@article {44618, title = {Specific stereoisomeric conformations determine the drug potency of cladosporin scaffold against malarial parasite}, journal = {Journal of Medicinal Chemistry}, volume = {61}, year = {2018}, month = {JUL}, pages = {5664-5678}, abstract = {

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.

}, issn = {0022-2623}, doi = {10.1021/acs.jmedchem.8b00565}, author = {Das, Pronay and Babbar, Palak and Malhotra, Nipun and Sharma, Manmohan and Jachak, Goraknath R. and Gonnade, Rajesh G. and Shanmugam, Dhanasekaran and Harlos, Karl and Yogavel, Manickam and Sharma, Amit and Reddy, D. Srinivasa} } @article {46163, title = {Scalable synthesis of cladosporin}, journal = {Tetrahedron Letters}, volume = {60}, year = {2019}, month = {MAR }, pages = {831-833}, type = {Article}, abstract = {

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.

}, keywords = {Anti-malarials, Cladosporin, Mitsunobu, Total synthesis}, issn = {0040-4039}, doi = {10.1016/j.tetlet.2019.02.012}, author = {Das, Pronay and Mankad, Yash and Reddy, D. Srinivasa} } @article {46931, title = {DFT/NMR approach for the configuration assignment of groups of stereoisomers by the combination and comparison of experimental and predicted sets of data}, journal = {Journal of Organic Chemistry}, volume = {85}, year = {2020}, month = {MAR}, pages = {3297-3306}, type = {Article}, abstract = {

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.

}, issn = {0022-3263}, doi = {10.1021/acs.joc.9b03129}, author = {Lauro, Gianluigi and Das, Pronay and Riccio, Raffaele and Reddy, D. Srinivasa and Bifulco, Giuseppe} } @article {46671, title = {Biological process of lysine-tRNA charging is therapeutically targetable in liver cancer}, journal = {Liver International}, volume = {41}, year = {2021}, month = {JAN }, pages = {206-219}, type = {Article }, abstract = {

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.

}, keywords = {Cladosporin, liver cancer, lysine, Lysyl-tRNA Synthetase, tRNA-Lys-CUU, tRNAome}, issn = {1478-3223}, doi = {10.1111/liv.14692}, author = {Zhang, Ruyi and Noordam, Lisanne and Ou, Xumin and Ma, Buyun and Li, Yunlong and Das, Pronay and Shi, Shaojun and Liu, Jiaye and Wang, Ling and Li, Pengfei and Verstegen, Monique M. A. and Reddy, D. Srinivasa and van Der Laan, Luc J. W. and Peppelenbosch, Maikel P. and Kwekkeboom, Jaap and Smits, Ron and Pan, Qiuwei} } @article {47457, title = {Design, synthesis, and structural analysis of cladosporin-based inhibitors of malaria parasites}, journal = {ACS Infectious Diseases}, volume = {7}, year = {2021}, month = {JUL}, pages = {1777{\textendash}1794}, type = {Article}, abstract = {

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.

}, doi = {10.1021/acsinfecdis.1c00092}, author = {Babbar, Palak and Das, Pronay and Manickam, Yogavel and Mankad, Yash and Yadav, Swati and Parvez, Suhel and Sharma, Amit and Reddy, Srinivasa} } @article {47093, title = {Herbicidal bio-assay of isocladosporin enantiomers and determination of its plausible absolute configuration}, journal = {Journal of Antibiotics}, volume = {74}, year = {2021}, month = {APR}, pages = {280-284}, type = {Article}, abstract = {

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.

}, issn = {0021-8820}, doi = {10.1038/s41429-020-00391-1, Early Access Date = FEB 2021}, author = {Mankad, Yash and Das, Pronay and Pathan, Ejaj and Deshpande, V. M. and Reddy, D. Srinivasa} } @article {47402, title = {Total synthesis of twelve membered resorcyclic acid lactones, (R)-penicimenolide A, (R)-resorcyclide and (R)-dihydroresorcyclide}, journal = {Tetrahedron}, volume = {85}, year = {2021}, month = {APR}, pages = {132059}, type = {Article}, abstract = {

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.

}, keywords = {Macrocycle, Natural product, organic synthesis, Total synthesis}, issn = {0040-4020}, doi = {10.1016/j.tet.2021.132059}, author = {Das, Pronay and Reddy, D. Srinivasa} } @article {48160, title = {Ready access to benzannulated [5,5]-oxaspirolactones using Au(III)-catalyzed cascade cyclizations}, journal = {Journal of Organic Chemistry}, volume = {87}, year = {2022}, month = {MAR}, pages = {3025-3041}, type = {Article}, abstract = {

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{\textquoteright}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.

}, issn = {0022-3263}, doi = {10.1021/acs.joc.1c02843}, author = {Mankad, Yash and Thorat, Sagar S. and Das, Pronay and Krishna, Gamidi Rama and Kontham, Ravindar and Reddy, D. Srinivasa} }