting anticancer activity. Further studies showed that complex 4 induced caspase-dependent apoptosis through mitochondrial damage, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The cytosolic localization of complex 4 in HeLa cells, having a curcumin moiety as a fluorophore, was proved from the confocal microscopic studies. The photocytotoxicity of the complexes (1-4) was directly correlated to the efficacy of the complexes to generate singlet oxygen, which resulted in the photocytotoxicity order of 4 > 3>2 ≫ 1. Photo-physical studies revealed that the chelation of curcumin by La(iii) facilitated intersystem crossing in curcumin by reducing the energy gap of the singlet to triplet excited state. Therefore, the presence of low-lying and long-lived triplet excited state was responsible for increasing the generation of singlet oxygen and, thereby, photo-cytotoxicity in HeLa and MCF-7 cells. The present study has given an overall (Chemistry to Biology) perspective on the effect of La(iii) on the photo-cytotoxicity of selected photo-active curcumin-based ß-diketonate ligands.