01881nas a2200265 4500008004100000022001400041245011900055210006900174260000800243300001400251490000700265520098400272100001601256700001801272700002001290700002101310700002601331700002401357700002801381700001701409700002201426700001701448700002101465856012901486 2018 eng d a0022-262300aSpecific stereoisomeric conformations determine the drug potency of cladosporin scaffold against malarial parasite0 aSpecific stereoisomeric conformations determine the drug potency cJUL a5664-56780 v613 a

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development.

1 aDas, Pronay1 aBabbar, Palak1 aMalhotra, Nipun1 aSharma, Manmohan1 aJachak, Goraknath, R.1 aGonnade, Rajesh, G.1 aShanmugam, Dhanasekaran1 aHarlos, Karl1 aYogavel, Manickam1 aSharma, Amit1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/specific-stereoisomeric-conformations-determine-drug-potency-cladosporin-scaffold-against01497nas a2200217 4500008004100000022001400041245003800055210003800093260000900131300001200140490000700152520092700159653001901086653001601105653001401121653002001135100001601155700001701171700002101188856007001209 2019 eng d a0040-403900aScalable synthesis of cladosporin0 aScalable synthesis of cladosporin cMAR  a831-8330 v603 a

Cladosporin, a secondary metabolite isolated from fungal sources like Cladosporium cladosporioides and Aspergillus flavus was found to exhibit selective nano-molar activity against malarial parasite Plasmodium falciparum by inhibiting parasitic protein biosynthesis. In addition, this natural product has a broad range of bioactivities including, antiparasitic, antifungal, antibacterial as well as plant growth inhibition. However, it has limited availability from the natural sources for further development. Herein, we report a modified and improved synthetic route which led us to produce this potent natural product in a gram scale. Conversion of the undesired diastereomer to desired one via Mitsunobu inversion of secondary alcohol and carbon monoxide insertion reaction towards the construction of isocoumarin unit are the key features of the present synthesis. (C) 2019 Elsevier Ltd. All rights reserved.

10aAnti-malarials10aCladosporin10aMitsunobu10aTotal synthesis1 aDas, Pronay1 aMankad, Yash1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/scalable-synthesis-cladosporin02283nas a2200193 4500008004100000022001400041245015800055210006900213260000800282300001400290490000700304520154900311100002101860700001601881700002101897700002101918700002201939856012801961 2020 eng d a0022-326300aDFT/NMR approach for the configuration assignment of groups of stereoisomers by the combination and comparison of experimental and predicted sets of data0 aDFTNMR approach for the configuration assignment of groups of st cMAR a3297-33060 v853 a

Quantum mechanical/nuclear magnetic resonance (NMR) approaches are widely used for the configuration assignment of organic compounds generally comparing one cluster of experimentally determined data (e.g., C-13 NMR chemical shifts) with those predicted for all possible theoretical stereoisomers. More than one set of experimental data, each related to a specific stereoisomer, may occur in some cases, and the accurate stereoassignments can be obtained by combining the experimental and computed data. We introduce here a straightforward methodology based on the simultaneous analysis, combination, and comparison of all sets of experimental/calculated C-13 chemical shifts for aiding the correct configuration assignment of groups of stereoisomers. The comparison of the differences between the calculated/experimental chemical shifts instead of the shifts themselves led to the advantage of avoiding errors arising from calibration procedures, reducing systematic errors, and highlighting the most diagnostic differences between calculated and experimental data. This methodology was applied on a tetrad of synthesized cladosporin stereoisomers (cladologs) and further corroborated on a tetrad of pochonicine stereoisomers, obtaining the correct correspondences between experimental and calculated sets of data. The new MAE(Delta Delta delta) parameter, useful for indicating the best fit between sets of experimental and calculated data, is here introduced for facilitating the stereochemical assignment of groups of stereoisomers.

1 aLauro, Gianluigi1 aDas, Pronay1 aRiccio, Raffaele1 aReddy, Srinivasa1 aBifulco, Giuseppe uhttps://library.ncl.res.in/content/dftnmr-approach-configuration-assignment-groups-stereoisomers-combination-and-comparison03127nas a2200409 4500008004100000022001400041245009300055210006900148260000900217300001200226490000700238520193200245653001602177653001702193653001102210653002602221653001702247653001202264100001602276700002102292700001402313700001402327700001602341700001602357700001702373700001502390700001502405700001602420700003002436700002102466700002902487700003002516700002102546700001502567700001602582856011902598 2021 eng d a1478-322300aBiological process of lysine-tRNA charging is therapeutically targetable in liver cancer0 aBiological process of lysinetRNA charging is therapeutically tar cJAN  a206-2190 v413 a

Background & Aims Mature transfer RNAs (tRNA) charged with amino acids decode mRNA to synthesize proteins. Dysregulation of translational machineries has a fundamental impact on cancer biology. This study aims to map the tRNAome landscape in liver cancer patients and to explore potential therapeutic targets at the interface of charging amino acid with tRNA. Methods Resected tumour and paired tumour-free (TFL) tissues from hepatocellular carcinoma (HCC) patients (n = 69), and healthy liver tissues from organ transplant donors (n = 21), HCC cell lines, and cholangiocarcinoma (CC) patient-derived tumour organoids were used. Results The expression levels of different mature tRNAs were highly correlated and closely clustered within individual tissues, suggesting that different members of the tRNAome function cooperatively in protein translation. Interestingly, high expression of tRNA-Lys-CUU in HCC tumours was associated with more tumour recurrence (HR 1.1;P = .022) and worse patient survival (HR 1.1;P = .0037). The expression of Lysyl-tRNA Synthetase (KARS), the enzyme catalysing the charge of lysine to tRNA-Lys-CUU, was significantly upregulated in HCC tumour tissues compared to tumour-free liver tissues. In HCC cell lines, lysine deprivation, KARS knockdown or treatment with the KARS inhibitor cladosporin effectively inhibited overall cell growth, single cell-based colony formation and cell migration. This was mechanistically mediated by cell cycling arrest and induction of apoptosis. Finally, these inhibitory effects were confirmed in 3D cultured patient-derived CC organoids. Conclusions The biological process of charging tRNA-Lys-CUU with lysine sustains liver cancer cell growth and migration, and is clinically relevant in HCC patients. This process can be therapeutically targeted and represents an unexplored territory for developing novel treatment strategies against liver cancer.

10aCladosporin10aliver cancer10alysine10aLysyl-tRNA Synthetase10atRNA-Lys-CUU10atRNAome1 aZhang, Ruyi1 aNoordam, Lisanne1 aOu, Xumin1 aMa, Buyun1 aLi, Yunlong1 aDas, Pronay1 aShi, Shaojun1 aLiu, Jiaye1 aWang, Ling1 aLi, Pengfei1 aVerstegen, Monique, M. A.1 aReddy, Srinivasa1 avan Der Laan, Luc, J. W.1 aPeppelenbosch, Maikel, P.1 aKwekkeboom, Jaap1 aSmits, Ron1 aPan, Qiuwei uhttps://library.ncl.res.in/content/biological-process-lysine-trna-charging-therapeutically-targetable-liver-cancer04015nas a2200217 4500008004100000245010000041210006900141260000800210300001600218490000600234520328400240100001803524700001603542700002203558700001703580700001703597700001803614700001703632700002103649856012703670 2021 eng d00aDesign, synthesis, and structural analysis of cladosporin-based inhibitors of malaria parasites0 aDesign synthesis and structural analysis of cladosporinbased inh cJUL a1777–17940 v73 a

Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.

1 aBabbar, Palak1 aDas, Pronay1 aManickam, Yogavel1 aMankad, Yash1 aYadav, Swati1 aParvez, Suhel1 aSharma, Amit1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/design-synthesis-and-structural-analysis-cladosporin-based-inhibitors-malaria-parasites01320nas a2200193 4500008004100000022001400041245011300055210006900168260000800237300001200245490000700257520064100264100001700905700001600922700001700938700002200955700002100977856012800998 2021 eng d a0021-882000aHerbicidal bio-assay of isocladosporin enantiomers and determination of its plausible absolute configuration0 aHerbicidal bioassay of isocladosporin enantiomers and determinat cAPR a280-2840 v743 a

A fungal metabolite, isocladosporin was isolated from natural fungus, Cladosporium cladosporioides in the mid of 90s. Due to the lack of optical rotation of isolated natural product sample, the absolute configuration of the natural product remained undetermined for more than two decades. Herein, we demonstrated an SAR study of enantiomers of isocladosporin in herbicidal bio-assay against wheat coleoptile. Using this study as a comparative tool we further proposed the plausible absolute configuration of natural isocladosporin for the first time. The assigned configuration was also supported through biogenetic precursors.

1 aMankad, Yash1 aDas, Pronay1 aPathan, Ejaj1 aDeshpande, V., M.1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/herbicidal-bio-assay-isocladosporin-enantiomers-and-determination-its-plausible-absolute01539nas a2200205 4500008004100000022001400041245013300055210006900188260000800257300001100265490000700276520080700283653001501090653002001105653002201125653002001147100001601167700002101183856012901204 2021 eng d a0040-402000aTotal synthesis of twelve membered resorcyclic acid lactones, (R)-penicimenolide A, (R)-resorcyclide and (R)-dihydroresorcyclide0 aTotal synthesis of twelve membered resorcyclic acid lactones Rpe cAPR a1320590 v853 a

Resorcyclic Acid Lactones or RALs are a class of fungal secondary polyketides isolated from a variety of fungal strains like Lasiodiplodia theobromae, Penicillium sp., Syncephalastrum racemosum etc. This class of macrocyclic lactones are found to exhibit a broad spectrum of biological activities and are of significant synthetic importance. Herein, we report the first total synthesis of (R)-penicimenolide A, twelve membered RAL (RAL12) isolated from Penicillium sp. (NO. SYP-F-7919). Besides, we also report the total synthesis of two other members, namely, (R)-trans-resorcyclide and (R)-dihydroresorcyclide. In the course of synthesis, we have utilized ring closing metathesis (RCM) as the key step in constructing the core macrolactone scaffold. (C) 2021 Elsevier Ltd. All rights reserved.

10aMacrocycle10aNatural product10aorganic synthesis10aTotal synthesis1 aDas, Pronay1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/total-synthesis-twelve-membered-resorcyclic-acid-lactones-r-penicimenolide-r-resorcyclide01462nas a2200205 4500008004100000022001400041245010200055210006900157260000800226300001400234490000700248520074800255100001701003700002201020700001601042700002601058700002201084700002101106856012901127 2022 eng d a0022-326300aReady access to benzannulated [5,5]-oxaspirolactones using Au(III)-catalyzed cascade cyclizations0 aReady access to benzannulated 55oxaspirolactones using AuIIIcata cMAR a3025-30410 v873 a

This work showcases an unprecedented Au(III)-catalyzed cascade cyclization of 2-(4-hydroxyalkynyl)benzoates to access benzannulated [5,5]-oxaspirolactones related to biologically active natural products. This reaction proceeds through an initial 5-endo-dig mode of hydroalkoxylation of the alkynol segment to give the oxocarbenium species (via cyclic enol-ether) followed by the addition of carboxylate onto the oxocarbenium that delivers the oxaspirolactone scaffold. While testing this method's scope, we found that the steric and electronic environment of the hydroxyl group could alter the reaction pathway that delivers isochromenone through a competitive 6-endo-dig mode of attack of the carboxylate onto the tethered alkyne.

1 aMankad, Yash1 aThorat, Sagar, S.1 aDas, Pronay1 aKrishna, Gamidi, Rama1 aKontham, Ravindar1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/ready-access-benzannulated-55-oxaspirolactones-using-auiii-catalyzed-cascade-cyclizations