BODIPY(aryl)iodonium salts in the efficient synthesis of diversely functionalized BODIPYs and selective detection of serum albumin.

BODIPY(aryl)iodonium salts were readily accessible from the high-yielding reaction of BODIPY with iodoarenes or hydroxyl(tosyloxy)iodoarenes in the presence of m-CPBA. The prepared BODIPY(aryl)iodonium salts bearing substituents of varied electronic nature were utilized for the direct syntheses of thiocyanate, azide, amine and acrylate functionalized BODIPYs and ß,ß'-bis-BODIPYs. The regioselective syntheses of α-piperidinyl and ß-piperidinyl substituted BODIPYs were achieved through the reaction of BODIPY(aryl)iodonium salts with piperidine in the absence and presence of copper(I). Expeditious and high yielding (79-82%) synthesis of ß,ß'-bis-BODIPYs was also developed through the palladium-catalyzed reductive coupling of the easily accessible BODIPY(aryl)iodonium salts. Some of the indole-appended BODIPYs and bis-BODIPYs displayed strong absorption in the visible region (∼610 nm). The BODIPY(aryl)iodonium salts also showed significant binding with serum albumin and were observed to be selective serum protein sensors with estimated limits of detection as low as 7 µg mL-1 in some cases.

Janus HfSSe monolayer: a promising candidate for SO2and COCl2gas sensing.

Janus monolayers based on transition metal dichalcogenides have garnered significant interest as potential materials for nano electronic device applications due to their exceptional physical and electronic properties. In this study, we investigate the stability of the Janus HfSSe monolayer usingab initiomolecular dynamics simulations and analyze the electronic properties in its pristine state. We then examine the impact of adsorbing toxic gas molecules (AsH3, COCl2, NH3, NO2, and SO2) on the monolayer's structure and electronic properties, testing their adsorption on different active sites on top of hafnium, selenium, and sulfur. The sensitivity of the gas molecules is quantified in terms of their adsorption energy, with the highest and lowest energies being observed for SO2(-0.278 eV) and NO2(-0.095 eV), respectively. Additionally, we calculate other properties such as recovery time, adsorption height, Bader charge, and charge difference density to determine the sensitivity and selectivity of the toxic gas molecules. Our findings suggest that the Janus HfSSe monolayer has the potential to function as SO2and COCl2gas sensor due to its high sensitivity for these two gases.

Design, synthesis and anticancer activity of N-aryl indolylsulfoximines: Identification of potent and selective anticancer agents.

A facile and efficient approach utilizing copper-mediated cross-coupling reaction of N-boc-3-indolylsulfoximines with aryl iodides was developed to synthesize a diverse range of N-arylated indolylsulfoximines 11a-m in excellent yields (up to 91%). The key precursors, free NH sulfoximines 9 were readily prepared by the treatment of N-boc-3-methylthioindoles 8 with a combination of IBD and ammonium carbamate. Under similar conditions NH-free indolylsulfoximine 9a was successfully prepared in gram-scale quantities. The reaction is highly chemoselective and tolerant of a wide range of functional groups. The process is environmentally friendly and is amenable to scale-up. Among the prepared N-arylated indolylsulfoximines 11a-m, compounds 11i-j (2.68-2.76 µM), 11f-g (1.9-3.7 µM) and 11k (1.28 µM) showed potent and selective cytotoxicity against 22Rv1, C4-2 and MCF7 cells, respectively. Indolylsulfoximine derivative 11l displayed a broad spectrum of activity (1.7-8.2 µM) against the tested cancer cell lines. These compounds were found to be non-cytotoxic to normal HEK293 cells, indicating their potential selectivity for cancer cells. We analysed the impact of 11l on various cellular assays to uncover its mechanism of action. Cellular assay shows that 11l increases the endogenous level of ROS, leading to the increased level of p-53 and c-jun inducing apoptosis. 11l also induced mitochondrial dysfunction, further promoting apoptotic pathways. Besides, 11l also restricts cell invasiveness, indicating that it could serve as an effective anti-metastatic agent. As oxidative stress severe F actin causing tubulin depolymerization, we examined the impact of 11l on tubulin dynamics. Accordingly, 11l treatment decreased the levels of polymerized tubulin in 22Rv1 and C4-2 cells. Although future studies are needed to determine their exact molecular target(s), our data shows that N-aryl indolylsulfoximines could serve as effective anti-cancer agents.

A Remarkable Difference in Pharmacokinetics of Fluorinated Versus Iodinated Photosensitizers Derived from Chlorophyll-a and a Direct Correlation between the Tumor Uptake and Anti-Cancer Activity.

To investigate and compare the pharmacokinetic profile and anti-cancer activity of fluorinated and iodinated photosensitizers (PSs), the 3-(1'-(o-fluorobenzyloxy)ethyl pyropheophorbide and the corresponding meta-(m-) and para (p-) fluorinated analogs (methyl esters and carboxylic acids) were synthesized. Replacing iodine with fluorine in PSs did not make any significant difference in fluorescence and singlet oxygen (a key cytotoxic agent) production. The nature of the delivery vehicle and tumor types showed a significant difference in uptake and long-term cure by photodynamic therapy (PDT), especially in the iodinated PS. An unexpected difference in the pharmacokinetic profiles of fluorinated vs. iodinated PSs was observed. At the same imaging parameters, the fluorinated PSs showed maximal tumor uptake at 2 h post injection of the PS, whereas the iodinated PS gave the highest uptake at 24 h post injection. Among all isomers, the m-fluoro PS showed the best in vivo anti-cancer activity in mice bearing U87 (brain) or bladder (UMUC3) tumors. A direct correlation between the tumor uptake and PDT efficacy was observed. The higher tumor uptake of m-fluoro PS at two hours post injection provides a solid rationale for developing the corresponding 18F-agent (half-life 110 min only) for positron imaging tomography (PET) of those cancers (e.g., bladder, prostate, kidney, pancreas, and brain) where 18F-FDG-PET shows limitations.

PIFA-promoted intramolecular oxidative cyclization of pyrrolo- and indolo[1,2-a]quinoxalino-appended porphyrins: an efficient synthesis of meso,ß-pyrrolo- and indolo[1,2-a]quinoxalino-fused porphyrins.

We have developed an efficient protocol for the synthesis of meso,ß-pyrrolo- and indolo[1,2-a]quinoxalino-fused porphyrin systems 7-9 by PIFA-promoted intramolecular oxidative cyclization of easily accessible meso-pyrrolo- and indolo[1,2-a]quinoxalino-appended porphyrins 6a-j. The absorption spectra of meso,ß-pyrrolo- and indolo[1,2-a]quinoxalino-fused porphyrins 7-9 displayed bathochromic shifted (100-150 nm) and broadened Soret bands and Q bands in addition to intense band near IR region. The indolo[1,2-a]quinoxalino-fused porphyrin 9bZn with lower fluorescence quantum yield (0.003) and reduced energy gap (∼1.3 eV) was found to sensitize singlet oxygen effectively.

Rhodium(III)-Catalyzed Dehydrogenative Annulation and Spirocyclization of 2-Arylindoles and 2-(1H-Pyrazol-1-yl)-1H-indoles with Maleimides: A Facile Access to Isogranulatimide Alkaloid Analogues.

A Rh(III)-catalyzed dehydrogenative annulation and spirocyclization of 2-arylindoles and 2-(1H-pyrazol-1-yl)-1H-indole with maleimides is described. The cascade protocol provided highly functionalized benzo[a]pyrrolo[3,4-c]carbazole-1,3(2H,8H)-diones and spiro[isoindolo[2,1-a]indole-6,3'-pyrrolidine]-2',5'-diones in good to excellent. The developed reaction methodology exhibited broad substrate scope with good functional group tolerance and is operationally simple and scalable. Photophysical properties of the annulated products were investigated. The annulated product of 2-(1H-pyrazol-1-yl)-1H-indole showed high absorption and emission values with a large red-shift as compared to that of 2-phenylindole.

Palladium-Catalyzed Weakly Coordinating Lactone-Directed C-H Bond Functionalization of 3-Arylcoumarins: Synthesis of Bioactive Coumestan Derivatives.

A palladium-catalyzed highly regioselective ortho-selective C-H functionalization of 3-arylcoumarins has been developed. The method utilizes the weakly coordinating lactone as a directing group. The versatility of the strategy is highlighted by developing methodologies for alkenylation, halogenation, fluoroalkoxylation, and hydroxylation. Different functional groups were well tolerated, and functionalized coumarins were obtained in moderate to high yields. The method also showed good selectivity for monofunctionalization versus difunctionalization. The generated ortho-hydroxy derivatives were cyclized in the presence of DDQ, thus developing a simple and fast method for the synthesis of bioactive coumestan from 3-arylcoumarins.

Asymmetric Synthesis of Bridged N-Heterocycles with Tertiary Carbon Center through Barbas Dienamine-Catalysis: Scope and Applications.

A direct aza-Diels-Alder reaction between 2-aryl-3H-indolin-3-ones and cyclic-enones has been developed to access chiral indolin-3-one fused polycyclic bridged compounds. This method proceeds via proline-catalyzed Barbas-dienamine intermediate formation from various cyclic-enones such as 2-cyclopenten-1-one, 2-cyclohexene-1-one, and 2-cycloheptene-1-one, followed by a reaction with 2-aryl-3H-indol-3-ones. Several indolin-3-ones fusing [2.2.2], [2.2.1], and [3.2.1] skeletons decorated with a tertiary carbon chiral center have been prepared. Computational studies (DFT) supported the observed stereoselectivity in the method. The synthesized compounds have shown exciting photophysical activities and selective sensing of Pd2+ and Fe3+ ions through the fluorescence quenching "switch-off" mode.

Indolyl-α-keto-1,3,4-oxadiazoles: Synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization.

A series of novel indolyl-α-keto-1,3,4-oxadiazole derivatives have been synthesized by employing molecular iodine-mediated oxidative cyclization of acylhydrazones. In vitro anti cell proliferation activity of these derivatives against various cancer cells lines such as human lymphoblast (U937), leukemia (Jurkat & SB) and human breast (BT474) was investigated. Among the synthesized indolyl-α-keto-1,3,4-oxadiazoles 19a-p, only one compound (19e) exhibited significant antiproliferative activity against a panel of cell lines. The compound 19e with 3,4,5-trimethoxyphenyl motif, endowed strong cytotoxicity against U937, Jurkat, BT474 and SB cancer cells with IC50 values of 7.1, 3.1, 4.1, and 0.8 µM, respectively. Molecular docking studies suggested a potential binding mode for 19e in the colchicine binding site of tubulin. When tested for in vitro tubulin polymerizaton, 19e inhibited tubulin polymezations (IC50 = 10.66 µM) and induced apoptosis through caspase 3/7 activation. Further, the derivative 19e did not cause necrosis when measured using lactate dehydrogenase assay.

Chemoselective Cu-catalyzed synthesis of diverse N-arylindole carboxamides, ß-oxo amides and N-arylindole-3-carbonitriles using diaryliodonium salts.

Chemoselective copper-catalyzed synthesis of diverse N-arylindole-3-carboxamides, ß-oxo amides and N-arylindole-3-carbonitriles from readily accessible indole-3-carbonitriles, α-cyano ketones and diaryliodonium salts has been developed. Diverse N-arylindole-3-carboxamides and ß-oxo amides were successfully achieved in high yields under copper-catalyzed neutral reaction conditions, and the addition of an organic base (DIPEA) resulted in a completely different selectivity pattern to produce N-arylindole-3-carbonitriles. Moreover, the importance of the developed methodology was realized by the synthesis of indoloquinolones and N-((1H-indol-3-yl)methyl)aniline and by a single-step gram-scale synthesis of the naturally occurring cephalandole A analogue.

Fluorescent glutamine and asparagine as promising probes for chemical biology.

Fluorescent probes have become valuable tools in chemical biology, providing interesting inferences for unfolding the complexities of natural biochemical processes. In this study, we report the synthesis and characterization of fluorescent labelled glutamine (Gln) and asparagine (Asn) derivatives via traceless Staudinger ligation, which exhibited high fluorescence quantum yields, excellent photostabilities and emission of blue fluorescence in the visible region. The successful permeation of these fluorescent amino acids into cellular components proved their potential as fluorescent probes for chemical biology.

A novel triazole, NMK-T-057, induces autophagic cell death in breast cancer cells by inhibiting γ-secretase-mediated activation of Notch signaling.

Notch signaling is reported to be deregulated in several malignancies, including breast, and the enzyme γ-secretase plays an important role in the activation and nuclear translocation of Notch intracellular domain (NICD). Hence, pharmacological inhibition of γ-secretase might lead to the subsequent inhibition of Notch signaling in cancer cells. In search of novel γ-secretase inhibitors (GSIs), we screened a series of triazole-based compounds for their potential to bind γ-secretase and observed that 3-(3'4',5'-trimethoxyphenyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole compound (also known as NMK-T-057) can bind to γ-secretase complex. Very interestingly, NMK-T-057 was found to inhibit proliferation, colony-forming ability, and motility in various breast cancer (BC) cells such as MDA-MB-231, MDA-MB-468, 4T1 (triple-negative cells), and MCF-7 (estrogen receptor (ER)/progesterone receptor (PR)-positive cell line) with negligible cytotoxicity against noncancerous cells (MCF-10A and peripheral blood mononuclear cells). Furthermore, significant induction of apoptosis and inhibition of epithelial-to-mesenchymal transition (EMT) and stemness were also observed in NMK-T-057-treated BC cells. The in silico study revealing the affinity of NMK-T-057 toward γ-secretase was further validated by a fluorescence-based γ-secretase activity assay, which confirmed inhibition of γ-secretase activity in NMK-T-057-treated BC cells. Interestingly, it was observed that NMK-T-057 induced significant autophagic responses in BC cells, which led to apoptosis. Moreover, NMK-T-057 was found to inhibit tumor progression in a 4T1-BALB/c mouse model. Hence, it may be concluded that NMK-T-057 could be a potential drug candidate against BC that can trigger autophagy-mediated cell death by inhibiting γ-secretase-mediated activation of Notch signaling.

Expansion of Phosphane Treasure Box for Staudinger Peptide Ligation.

A smooth traceless ligation strategy using an air-stable phosphane probe (2-(diphenylphosphanyl)phenyl)methanol as a C-terminus activator has been demonstrated at simple and sterically hindered amino acid junctions (Gly, Ala, Trp, Glu). This Staudinger peptide ligation proceeds via formation of a seven-membered transition state to afford di-, tetra-, and pentapeptides in 78-95% yields. The experimental results of ligation at Gly junction and regioselective ligation at Glu junction were theoretically studied by computational calculations. These findings established the versatile behavior of our synthesized phosphane probe for Staudinger peptide ligation toward synthesizing peptides and proteins of choice.

Direct Amine-Catalyzed Enantioselective Synthesis of Pentacyclic Dibenzo[b,f][1,4]oxazepine/Thiazepine-Fused Isoquinuclidines along with DFT Calculations.

A direct protocol for the asymmetric synthesis of dibenzoxazepine/thiazepine-fused [2.2.2] isoquinuclidines is developed. The reaction proceeds through a proline-catalyzed direct Mannich reaction followed by an intramolecular aza-Michael cascade sequence between 2-cyclohexene-1-one and various tricyclic imines, like dibenzoxazepines/thiazepines, as an overall [4 + 2] aza-Diels-Alder reaction. A series of pentacyclic isoquinuclidines have been prepared, with complete endo-selectivity, in good to high yields and excellent enantioselectivity (>99:1). Density functional theory (DFT) calculations further support the observed high stereochemical outcome of the reaction.

Synthesis and investigations into the anticancer and antibacterial activity studies of ß-carboline chalcones and their bromide salts.

A series of sixteen ß-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-ß-carboline and various aldehydes under basic conditions followed by N2-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N2-Alkylated-ß-carboline chalcones 13a-i represented the interesting anticancer activities compared to N2-unsubstituted ß-carboline chalcones 12a-g. Off the prepared ß-carbolines, 13g exhibited broad spectrum of activity with IC50 values lower than 22.5 µM against all the tested cancer cell lines. Further, the N2-alkylated-ß-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared ß-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains.

Synthesis and anticancer activity studies of indolylisoxazoline analogues.

A new library of thirteen indolylisoxazolines 6a-m has been synthesized by the treatment of indolylchalcones with hydroxylamine hydrochloride. Evaluation of anticancer activity of indolylisoxazolines 6a-m led to the identification of potent compounds 6c-d, 6i and 6l, with IC50 ranging 2.5-5.0 µM against the tested cancer cell lines. Using a number of complementary techniques such as acridine orange/ethidium bromide staining, PARP1 cleavage and DNA strand breaks assay, we show that the compounds 6c and 6i induce apoptosis in highly aggressive C4-2 cells. Our data further revealed that 6c and 6i inhibited C4-2 cells proliferation without inducing reactive oxygen species (ROS). Finally, we show that compounds 6c and 6i also potently inhibit cell migration, indicating these compounds have the potential to serve as effective anti-cancer agents.

Metal-catalyzed direct heteroarylation of C-H (meso) bonds in porphyrins: facile synthesis and photophysical properties of novel meso-heteroaromatic appended porphyrins.

A simple and rapid microwave-assisted synthesis of heteroaromatic appended porphyrins using the Pd/Cu-catalyzed C-C coupling of meso-bromoporphyrins with various five- and six-membered heteroaromatic azoles has been successfully developed. The prepared heteroaromatic porphyrins 7a-lNi were found to exhibit slightly red-shifted (∼5-10 nm) Soret and Q bands. The developed reaction conditions are useful for the preparation of diversely substituted heteroaromatic porphyrins (A3B- and A2B2-types).

Synthesis of imidazopyridine-fused indoles via one-pot sequential Knoevenagel condensation and cross dehydrogenative coupling.

A simple and efficient strategy for the synthesis of imidazopyridine-fused indoles has been developed that involves one-pot sequential Knoevenagel condensation of readily available active methylene azoles with N-substituted-1H-indole-3-carboxaldehydes or N-substituted-1H-indole-2-carboxaldehydes followed by palladium-catalyzed intramolecular cross dehydrogenative coupling reaction. A series of 36 derivatives was prepared by using this strategy. The products were obtained in moderate to excellent (32-94%) yields and showed broad substrate scope with tolerance of various functional groups and was amiable for gram scale preparation without problems.

An efficient synthesis of triazolium ion based NHC precursors using diaryliodonium salts and their photophysical properties.

Copper-catalysed N-arylation of fused triazoles using diaryliodonium salts as an aryl source is described. This scalable protocol displayed good compatibility towards diverse sensitive functional groups like ester, alkyl and nitro groups and halogens (F, Cl, Br). The synthetic usefulness of the prepared triazolium salts was proved by preparing α-hydroxyketone through benzoin condensation. Photophysical studies of these compounds showed promising Stokes-shifted fluorescence emission in aqueous medium, so this molecular framework could be a proficient probe for biological applications.

Design, synthesis and in vitro cytotoxicity studies of novel ß-carbolinium bromides.

A series of novel ß-carbolinium bromides has been synthesized from easily accessible ß-carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and 16s exhibited potent anticancer activity with IC50 values of <10µM against tested cancer cell lines. The most potent analogue 16l was broadly active against all the tested cancer cell lines (IC50=3.16-7.93µM). In order to test the mechanism of cell death, we exposed castration resistant prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of cleaved PARP1 and AO/EB staining, indicating that ß-carbolinium salts induce apoptosis in these cells. Additionally, the most potent ß-carbolines 16l and 16s were found to inhibit tubulin polymerization.