Enantiopure synthesis of dihydrobenzo[1,4]-oxazine-3-carboxylic acids and a route to benzoxazinyl oxazolidinones

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 13, Issue : 11, Pages : 3211-3219

DOI : 10.1039/c4ob02475c

Author : Malhotra, Rajesh; Dey, Tushar K.; Basu, Sourav; Hajra, Saumen

Abstract : A two step protocol is developed for the efficient synthesis of enantiopure N-Boc-dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids from serine derived cyclic sulfamidate via intramol. arylamination. The RuPhos Palladacycle along with addnl. RuPhos ligand is an efficient catalyst for the arylamination of β-(2-bromoaryloxy)amino acids 3 to provide easy and direct access to a variety of dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4 with complete retention of enantiopurity in moderate to high yields. Dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids are not only important unnatural amino acids, but are key precursors for the synthesis of important compounds such as benzoxazinyl oxazolidinones. A general approach for the synthesis of benzoxazinyl oxazolidinone is presented.

A Palladium on Carbon Catalyzed One-Pot Synthesis of Substituted Benzimidazoles

Published in: Journal, Volume : 46, Issue : 22, Pages : 3121-3132

DOI : 10.1055/s-0034-1378454

Author : Joardar, Soumen; Bhattacharyya, Anjan; Das, Saktipada

Abstract : A new and efficient palladium on carbon catalyzed one-pot intramol. nitro reduction/cyclization reaction has been developed for the preparation of a series of substituted benzimidazoles, including some novel ring-fused [1,2-a]-tricyclic, [1,2-a]-tetracyclic, and chiral benzimidazoles. The main advantages of this method are the mild and simple reaction conditions, the easy isolation of the products, and the excellent yields. The reaction has the potential to be used as a general procedure for the preparation of 7-aminobenzimidazoles in good yields. A plausible mechanism for the reaction is proposed.

A water compatible turn ‘on’ optical probe for Cu2+ based on a fluorescein-sugar conjugate

Published in: Journal, Volume : 196, Pages : 345-351

DOI : 10.1016/j.snb.2014.02.031

Author : Diwan, Uzra; Kumar, Ajit; Kumar, Virendra; Upadhyay, K. K.; Roychowdhury, P. K.

Abstract : A fluorescein-sugar conjugated chromo-fluorogenic turn ‘on’ probe (FG) has been synthesized for detection of Cu2+. The FG comprises of fluorescein as an efficient fluorophore and a sugar moiety, viz., galactose as the binding unit. The inclusion of galactose into FG led towards its good water compatibility. When Cu2+ was added in 70% aqueous HEPES buffered solution (pH 7.4) of FG, the absorbance and the fluorescence spectral pattern of the same were modulated dramatically with observation of absorption and emission bands at 632 and 515 nm, resp. The detection limit from fluorescence titration was calculated as 6.32 nM which further establishes high sensitivity of FG towards Cu2+. The spectral studies for the interaction of FG with Cu2+ indicated towards metal ion triggered spirolactam ring opening of FG as the mechanistic pathway of the sensing phenomenon.

Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists

Published in: Journal, Article, Volume : 24, Issue : 3, Pages : 949-953

DOI : 10.1016/j.bmcl.2013.12.063

Author : Gillespie, Paul; Goodnow, Robert A.; Saha, Goutam; Bose, Gopal; Moulik, Kakali; Zwingelstein, Catherine; Myers, Michael; Conde-Knape, Karin; Pietranico-Cole, Sherrie; So, Sung-Sau

Abstract : We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the Ph ring are important for potency and full efficacy. Compound I combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 460, Issue : 1-2, Pages : 949-953

DOI : 10.1016/j.ijpharm.2013.10.055

Author : Choudhury, Hira; Gorain, Bapi; Karmakar, Sanmoy; Biswas, Easha; Dey, Goutam; Barik, Rajib; Mandal, Mahitosh; Pal, Tapan Kumar

Abstract : Paclitaxel, a potential anticancer agent against solid tumors has been restricted from its oral use due to poor water solubility as well as Pgp efflux property. The present study was aimed to improve the oral bioavailability of paclitaxel through development of (o/w) nanoemulsion consisting of Capryol 90 as internal phase with Tween 20 as emulsifier with water as an external phase. Formulations were selected from the nanoemulsion region of pseudo-ternary phase diagrams, formulated by aqueous titration method. The developed nanoemulsion has been characterized by its thermodn. stability, morphol., droplet size, zeta potential, viscosity where in vitro release was evaluated through dialysis. Paclitaxel nanoemulsion exhibited thermodynamical stability with low viscosity, nano-sized oil droplets in water with low poly-dispersity index. The shelf life of the paclitaxel nanoemulsion was found to be approx. 2.38 years. Increased permeability through the Caco-2 cell monolayer and decreased efflux is great advantageous for nanoemulsion formulation. The effects of paclitaxel nanoemulsion on breast cancer cell proliferation, morphol. and DNA fragmentation were analyzed in vitro which showed significant anti-proliferation and decreased IC50 values in nanoemulsion group which may be due to enhanced uptake of paclitaxel through the oil core. Moreover, the absolute oral bioavailability and sustained release profile of the paclitaxel nanoemulsion evaluated in mouse model was found to improve up to 55.9%. The concentration of paclitaxel in mice plasma was determined by our validated LC-MS/MS method. By reviewing the significant outcome of the present investigation based on stability study, Caco-2 permeability, cell proliferative assay and pharmacokinetic profile it may be concluded that the oral nanoemulsion has got encouraging advantages over the presently available formulations of this injectable chemotherapeutic drug.

Protecting group directed cyclization: asymmetric synthesis of both cis- and trans-dihydrexidine from a common precursor

Published in: Journal, Volume : 69, Issue : 43, Pages : 8994-9000

DOI : 10.1016/j.tet.2013.08.042

Author : Malhotra, Rajesh; Chakrabarti, Sagar; Dey, Tushar K.; Dutta, Swarup; Alapati, Krishna Babu; Dutta, Shantanu; Roy, Subho; Basu, Sourav; Hajra, Saumen

Abstract : Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alc. undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel-Crafts cyclization control the cis-stereochem. of the B-ring. N-Cbz and O-benzyl protection direct first F-C cyclization yielding the trans-1-aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine.

An in silico method for designing thermostable variant of a dimeric mesophilic protein based on its 3D structure

Published in: Journal, Article, Volume : 42, Pages : 92-103

DOI : 10.1016/j.jmgm.2013.02.011

Author : Basu, Sohini; Sen, Srikanta

Abstract : Designing proteins with enhanced thermostability has been a major interest of protein engineering because of its potential industrial applications. Here, we have presented a computational method for designing dimeric thermostable protein based on rational mutations on a mesophilic protein. Exptl. and structural data indicate that the surface stability of a protein is a major factor controlling denaturation of a protein and ion-pairs are most efficient in enhancing the stability of the surfaces of the monomers and the interface between them. Our mutation based strategy is to first identify several polar or charged residues on the protein surface, interacting weakly with the rest of the protein and then replacing the side-chains of suitable neighboring residues to increase the interaction between these two residues. In stabilizing the interface, mutation is done in the interface for forming an ion pairs between the monomers. Application of this design strategy to a homo-dimeric protein and a hetero-dimeric protein as examples has produced excellent results. In both the cases the designed mutated proteins including the individual monomers and the interfaces were found to be considerably more stable than the resp. mesophilic proteins as judged by self-energies and residue-wise interaction patterns. This method is easily applicable to any multi-meric proteins.

Inculcating total selectivity for fluoride in pyrene based chromogenic receptors: An experimental and theoretical study

Published in: Journal, Volume : 1035, Pages : 174-182

DOI : 10.1016/j.molstruc.2012.09.017

Author : Kumar, Ajit; Kumar, Virendra; Neeraj; Upadhyay, K. K.; Roychowdhury, P. K.

Abstract : Three simple Schiff base receptors I-III containing pyrene skeletons were designed and synthesized. The intramol. hydrogen bonding between aldimine N-atom and phenolic OH of these Schiff bases play a crucial role towards their sensing behavior against fluoride. The receptor III exhibited total selectivity towards fluoride in acetonitrile. The basis of the above designing at the MO level was studied through d. functional theory (DFT) and time dependent d. functional theory (TD-DFT). The observed structure dependence of the binding selectivity may provide guidelines for the development of new colorimetric/fluorescent sensors for F- of further high selectivity.

Divergent asymmetric synthesis of hexahydrobenzophenanthridine dopamine D1 agonists, A-86929, and dihydrexidine

Published in: Journal, Volume : 24, Issue : 5-6, Pages : 278-284

DOI : 10.1016/j.tetasy.2013.02.003

Author : Malhotra, Rajesh; Chakrabarti, Sagar; Ghosh, Amit; Ghosh, Rajib; Dey, Tushar K.; Dutta, Swarup; Dutta, Shantanu; Roy, Subho; Basu, Sourav; Hajra, Saumen

Abstract : A divergent and scalable asym. synthesis of the dopamine D1 agonists, A-86929, and dihydrexidine with high diastereo- and enantioselectivity was accomplished from Weinreb amide 8 derived from inexpensive and easily available L-serine. The synthesis of A-86929 involves only one chromatog. purification