Surajit Sinha

Indian Association for the Cultivation of Science · Department of Organic Chemistry

Synthesis of Chlorophosphoramidates monomers using Fmoc chemistry and PMO synthesis using both trityl and Fmoc protected monomers

We report the synthesis of piperidino nucleoside phosphoramidates functionalized with uracil, cytosine, guanine, and adenine and their incorporation into oligomers. High-performance liquid chromatography analyses demonstrated that a phosphorodiamidate piperidino oligomer (PPO) is more lipophilic than a phosphorodiamidate morpholino oligomer (PMO) o...

Thiol functionalized oligonucleotides are useful intermediates for a wide range of applications including DNA nanobiotechnology field through conjugation with various types of probes and cargos. Due to the limitation of synthetic process, phosphorodiamidate morpholino oligonucleotides (PMOs) have not been explored like other oligonucleotides throug...

Introduction and objective: Cholesterol homeostasis is a culmination of cellular synthesis, efflux, and catabolism to important physiological entities where short chain fatty acid, butyrate embodied as a key player. This discourse probes the mechanistic molecular details of butyrate action in maintaining host-cholesterol balance. Methods: Hepatic...

Despite the enormous potential of siRNAs to transcriptionally downregulate disease causing proteins in many genetic diseases, efficient delivery and endosomal escape are the two bottlenecks that have resulted in only a handful of FDA approved drugs. In this report, we have successfully delivered siRNA against Nanog with the help of pentafluorobenzy...

Phosphorodiamidate morpholino oligonucleotides (PMOs) constitute 3 out of the 11 FDA-approved oligonucleotide-based drugs in the last 6 years. PMOs can effectively silence disease-causing genes and modify splicing. However, PMO synthesis has remained challenging for a variety of reasons: inefficient deprotection and coupling methods and instability...

This discourse probes the mechanistic molecular details of butyrate action in maintaining host- cholesterol balance. Hepatic miR122 being the most indispensable regulator of cholesterol metabolic enzymes, we studied upstream players of miR122 biogenesis in the presence and absence of butyrate in Huh7 cells and mice model. We showed that butyrate tr...

Nucleic acid-based biosensors, where the capture probe is a nucleic acid, e.g., DNA or its synthetic analogue xeno nucleic acid (XNA), offer interesting ways of eliciting clinically relevant information from hybridization/dehybridization signals. In this respect, the application of XNA probes is attractive since the drawbacks of DNA probes might be...

Cananginones, a family of linear acetogenins found as secondary metabolites in the plant kingdom, show cytotoxicity against several types of cancer cells. We aimed to investigate the efficacy of cananginone and its mechanism as an anti‐cancer agent. Our initial screening of Cananginone against HepG2, PC3, A549, and MCF7 cells showed anti‐cancer act...

Phosphorodiamidate Morpholino Oligonucleotides (PMOs)-based antisense reagents cannot enter inside cells by itself without the help of any delivery technique which is the last hurdle for their clinical applications. To overcome this limitation, a self-transfecting GMO-PMO or PMO-GMO chimeras has been explored as a gene silencing reagent where GMO s...

3,4-Dimercaptophenylalanines and 2,3-dimercaptophenylalanines have been synthesized for the first time by nucleophilic substitution of a protected aminomalonate on 3,4- and 2,3-dimercaptobenzyl bromide derivatives. The dithiol functions were protected as thioketals, and the key precursors, diphenylthioketal-protected dimercaptobenzyl bromides, were...

Several small molecules targeting microtubule dynamics have been developed because microtubules are considered to be one of the most successful cancer chemotherapeutic targets. In this regard, taxol is most worthy to mention which stabilizes microtubule polymer thereby causing defectsinmitotic spindle assembly, chromosome segregation and cell divis...

A non toxic delivery vehicle is essential for the therapeutic applications of antisense phosphorodiamidate morpholino oligonucleotides (PMOs). Though guanidinium rich or arginine rich cellular transporter conjugated Vivo-PMO or PPMO has been developed for in vivo application, however, either their toxicity or stability has become an issue. Previous...

p>Phosphorodiamidatemorpholino oligonucleotides (PMO) are routinely used for gene silencing and the recently developed PMO-based drug “Exondys51” has highlighted the importance of PMO as excellent antisense reagents. However, the synthesis of PMO has remained challenging. Here a method for the synthesis of PMO using either trityl or Fmoc-protected...

We present a practical method for Suzuki coupling by which unprotected or N-protected indoles may be selectively arylated in the C2-position through direct C–H bond activation by electrophilic \(\hbox {Pd(TFA)}_{2}\) catalyst. The protocol is operationally simple as it is carried out in dioxane/water mixture, and air as the sole oxidant at room tem...

Morpholino antisense oligonucleotides are used as routine tools in developmental biology to investigate gene function during early embryogenesis. These chemically modified oligos contain morpholine ring connected with phosphorodiamidate linkages as backbone but carry unmodified nucleobases. In this chapter, we describe the methods to further modify...

A solution phase method was adopted for the synthesis of proline-containing cyclic pentapeptide 2 and total synthesis of naturally occurring cyclic heptapeptide Reniochalistatin B 3. For the synthesis of 3, both divergent and convergent strategies were used to improve the overall yield from 12 to 25%. Different N and C terminal modified linear anal...

A series of β‐hydroxyazides were effectively synthesized from the regioselective ring opening of epoxides by sodium azide using montmorillonite K10 as a novel heterogeneous catalyst in aqueous acetonitrile in good to excellent yields. The utility of this method has been demonstrated by achieving a short synthesis of phenylglycine in 33.5% overall y...

Cationic guanidinium and phosphonium functionalized cytosine morpholino tetramer (G3) and trimer (P3) have been reported for the first time. They show efficient cellular uptake properties in full growth medium, quantified by fluorescence activated cell sorting (FACS) and visualized by fluorescence microscopy. An interesting feature of these transpo...

Background: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeut...

Progress in the subject of peptides and amino acids has enabled us to think beyond the standard 20 proteinogenic amino acids, the majority of which belong to a certain class of peptide secondary metabolites known as nonribosomal peptides (NRPs). The discovery of amino acids like pyrrolysine, selenocystine, D-amino acids, etc., (now classified as no...

Efficient cellular transporter is highly desirable for the therapeutic applications of antisense phosphorodiamidate morpholino oligonucleotides (PMOs) as Vivo-PMO and PPMO have limitations for in-vivo study. We report here a novel internally tetraguanidinium linked nonpeptidic cellular transporter having conformationally rigid backbone com-posed of...

Piperazic acid, a non-proteinogenic amino acid, found in complex secondary metabolites and peptide natural substances, has shown down regulation of Gli1 expression in Hedgehog signaling pathway in cell based assays. Further structure activity relationship study indicated that amide derivatives of piperazic acid are more potent than piperazic acid i...

Synthesis of cyclic α-hydrazino acid containing tripeptides Phe-X-Val and evaluation their proteolytic stability against digestive enzymes has been reported for the first time. Tripeptides were treated with the digestive juice of mice and incubated in buffer at 37 °C for 45 min and was found to be stable when X = 5,6,7-membered hydrazino acids with...

The cis-trans isomerisation and conformer specificity of δ-azaproline and its carbamate protected form in linear and cyclic peptides were investigated using NMR and α-chymotrypsin assay. Comparisons of chemical shift value of the α - hydrogen in each case of δ-azaproline-containing peptides with conformer specific locked diketopiperazines reveal th...

Phosphorodiamidate morpholino oligomers (PMOs) are a highly capable class of synthetic antisense oligonucleotides that are used to study gene functions in in vitro and in vivo models. This unit describes the synthesis of exocyclic-amine-protected 7-hydroxy and 7-chlorophosphoramidate-activated morpholino monomers of A, T, G, and C, together with th...

Synthesis of T-containing phosphorodiamidate morpholino oligomers (PMO) by H-phosphonate method on solid support has been reported for the first time. Initially, 5-mer then 15-mer of T-containing PMO using H-phosphonate-T monomer was synthesized on polystyrene resin bead. The phosphonamidate backbone was oxidized by iodine-dimethylamine mixture fol...

The stereoselectivity of the prepared indole derivatives is controlled by the N-protecting group of the 2-((trimethylsilyl)ethynyl)aniline substrates.

catalyzed synthesis of 2-allylindole and 2-allylbenzofuran derivatives from 2-((trimethylsilyl)ethynyl)arenes, Tetrahedron Letters (2014), doi: http:// dx.doi.org/10.1016/j.tetlet.2014.10.049 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the...

Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the μ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR a...

Synthesis of cyclic α-hydrazino acids of 5, 6, 7, 8, and 9-membered rings has been described. Di-tert-butyl or dibenzyl malonate was used as starting materials instead of diethyl malonate which was used in our first report. Deprotection of tert-butyl or benzyl ester of the final compounds was much easier than ethyl or methyl esters. Overall yield o...

Synthesis and cell transfection properties of guanidinium-functionalized uracil morpholino tetramer have been reported for the first time. Due to the basic nature of guanidinium groups they remain protonated under physiological conditions. Such cationic tetramer exhibits efficient cellular uptake properties as visualized by microscopy imaging using...

A guanidinium-linked morpholino pentamer is synthesized and evaluated for cellular penetration properties. A regular morpholino and the pentamer conjugate can exhibit antisense effects when designed against Gli1-transcription factors of the Hh signalling pathway, which is a potential target for cancer therapy. Evidence was found from luciferase ass...

A guanidinium-linked morpholino pentamer is synthesized and evaluated for cellular penetration properties. A regular morpholino and the pentamer conjugate can exhibit antisense effects when designed against Gli1-transcription factors of the Hh signalling pathway, which is a potential target for cancer therapy. Evidence was found from luciferase ass...

A NaOH-mediated protocol was developed for the syntheses of a series of 2′-arylspiro[cyclopent[3]ene-1,3′-indole]s and 6-alkyl-5,6,7,10-tetrahydrocyclohepta[b]indoles in good yields by cyclization through a sigmatropic rearrangement of suitable 2,3-disubstituted indoles. These precursors that contain a 4-chloro-2-butenyl side chain at the 3-positio...

Synthesis, photophysical properties and submicron ring formation of functionalized uracil morpholino monomers have been reported. A series of characterization techniques indicated that the rings are formed by the inter-molecular hydrogen bonding of the uracil nucleus having a trityl-protected morpholino moiety. This is the smallest nucleoside unit...

Morpholino-modified nucleoside analogues have widespread applications in developmental biology. To achieve nucleobase-functionalized forms of morpholino nucleosides, syntheses of 5-substituted cytidine, 8-substituted adenosine, and 8-substituted guanosine morpholino nucleoside monomers are described for the first time. The syntheses are based on th...

Selenoisotryptophan and its higher homologues were synthesized by Sonogashira coupling of iodophenyl methyl selenide and alkynyloxazolidines followed by iodocyclization as the key step. Sonogashira coupling of 3-iodobenzoselenophene with ethynyloxazolidine allowed the synthesis of selenohomotryptophan. Selenium analogues of isotryptophan and homois...

Starting from readily available raw materials, novel approaches toward the synthesis of title compounds with 5- to 9-membered ring size are developed.

An inexpensive and much improved protocol has been developed for the synthesis of protected morpholino monomers from unprotected ribonucleosides in high overall yield, using oxidative glycol cleavage and reductive amination strategy. Unlike the previous methods, the present strategy allows installing the exocyclic amine protections at a later stage...

Efficient total synthesis of ibogaine, epiibogaine and their analogues has been described. An intramolecular reductive-Heck type cyclization was used for the construction of seven-membered indoloazepine ring to access iboga-skeleton. Larock’s heteroannulation reaction was employed for the creation of suitably substituted indole and DielseAlder reac...

2-Indolylglycine derivative and its oxygen analogue have been synthesized by Sonogashira coupling followed by cyclization in one pot between 2-iodoheteroarenes and ethynyloxazolidinone where 3-indolylglycine derivative and its oxygen analogue have been synthesized from silylated internal alkyne using Larock's heteroannulation as the key reaction.

Starting from o-iodoaryl carbamates (I), a novel synthesis of the title butadienylindoles (VI) is developed.

A mild and efficient synthetic route to the iboga scaffold by employing reductive-Heck type annulation is described. The utility of this process is demonstrated by the direct access to the ibogamine, epiibogamine and iboga-analogs. The cyclization precursors were readily obtained from 2-iodoaniline by heteroannulation reaction with suitable alkynes...

An efficient and rapid protocol for the synthesis of chlorophosphoramidate-activated morpholino subunits has been developed. A unique combination of lithium bromide–DBU has been found to activate the 70-hydroxyl toward the reaction. All the four morpholino units of adenosine, guanosine, cytosine, and thymine responded smoothly to the developed prot...

Sonogashira coupling of 5-iodo uracil–morpholino monomer with different terminal alkynes has been achieved for first time in good to excellent yields (67–86%). We have optimized the iodination conditions for the preparation of 5-iodo uracil–morpholino monomer under basic condition.

A three-step procedure has been developed for the synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles. TBAF was proved to be an effective reagent for dehydrobromination and carbomethoxy deprotection in one step to give 3-[2-(1,3-butadienyl)]-1H-indoles from the corresponding bromo-derivatives. Suitably substituted indolyl-1,3-butadiene has been successf...

Progress made in the synthesis of Iboga-alkaloids and their congeners is presented. Iboga-conjugated natural products such as conoliferine, isoconoliferine, conomicidines A and B, and isoconomicidines A and B have been isolated from Tabernaemontana species as a mixture of (1'S, 2'S)-and (1'R, 2'R)-diastereomers. Ibogaine causes degeneration of cere...

Synthesis of new iboga-analogues, replacing the indole ring with a benzofuran moiety has been described. Starting materials are the suitably substituted benzofuran derivatives and have been synthesized by Pd-catalyzed reactions. The conversion of endo-6-methylcarboxylate substituted dehydroisoquinuclidine to exo-isomer, a key component of iboga-alk...

Alkoxy Fischer carbene complexes have been synthesized by alkylation of lithium acylmetalates with alkyl halides in the presence of catalytic amount (5–10 mol %) of n-tetrabutylammonium bromide (n-Bu4NBr) restricting the temperature below 55 °C to minimize decomposition of the product. The reaction occurs in a biphasic condition involving water and...

Efficient deprotection of tritylated amines to the corresponding amines mediated by 20mol% ceric ammonium nitrate [Ce(NH4)2(NO3)6, CAN], 10equiv of acetic acid and 15equiv of water in dichloromethane is presented. This method equally worked well in the case of morpholino nucleosides.

Ytterbium triflate catalyses the deprotection of tert-butyl esters selectively in the presence of other esters under mild conditions in almost quantitative yields. The reactions are carried out in nitromethane (45°-50°C) using 5 mole percent of the catalyst.

A concise route to iboga-analogues has been developed. Important steps include a Pd-catalyzed Sonogashira coupling of Boc-2-idodaniline with terminal alkynes and the formation of 2-substituted indoles in the presence of tetrabutylammonium fluoride to give the key intermediate, dehydroisoquinuclidine-containing indole. The final step cyclization bet...

A convenient synthetic route to the iboga-scaffolds is described. Important steps include a Pd-catalyzed regiospecific indole formation between internal alkyne-substituted isoquinuclidine and 2-iodoaniline. The final cyclization was done using Trost's Pd(II)-Ag(I) mixed-metal-mediated cyclization method originally developed for the synthesis of ibo...

Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more c...

Embryogenesis is regulated by genetic programs that are dynamically executed in a stereotypic manner, and deciphering these molecular mechanisms requires the ability to control embryonic gene function with similar spatial and temporal precision. Chemical technologies can enable such genetic manipulations, as exemplified by the use of caged morpholi...

Eradicating hedgehogs: The title molecule has been previously identified as a potent inhibitor of the Hedgehog signaling pathway, which gives embryonic cells information needed to develop properly. This molecule is shown to modulate Hedgehog target gene expression by depolymerizing microtubules, thus revealing dual roles of the cytoskeleton in path...

Functional genomic studies in zebrafish frequently use synthetic oligonucleotides called morpholinos that block RNA splicing or translation. However, the constitutive activity of these reagents limits their experimental utility. We report here the synthesis of a photoactivatable morpholino targeting the no tail (ntl) gene. This caged reagent permit...

Hedgehog (Hh) signaling is an important regulator of embryonic patterning, tissue regeneration, stem cell renewal and cancer growth. A purine derivative named purmorphamine was previously found to activate the Hh pathway and affect osteoblast differentiation through an unknown mechanism. We demonstrate here that purmorphamine directly targets Smoot...

A simple synthesis of trans-3-hydroxy-L-proline has been achieved starting from β-alanine making use of Sharpless asymmetric epoxidation as a key step in the synthesis.

Mit dem Metall in der Mitte: Ein Metallobasenpaar auf der Grundlage von 6-Pyridylpurin (Purp) wurde synthetisiert und charakterisiert. PurP bevorzugt Nickel(II) gegenüber anderen zweiwertigen Ionen, und mit hoher Kombinationsselektivität entsteht ein Basenpaar, das die natürlichen Watson-Crick-Paare an Stabilität übertrifft. Rechnungen bestätigen ä...

Genomes are composed of nucleic acids bearing 3',5'-phosphodiester-linked sugars. The 2',5'-phosphodiester linkage is a fundamental alternative to the natural linkage and is the predominant product of most nontemplate, nonenzymatic oligomerizations of nucleotide monomers. This fact suggests a chemical bias for the formation of 2',5'-phosphodiester...

The Up.D base-pair (5-propynyl uracil.diaminopurine) is found to be more effective at non-enzymatic transcription than the corresponding natural T.A pair; under non-enzymatic reaction conditions where the natural T.A base-pair fails, a DNA template bearing Up efficiently directs the incorporation of D into a product RNA strand.

Synthesis of short peptides using propargyloxycarbonyl amino acid chlorides as effective coupling reagents and polymer supported tetrathiomolybdate as an efficient deblocking agent are reported.

An efficient Friedel–Crafts alkylation of aromatic compounds with ethyl α-chloro-α-(ethylthio)acetate catalysed by ytterbium triflate, followed by desulfurisation of the product provides a convenient methodology for the synthesis of ethyl arylacetates of aromatic and heteroaromatic compounds.

The potassium salt of 3-methoxy and 3,5-dimethoxy benzoic acids undergoes deprotonation at the position para to the carboxylate group selectively when treated with LIC–KOR in THF at −78°C and it has been extended to the synthesis of 3,5-dimethoxy-4-methyl benzoic acid.

A one pot conversion of alcohols to disulfides in good yields via the activation of a hydroxyl group with DCC or P(NMe2)3 / CCl4 followed by treatment with benzyltriethylammonium tetrathiomolybdate is reported.

Diisopropoxytitanium(III) tetrahydroborate, ((PrO)-Pr-i)(2)TiBH4, formed in situ in dichloromethane from diisopropoxytitanium dichloride and benzyltriethylammonium tetrahydroborate (1:2) reduces alpha-hydroxyketones/1,2-diketones and beta-hydroxyketones/1,3-diketones to the corresponding diols with high stereoselectivity. In the case of alpha-hydro...

The prop-2-ynyloxy carbonyl function (POC) which can be cleaved under mild and neutral conditions in the presence of benzyltriethylammonium tetrathiomolybdate has been developed as a new protecting group for amines.