Jyotirmayee Dash

Synthesis of Carbazole Alkaloids by Ring-Closing Metathesis and Ring Rearrangement–Aromatization

Aprocess for the assembly of carbazole alkaloids has been developed on the basis of ring-closing metathesis (RCM) and ringrearrangement-aromatization (RRA) as the key steps. This method is based on allyl Grignard addition to isatin derivatives to provide smooth access to 2,2-diallyl 3-oxindole derivatives through a 1,2-allyl shift. The diallyl derivatives were used as RCM precursors to afford a novel class of spirocyclopentene-3-oxindole derivatives, which underwent a novel RRA reaction to afford carbazole derivatives. The synthetic sequence to carbazoles was shortened by combining the RCM and RRA steps in an orthogonal tandem catalytic process. The utility of this methodology was further demonstrated by the straightforward synthesis of carbazole alkaloids, including amukonal derivative, girinimbilol, heptaphylline, and bis(2-hydroxy-3-methylcarbazole).

Guanosine-Derived Supramolecular Hydrogels: Recent Developments and Future Opportunities

Hydrogels are attractive materials for designing sensors, catalysts, scaffolds for tissue engineering, stimuli responsive soft materials, and controlled-release drug delivery systems. In recent years, self-assembly of guanosine and its derivatives has received immense interests for devising programmable supramolecular biomaterials including hydrogels. This perspective highlights some of the history and the recent developments of guanosine-based supramolecular hydrogels and their applications. Future prospects and scope of the guanosine-based hydrogels have also been discussed.

Fluorescent Dansyl-Guanosine Conjugates that Bind c-MYC Promoter G-Quadruplex and Downregulate c-MYC Expression.

The four‐stranded G‐quadruplex present in the c‐MYC P1 promoter has been shown to play a pivotal role in the regulation of c‐MYC transcription. Small‐molecule compounds capable of inhibiting the c‐MYC promoter activity by stabilising the c‐MYC G‐quadruplex could potentially be used as anticancer agents. In this context, here we report the synthesis of dansyl‐guanosine conjugates through one‐pot modular click reactions. The dansyl‐guanosine conjugates can selectively detect c‐MYC G‐quadruplex over other biologically relevant quadruplexes and duplex DNA and can be useful as staining reagents for selective visualisation of c‐MYC G‐quadruplex over duplex DNA by gel electrophoresis. NMR spectroscopic titrations revealed the preferential binding sites of these dansyl ligands to the c‐MYC G‐quadruplex. A dual luciferase assay and qRT‐PCR revealed that a dansyl‐bisguanosine ligand represses the c‐MYC expression, possibly by stabilising the c‐MYC G‐quadruplex.

Cell penetrating thiazole peptides inhibit c-MYC expression via site-specific targeting of c-MYC G-quadruplex

Abstract The structural differences among different G-quadruplexes provide an opportunity for site-specific targeting of a particular G-quadruplex structure. However, majority of G-quadruplex ligands described thus far show little selectivity among different G-quadruplexes. In this work, we delineate the design and synthesis of a crescent-shaped thiazole peptide that preferentially stabilizes c-MYC quadruplex over other promoter G-quadruplexes and inhibits c-MYC oncogene expression. Biophysical analysis such as Förster resonance energy transfer (FRET) melting and fluorescence spectroscopy show that the thiazole peptide TH3 can selectively interact with the c-MYC G-quadruplex over other investigated G-quadruplexes and duplex DNA. NMR spectroscopy reveals that peptide TH3 binds to the terminal G-quartets and capping regions present in the 5′- and 3′-ends of c-MYC G-quadruplex with a 2:1 stoichiometry; whereas structurally related distamycin A is reported to interact with quadruplex structures via groove binding and end stacking modes with 4:1 stoichiometry. Importantly, qRT-PCR, western blot and dual luciferase reporter assay show that TH3 downregulates c-MYC expression by stabilizing the c-MYC G-quadruplex in cancer cells. Moreover, TH3 localizes within the nucleus of cancer cells and exhibits antiproliferative activities by inducing S phase cell cycle arrest and apoptosis.

Self-Assembly of a Guanosine Derivative To Form Nanostructures and Transmembrane Channels

We herein report the self-assembly of a lipophilic bromoguanosine derivative (G1) in homogeneous solution, in the solid state and in planar bilayer membranes. The self-assembly of G1, driven by H-bonding and π-π stacking interactions can form different nano-structures depending on incubation time. The G1 nanostructure is able to bind a bioactive dye like Rose Bengal. In crystal state, it shows ribbon type H-bonding pattern and exhibits birefringence in polarized light. And further, the self-assembled nanostructure of G1 can form discrete transmembrane ion channels in lipid bilayer membranes, enabling passage of potassium ions.

In vitro s creening of known drugs identified by scaffold hopping techniques shows promising leishmanicidal activity for suramin and netilmicin

ObjectiveThe rapid emergence of drug resistant Leishmanial strains makes it imperative to continue the development of cheap and effective drugs against the parasite. Due to the absence of effective vaccines against leishmaniasis, current therapeutic measures exclusively rely on chemotherapy. Here we attempt, to identify novel antileishmanial from a list of known drugs determined from a previous bioinformatics study. Synergism between various drug combinations (involving netilmicin, suramin, paromomycin and curcumin) have been estimated to identify potent multidrug therapies to combat the disease.ResultsThe drugs were screened against Leishmania promastigotes by utilizing the MTT assay and against intracellular amastigotes using murine Macrophage like tumor cell, RAW 264.7 as a host. In vitro drug interactions were tested for several drug combinations with a modified fixed ratio isobologram method against both Leishmania major and Leishmania donovani. This work reports the in vitro antileishmanial activity for the aminoglycoside netilmicin (for some Leishmania parasites) and the anti-trypanosomatid suramin. Synergism was also observed between paromomycin–suramin and netilmicin–curcumin.

Divergent and Orthogonal Approach to Carbazoles and Pyridoindoles from Oxindoles via Indole Intermediates

The previously unexplored Grignard addition to oxindoles provides a regiospecific approach to 2- and 2,3-disubstituted indole derivatives in high yields via a one-pot aromatization driven dehydration pathway. This method allows a convenient preparation of diallyl indoles that are used as ring-closing metathesis (RCM) precursors for the orthogonal synthesis of pyrido[1,2- a]indoles and carbazoles. The synthetic utility of this method is illustrated by the synthesis of a microtubulin inhibitor and naturally occurring carbazole alkaloids.

“On Water’’ Promoted Ullmann-Type C–N Bond-Forming Reactions: Application to Carbazole Alkaloids by Selective N-Arylation of Aminophenols

The Ullmann-type cross coupling of a variety of aromatic, aliphatic amines with aryl halides is reported using a CuI-based catalytic system in combination with an easily accessible prolinamide ligand in aqueous media. The method is mild and tolerant to air, moisture, and a wide range of functional groups, providing a novel way to access a variety of aminated products. Secondary amines like heteroaromatic amines and nucleobases have also been used, affording the corresponding coupling products in good to excellent yields. Moreover, this method has been employed for chemoselective C-N arylation of aminophenols and further utilized for the synthesis of carbazole natural products, avoiding the protection and deprotection steps.

Small Molecule Driven Stabilization of Promoter G-Quadruplexes and Transcriptional Regulation of c-MYC

G-quadruplexes have been considered attractive therapeutic targets for the development of anticancer agents. We herein report synthesis of a series of carbazole derivatives by employing modular one-pot Cu(I) catalyzed cycloaddition. These carbazole derivatives are easily synthesizable, soluble in aqueous media, and able to strongly interact with quadruplexes. FRET based melting assay and fluorescence titration experiments suggest that a carbazole derivative, Cz-1, preferentially binds c-MYC quadruplex DNA over other investigated quadruplex and duplex DNAs. The biological studies revealed that Cz-1 inhibits cancer cell proliferation by inducing apoptosis. Moreover, Cz-1 inhibits the expression of c-MYC at transcriptional as well as translational levels. Exon-specific-assay confirms that the downregulation of MYC expression is mainly driven by the binding of Cz-1 with the promoter G-quadruplex structures. Immunocytochemistry, using quadruplex binding antibody BG4, further suggests that Cz-1 induces and stabilizes G-quadruplexes in a cellular system.

Enzyme-Regulated DNA-Based Logic Device

Herein, we report a carbazole (Cz) ligand that displays distinct turn-on fluorescence signals upon interaction with human telomeric G-quadruplex ( h-TELO) and nuclease enzymes. Interestingly, Cz selectively binds and stabilizes the mixed hybrid topology of h-TELO G-quadruplex that withstands digestion by exonucleases and nuclease S1. The distinct fluorescence signatures of Cz-stabilized h-TELO with nucleases are used to design conceptually novel DNA devices for selectively detecting the enzymatic activity of DNase I as well as performing logic operations. An INHIBIT logic gate is constructed using h-TELO and DNase I as the inputs while the inputs of h-TELO and nuclease S1 form a YES logic gate. Furthermore, a two-input two-output reusable logic device with multireset function is developed by using h-TELO and DNase I as inputs. On the basis of this platform, combinatorial logic systems (INHIBIT-INHIBIT and NOR-OR) have been successfully installed using different combinations of nucleases as inputs. Moreover, this new strategy of using a synthetic dual emissive probe and enzyme/DNA inputs for constructing reusable logic device may find important applications in biological computing and information processing.