Publications by authors named "Ramana R Mittapalli"

5 Publications

  • Page 1 of 1

A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

ChemMedChem 2021 Jul 26;16(14):2195-2205. Epub 2021 May 26.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC =0.16 μM, EC =0.3 μM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100107DOI Listing
July 2021

The Asymmetric Aza-silyl-Prins Reaction: Synthesis of Enantiopure Piperidines.

Org Lett 2019 01 28;21(2):350-355. Epub 2018 Dec 28.

Department of Pharmaceutical and Chemical Sciences , University of Greenwich , Central Avenue , Chatham Maritime, Kent ME4 4TB , United Kingdom.

The design and development of the first asymmetric aza-silyl-Prins reaction is reported, giving rise to valuable and diverse piperidines and pipecolic acid derivatives in both high yields and as single enantiomers. The creation of a novel chiral auxiliary-homoallylic amine for the aza-silyl-Prins reaction is essential to its success.
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http://dx.doi.org/10.1021/acs.orglett.8b03283DOI Listing
January 2019

Selective recognition of oxalate in water: effect of pH on binding strength and sensing mechanisms.

Chem Commun (Camb) 2017 Oct;53(82):11345-11348

University of Greenwich Medway Campus, Grenville building, School of Science, Gillingham, ME4 4TB, UK.

Bicyclic receptors bearing anthracene as a strap were designed for selective oxalate binding in a buffered aqueous solution. The receptors were found to possess two mechanisms of fluorescence response depending on the pH of a buffered solution. Receptor 2 binds oxalate at pH 6.2 showing a 10-fold fluorescence enhancement and a two orders of magnitude selectivity over other anions.
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http://dx.doi.org/10.1039/c7cc06955cDOI Listing
October 2017

Naphthalimide-Based Polyammonium Chemosensors for Anions: Study of Binding Properties and Sensing Mechanisms.

Chemistry 2017 Jul 29;23(40):9657-9665. Epub 2017 Jun 29.

Institute of Chemistry, Technische Universität Chemnitz, 09107, Chemnitz, Germany.

New naphthalimide-based receptors for anions have been synthesized. Efficient synthetic routes have been discovered to functionalize the naphthalimide core with branched polyamines. Binding and sensing properties of the receptors were studied by potentiometric, NMR and fluorescence titrations. The receptors bind selectively to the pyrophosphate anion in buffered aqueous solutions. The receptors with more than six amine groups in the structure demonstrated the highest affinities for pyrophosphate. The fluorescence response towards anions was found to be dependent on the position of the amine groups relative to the naphthalimide core, and on the pH of the buffered solution. Three sensing mechanisms have been found that explain fluorescence responses of receptors towards anions in an aqueous solution.
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http://dx.doi.org/10.1002/chem.201701515DOI Listing
July 2017

Design of anion-selective PET probes based on azacryptands: the effect of pH on binding and fluorescence properties.

Chem Commun (Camb) 2017 Apr;53(35):4822-4825

Institute of Chemistry, Faculty of Natural Sciences, Technische Universität Chemnitz, 09107 Chemnitz, Germany.

Design of PET probes for anions working in an aqueous buffered solution is described. The design has been used to develop selective fluorescent probes for sulfate and pyrophosphate. The relationship between the selectivity of receptors towards anions, their conformation, fluorescence response and the pH of the solution has been studied in detail.
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http://dx.doi.org/10.1039/c7cc01255aDOI Listing
April 2017
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