BITS Faculty Publications

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Amino Acyl Conjugates of Nitrogen Heterocycles as Potential Pharmacophores
(ACS, 2010-05-11) Bajaj, Kiran
2-Methyl- and 4-methylpyridine and 2-methylquinoline are converted by benzotriazole-activated (Cbz)-protected amino acids into chiral potential novel pharmacophore aminoacyl conjugates (33−53%). α-Amino acids and their derivatives are central to the chemistry and biology of peptides and proteins as well as versatile synthetic building blocks for pharmaceutical applications, precursors for the generation of molecular diversity, important templates in asymmetric catalysis, and common subunits in many bioactive compounds and natural products
Aziridine based electrophilic handle for aspartic acid ligation
(RSC, 2018) Sakhuja, Rajeev; Bajaj, Kiran
A one-pot ligation strategy at aspartic acid junctions has been developed by successfully incorporating aziridin-2,3-dicarboxylate to the N-side of a peptide fragment, affording N-aziridine appended peptides, which were ligated in solution phase with a variety of small peptide thio acids to afford native peptides, following a ring-opening/peptidyl migration/desulfurization strategy. The reaction proceeds in a highly regiospecific manner, and provides short native peptides in good isolable yields. A variety of aspartame based peptides were synthesized to showcase the generality of this aziridine based ligation. Computational studies have also been performed to obtain insight about the reaction pathway.
Aziridine-Mediated Ligation at Phenylalanine and Tryptophan Sites
(Wiley, 2017-05-23) Sakhuja, Rajeev; Bajaj, Kiran
An efficient approach towards peptide synthesis that allows easy access to variety of small peptides via one-pot aziridine-mediated ligation/desulfurization strategy has been described. The protocol afforded a library of phenylalanine- and tryptophan-containing α-peptides in good yields by regioselective ring-opening of aziridine-3-aryl-2-carboxylates with peptide thioacids, followed by desulfurization.
Copper-catalysed Csingle bondN/Csingle bondO coupling in water: a facile access to N-coumaryl amino acids and fluorescent tyrosine & lysine labels
(Elsiever, 2016-06) Bajaj, Kiran; Sakhuja, Rajeev
A mild, efficient, ligand free and environmentally benign approach towards the construction of sp2 C-sp3 N bond has been developed via copper catalysed Ullmann type of coupling between 4-chlorocoumarin with N-terminus unprotected amino acids in microwave-aqua conditions, yielding a series of N-coumaryl amino acids in good to excellent yields. Excellent photo-physical properties exhibited by these N-coumaryl amino acids and their chemical applicability as C-terminus coupling partners for N-terminus peptides make them potential fluorescent probes in labelling studies. The methodology was extended towards the Csingle bondO and Csingle bondN coupling for the synthesis of fluorescent coumaryl labelled tyrosine and lysine labels respectively. Application of coumaryl labelled tyrosine was further explored towards the synthesis of fluorescent labelled opioid tetrapeptide, Endomorphin-2 derivative.
Copper-catalysed Csingle bondN/Csingle bondO coupling in water: a facile access to N-coumaryl amino acids and fluorescent tyrosine & lysine labels
(Elsiever, 2016-06-22) Sakhuja, Rajeev; Bajaj, Kiran
A mild, efficient, ligand free and environmentally benign approach towards the construction of sp2 C-sp3 N bond has been developed via copper catalysed Ullmann type of coupling between 4-chlorocoumarin with N-terminus unprotected amino acids in microwave-aqua conditions, yielding a series of N-coumaryl amino acids in good to excellent yields. Excellent photo-physical properties exhibited by these N-coumaryl amino acids and their chemical applicability as C-terminus coupling partners for N-terminus peptides make them potential fluorescent probes in labelling studies. The methodology was extended towards the Csingle bondO and Csingle bondN coupling for the synthesis of fluorescent coumaryl labelled tyrosine and lysine labels respectively. Application of coumaryl labelled tyrosine was further explored towards the synthesis of fluorescent labelled opioid tetrapeptide, Endomorphin-2 derivative.
Efficient and Selective Syntheses of S-Acyl and N-Acyl Glutathiones
(Thieme, 2010-06) Bajaj, Kiran
Selective syntheses of S-acyl glutathiones are achieved in 79–98% yields using 1-acyl-1H-benzotriazoles in the presence of potassium bicarbonate in aqueous methanol at 20 °C. N-Acylation of S-(p-nitrobenzoyl) glutathione with 1-acyl-1H-benzotriazoles followed by deprotection of the p-nitrobenzoyl groups under mild conditions gave 63–78% yields of N-acyl glutathiones. These meth-odologies should be useful for the S-acylation and N-acylation of peptides and glycopeptides.
Efficient Syntheses of Thiadiazole Peptides
(ACS, 2010-08-09) Bajaj, Kiran
Novel N-(Cbz-aminoacyl)thiosemicarbazides 3a−c were cyclized by treatment with sulfuric acid to give 1,3,4-thiadiazoles 4a−c. Compounds 4a−c reacted with N-(Cbz-aminoacyl)- and -dipeptidoylbenzotriazoles to afford chirally pure 1,3,4-thiadiazol-2-yl-substituted amino acids 6a−c and dipeptides 7a−c.
Expansion of Phosphane Treasure Box for Staudinger Peptide Ligation
(RSC, 2020-09-04) Kumar, Dalip; Sakhuja, Rajeev; Bajaj, Kiran
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.
Imidazolium-supported benzotriazole: an efficient and recoverable activating reagent for amide, ester and thioester bond formation in wate
(RSC, 2015) Kumar, Anil; Sakhuja, Rajeev; Bajaj, Kiran
An efficient and recyclable imidazolium-supported benzotriazole reagent (Im-CH2-BtH) as a novel synthetic auxiliary has been synthesized and its utility as a carboxyl group activating reagent via the formation of stable imidazolium-supported acyl benzotriazoles was explored for the synthesis of amides, esters and thioesters in water under microwave conditions. The reagent was reused five times without any noticeable loss in activity. It is moisture insensitive and highly stable under thermal and aerobic conditions. The application of imidazolium-supported N-acetyl benzotriazole leads to synthesis of paracetamol on the gram scale under greener conditions in 93% yield.
Introduction of histidine units using benzotriazolide activation
(Wiley, 2013-01-16) Bajaj, Kiran
Nα-Boc-Nim-(4-toluenesulfonyl-l-histidylbenzotriazole) enables convenient acylation of N-, O-, S-, and C-nucleophiles with no detectable racemization. We report efficient syntheses of novel histidine-containing di-, tri-, and tetra-peptides and models for the preparation of potentially biologically active histidine N-, O-, S-, and C-conjugates. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.
Kinetic studies on the reactions of various 9-chloroacridines with some arylsulphonyl hydrazides and antiinflammatory and kinase inhibition activitiy of the products
(NISCAIR, 2005-02) Bajaj, Kiran
9-Chloro-2,4(un)substituted acridines (1a-e) have been condensed with benzenesulphonyl hydrazide (2a), p-toluene sulphonyl hydrazide (2b), and 4-methoxybenzenesulphonyl-hydrazides (2c) to obtain the corresponding condensed products 3a-o. The structures of all the compounds synthesized have been confirmed by spectroscopic methods. Antiinflammatory and kinase inhibition activities of all the compounds (3a-o) have been investigated. Compounds 3e, h, i, n exhibit good and 3a-d, f, g,J-m,o exhibit moderate anti-inflammatory activity. Kinetic studies on the concerned aromatic nucleophilic substitution (SNAr) have been carried out in methanol (MeOH). Another three reactions of 1a with suphonyl hydrazide 2a-c have been studied in DMSO under the same conditions for compari son. The base catalysed mechanism (modified heteroconjugate BH+SB, BH+B) has been proposed for the reaction in MeOH. The effect of substituents on the benzene ring of the sulphonyl hydrazide is in the order: MeO>Me>H, reflecting the importance of electron-donating behaviour of the substituent in enhancing the nucleophilcity of hydrazide group and also in stabilizing the zwitterionic complex
Microwave Assisted Synthesis of Five Membered Azaheterocyclic Systems
(Bentham Science, 2012) Sakhuja, Rajeev; Bajaj, Kiran
The present review provides a comprehensive summary of microwave-assisted preparation of five-membered azaheterocyclic systems, such as pyrrole, pyrazole, imidazole, triazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole and tetrazole.
Microwave-assisted formation of peptide-vitamin conjugates
(Wiley, 2012-06-21) Bajaj, Kiran
Amino acid and peptide bioconjugates of niacin I, biotin II, α-tocopherol III and cholecalciferol IV are prepared in good to satisfactory yields by using microwave assistance. In addition, a new benzotriazole-activated biotin intermediate is synthesized, which may serve as an advantageous alternative biotinylation reagent.
Microwave-Assisted Synthesis of Benzo-fused Seven-membered Azaheterocycles
(Bentham Science, 2014) Kumar, Anil; Sakhuja, Rajeev; Bajaj, Kiran
The use of microwave energy in chemical reactions has revolutionized the field of heterocyclic chemistry in the past two decades. Synergy of microwave methodology with reactions performed on support media and/or in the absence of solvent constitutes an environmentally clean technique, that offers tremendous advantages such as clean chemistry, reduction in reaction times, improved yields, and applicability to wide range of reactions, safety and tremendous scope for automation over the traditional heating. The benzoannulated azaheterocycles display an impressive repertoire of biological activities. The present review will provide an in-depth view of microwave-assisted synthetic methodologies of benzo-fused seven-membered azaheterocycles such as benzodiazepines, benzothiazepines and benzoxazepines.
Newer Substituted Benzoxazepinylquinazolinones as Potent Antipsychotic and Anticonvulsant Agents
(Thieme, 2003) Bajaj, Kiran
3-Amino-[2’-substitutedaryl-3’-substitutedarylaminomethylene-2’,3’-dihydro-1’,5’-benzoxazepin-4’-yl]-2-methylquinazolin-4(3H)-ones 11−18 and 3-amino-[2’-substituted aryl-3’-substitutedaryl-azo-2’,3’-dihydro-1’,5’-benzoxazepin-4’-yl]-2-methyl-quinazolin-4(3H)-ones 19− 26 were synthesized from 3-amino-[2’-substitutedaryl-2’,3’-dihydro-1’,5’-benzoxazepin-4’-yl]-2-methyl-quinazolin-4(3H)-ones 7−10 by Mannich’s reaction and by diazotisation, respectively, on the 3rd position of the benzoxazepine ring of the compounds 7−10. The newly synthesized compounds showed potent antipsychotic and anticonvulsant activities.
Quinine bis-conjugates with quinoloneantibiotics and peptides: synthesis and antimalarial bioassay
(RSC, 2012) Bajaj, Kiran
Benzotriazole-mediated syntheses led to novel bis-conjugates of quinine with quinolone antibiotics and amino acid linkers which were successfully prepared by two alternative routes with excellent yields and retention of chirality. These bis conjugates retain in vitro antimalarial activity with IC50 values ranging from 12 to 207 nM, similar to quinine itself.
Some new 2,3,6-trisubstituted quinazolinones as potent anti-inflammatory, analgesic and COX-II inhibitors
(Elsiever, 2003-11-17) Bajaj, Kiran
Various 2-(substitutedphenylmethyleneimino)aminoacetylmethylene-3-(2′-substitutedindol-3′-yl)-halosubstituted-4(3H)quinazolinones (5a–5i) and 2-(substituted phenylaminomethyleneacetyl-4′-oxo-1′-thiazolidinyl-3-(2″-substitutedindol-3″-yl) 4(3H)-quinazolinones (6a–6i) have been synthesized in the present studies. The structure of these compounds have been elucidated by elemental (C, H, N) and spectral (IR, 1H NMR and mass) analysis. Furthermore, above said compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic activities and acute toxicity study. Compound 6d was found to be most potent. Compound exihibiting less ulcerogenic liability and ALD50 >2000 mg/kg po. Some 2-(substitutedphenylmethyleneimino)aminoacetylmethylene-3-(2′-substitutedindol-3′-yl)-halosubstituted-4(3H)quinazolinones (5a–5i) and 2-(substituted phenylaminomethyleneacetyl-4′-oxo-1′-thiazolidinyl-3-(2″-substitutedindol-3″-yl)-4(3H)-quinazolinones (6a–6i) have been synthesized. Compound 2-(o-Methoxyphenylaminomethylacetyl-4′-oxo-1′-thiazolidinyl)-3-(indol-3″-yl)-6-iodo-4(3H)-quinazolinone (6d) was found to be the most potent compound of the present study.
Study of Chemical Ligation Via 17-, 18- and 19-Membered Cyclic Transition States
(Wiley, 2012-09-14) Bajaj, Kiran
Unprotected S-acylated cysteine isopeptides containing α-, β- or γ-amino acid units have been synthesized, and their conversion to native hexapeptides by S- to the N-terminus ligations involving 17-, 18- and 19-membered cyclic transition states have been demonstrated both experimentally and computationally to be more favorable than intermolecular cross-ligations.
Syntheses of Chiral N-(Protected) Tri- and Tetrapeptide Conjugates
(Wiley, 2012-02-28) Bajaj, Kiran
Cbz-(protected)-tri- and tetrapeptide conjugates with steroids, sugars, terpenes, and heterocycles were prepared using Cbz-(protected)-tri- and tetrapeptidoylbenzotriazoles as active intermediates.Peptides and their derivatives such as hormones, neurotransmitters, and neuromodulators act as signal molecules in diverse biological and medicinal applications and thus have attracted considerable synthetic attention (1, 2). Esterifications of amino acids and peptides for the protection of carboxylic acid functionality and for their activation to make peptide conjugates are well known (3-5).
Syntheses of hydrazino peptides and conjugates
(Elsiever, 2013-07) Bajaj, Kiran
(α-Benzyloxycarbonyl-aminoacyl)benzotriazolides (Cbz = benzyloxycarbonyl) underwent a coupling reaction with α-hydrazino acids under microwave irradiation to form hybrid hydrazino dipeptides (42-71 %). Chiral acylations of β-N-Cbz-α-hydrazino acylbenzotriazolides were successfully carried out with N-, S-, O-, and C-nucleophiles in yields of 49-88 %. Benzyloxycarbonyl-protected hybrid hydrazino dipeptides and benzyloxycarbonyl-protected hydrazino aminoacyl conjugates with N-, S-, O-, and C-nucleophiles were prepared by using benzotriazole methodology.