My lab is interested in designing functional molecules for diverse applications in chemistry and biology. In the area of synthetic chemistry, we are developing new organic synthetic methodologies. These methodologies are applied for small molecule natural and nonnatural product libraries. We also design, synthesize and evaluate organic molecules for self-assembly and molecular recognition studies. Presently, we are developing synthetic ion channels and transporters for supramolecular chemistry and biology applications. We are also designing fluorescent probes for the detection of biologically relevant species.
Self-Assembly and Molecular Recognition
Noncovalent interactions play crucial role in assembling multiple organic molecules. We are developing small organic molecules and studying their self construction of supramolecular structures to study their functions.
Cyclo-oligo-(1->6)-ß-D-Glucosamine Based Artificial Channels for Tunable Transmembrane Ion Transport: Unimolecular ion channels were designed by functionalization of a new type of cyclic oligosaccharides, cyclo-oligo-(1->6)-ß-D-glucosamines, with pentabutylene glycol hydrophobic chains. Their ion transporting activity was tuned by varying oligomericity. A halide selectivity sequence, Cl- > Br- > I- was displayed by these molecules. (Reference: Chem. Eur. J. 2015, DOI: 10.1002/chem.201502656; Chem. Commun. 2014, 50, 5514-5516; Pure Appl. Chem. 2013, 85, 1879-1891.)
Rosette Type Synthetic Ion Channel from Small Molecules: The transport of ions across biological membranes is facilitated by a certain class of complex channel forming proteins. In these channel forming molecules, a number of ion-recognition sites are often disposed of along the narrow pore and the ions hop from one binding site to the next in single-file as the permeation proceeds. Natural ion channels allow the passage of a particular ion and the selectivity is primarily governed by the strengths of ion binding at these sites. Synthetic ion channel design strategies for incorporating multiple ion-recognition sites have primarily resulted in cation selectivity.
We have designed artificial supramolecular ion channels from diketal protected mannitol. In these supramolecules, the free –OH groups of mannitols are responsible for the self-assembled rosette-based nanotube formation and providing single-file anion recognition sites. BLM studies and molecular dynamics (MD) simulations indicate that the trimeric rosette. Theoretical studies also indicate that the channel molecules present in a rosette surround and interact with the Cl- ion via multiple O–H∙∙∙Cl- hydrogen bonding and the ion is then passed to the next layer of molecules ensuring a relay mechanism during transport. (Reference: J. Am. Chem. Soc. 2014, 136, 14128-14135.)
Alteration of level of a biologically relevant species is generally associated with the diseased state. Selective and quantitative imaging of such species is helpful in early detection of the disease. Our research is aimed towards the design and development of fluorescent probes for sensing these species. Our approach is to use theoretical calculations to predicting fluorescence properties before and after sensing. Present designs are focused towards the development of probes for the selective detection of cations, anions, biological thiols, thiophenols, hydrogen sulfide, etc. We are also working on development of dyes for based on fluorogenic click reaction.
Fluorescent probes for detection of biothiols: We are interested in developing fluorescent probes for biothiol detection. Our aim is to design probes for discrimination among biothiols such as Cys, Hcy and GSH. Recently, we have developed chromenoquinolines based probes for better sensitivity towards steric biothiols. We have also reported NBD-chloride as selective probe for sensing of Cys. This probe functions via two step process involving SNAr reaction followed by Smiles rearrangement. (References: Chem. Commun., 2012, 48, 2722-2724.; Org. Biomol. Chem., 2013, 11, 1691-1701; Sensor. Actuat. B-Chem. 2014, 196, 440–449.)
Fluorescent probes for detection of hydrogen sulfide: Hydrogen sulfide (H2S) has traditionally been known as a toxic chemical species in biological systems. However, emerging studies have challenged this view, and recognized the importance of H2S as one of the three essential gasotransmitters (NO and CO being other two). Considering the complex biological roles of H2S along with its volatile and reactive nature, the accurate detection of H2S is necessary in order to monitor its production and consumption in biological systems. We are interested in developing fluorescent probes owing to high sensitivity and the ability to conduct analysis in live systems.
Our first probe was based on the azide to amine reduction by H2S and BODIPY system was used as the off-on responsive fluorophore. The probe displayed very fast response times (10 min in HEPES, 30 second in BSA), 28-fold fluorescence enhancement and low detection limits (259 nM in HEPES, 265 nM in BSA). Application of the probe for the estimation of H2S in live cells was demonstrated (Reference: Org. Biomol. Chem. 2013, 11, 8166-8170).
We further designed two cascade-reaction based probes Reso-Br and Reso-N3. In one the H2S acts as nuclophile while while in other it functinos as reducing agent. The Reso-N3 probe was found to be superior over Reso-Br due to stability, and response behavior upon addition of H2S. During H2S sensing under these conditions, the Reso-N3 probe displayed k = 0.13 min-1, t1/2 = 5.33 min and sensitivity of 110-fold. Live cell imaging studies demonstrated applicability of Reso-N3 in the detection of intracellular H2S. (Reference: RSC Adv. 2015, 5, 1438-1446).
We have also devloped a metal-organic framework based fluorescence turn-on probe for highly selective detection of H2S. The probe displayed very low cytotoxicity in HeLa cells and strong turn-on fluorescence response during imaging of these cells (Reference: Sci. Rep. 2014, DOI: doi:10.1038/srep07053).
Fluorescent probes for detection of arylthiols: Aromatic thiols are widely used chemical intermediates in pharmaceutical, pesticide, polymers and amber dyes industries. In spite of their broad synthetic utility, aromatic thiols are the class of hazardous, highly toxic and pollutant chemicals. Presence of aromatic thiols in water and soil are reported to cause damage to natural habitats. Aromatic thiols exert adverse effect on human health by targeting central nervous system (CNS), kidney, and liver. Therefore we aimed to develop fluorescent probes for rapid and selective detection of aromatic thiols. (References: Analyst, 2012, 137, 3921-3924; Dyes Pigments. 2014, 106, 25-31.)
Fluorescent probes for detection of fluoride ion: Biological importance of fluoride ion (F-) in preventing enamel demineralization, dental and skeletal fluorosis, osteoporosis treatment, etc. encouraged us to design new fluorescent probe for selective detection of the ion. We have developed off-on fluorescent probes which work via the cascade reactions. (References: Tetrahedron Lett. 2015, 56, 4975-4979: RSC Adv. 2014, 4, 33890-33896; Chem. Commun. 2014, 50, 5510-5513; Org. Biomol. Chem. 2014, 12, 2143-2149.)
Fluorescent probes for Cu+ ion detection: We have established pyranine (1) as a new class of fluorescent chemosensor for the Cu+ ion. The probe is capable of discriminating ranges of cations from the Cu+ ion, even in competing environment. The dye displayed a rapid fluorescence response (t1/2 = 1.66 min) towards the Cu+ ion, and the micromolar detection limit enabled the detection of the ion in environmental samples. The observed stoichiometry of complexation between pyranine and Cu+ was 2:1. Interestingly, the sensing characteristic was specific to only neutral pH. A metal-to-ligand charge-transfer (MLCT)-based mechanism of sensing was proposed based on electron spin resonance (EPR), Raman spectroscopic and cyclic voltammetric studies (Reference: Photochem. Photobiol. Sci. 2014, 13, 1427-1433).
We are working on development of new methodologies and their applications in the synthesis of small molecule natural, unnatural product libraries. Our recent successful projects are:
Enantiodivergent synthesis of δ-unsaturated-γ-amino acid analogues: We have developed enantiodivergent strategy for the synthesis of R- and S-isomers of δ-unsaturated-γ-amino acids. The [3,3] sigmatropic rearrangements on E- and Z-alkenes were applied to achieve two opposite stereochemistries around the γ-amino acid backbone. Excellent ee > 94% are observed in the strategy. Cell permeability of a fluorescent amino acid derivative is evaluated by live-cell imaging. (Reference: Chem. Commun. 2013, 49, 3591-3593.)
Diastreoselective construction of syn-α-oxyamines and synthesis of (+)-ß-conhydrine and its analogues: We have developed a Cu(I) catalyzed a-oxyaldehyde-dibenzylamine-alkyne coupling reaction for obtaining syn-α-oxyamine with excellent diastereoselectivity. The methodology was applied for the synthesis of (+)-ß-conhydrine. The flexibility of methodology allowed us to synthesize pipiridine and pyrrolidine analogues of (+)-ß-conhydrine. (Reference: Org. Biomol. Chem. 2012, 10, 7536-7544.)
Stereoselective synthesis of (2S,3R)-alpha-hydroxy-ß-amino acids (AHBAs): We have developed a new methodology for the stereoselective synthesis of an alkynyl side-chain containing (2S,3R)-alpha-hydroxy-beta-amino acid ((2S,3R)-AHBA) analogues. The Cu(I)-catalyzed reactions of (R)-glyceraldehyde acetonide and dibenzylamine with terminal alkynes provided the corresponding (2S,3R)-alpha-amino alcohols with good-to-excellent diastereoselectivity. Subsequent chemical transformations provided easy access to the alkynyl side-chain containing (2S,3R)-AHBAs. The utility of the methodology was demonstrated by the stereoselective synthesis of valinoctin A and (2S,3R)-3-amino-2-hydroxydecanoic acid ((2S,3R)-AHDA). Photophysical properties and cell permeability of a pyrene-labeled (2S,3R)-AHBA were also determined. (Reference: J. Org. Chem. 2014, 79, 11215-11225.)
1,3-Amino group migration route to form acrylamidines: A novel 1,3-amino group migration strategy for the synthesis of acrylamidines is presented. Cu(I) catalyzed reaction of N,N-disubstituted propargylamine with tosylazide generates highly reactive ketenimine intermediate which is trapped by tethered amino group leading to the rearrangement reaction. (Reference: Chem. Commun. 2014, 50, 323-325.)