Publications by authors named "Irina Sagamanova"

8 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

Palladium catalyzed diaryl sulfoxide generation from aryl benzyl sulfoxides and aryl chlorides.

Org Lett 2015 Mar 16;17(5):1168-71. Epub 2015 Feb 16.

Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.

Diaryl sulfoxides are synthesized from aryl benzyl sulfoxides and aryl chlorides via three sequential catalytic cycles all promoted by a NiXantPhos-based palladium catalyst. The key step is S-arylation of a sulfenate anion. An air- and moisture-stable precatalyst derived from NiXantPhos efficiently facilitates the transformation. Various functional groups, including those with acidic protons, were tolerated. This method can also be extended to methyl and dibenzyl sulfoxides substrates.
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http://dx.doi.org/10.1021/acs.orglett.5b00092DOI Listing
March 2015

tert-Butyl phenyl sulfoxide: a traceless sulfenate anion precatalyst.

Org Lett 2015 Mar 16;17(5):1164-7. Epub 2015 Feb 16.

Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.

tert-Butyl phenyl sulfoxide is employed as a traceless precatalyst for the generation of sulfenate anions under basic conditions and has been used to catalyze the coupling of benzyl halides to trans-stilbenes. The advantage of this precatalyst over previous precatalysts is that the byproduct generated on catalyst formation is a gas, facilitating product isolation in high purity. Using this second generation catalyst, a variety of trans-stilbenes were generated in 39-98% isolated yield.
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http://dx.doi.org/10.1021/acs.orglett.5b00117DOI Listing
March 2015

Application of plant allylpolyalkoxybenzenes in synthesis of antimitotic phenstatin analogues.

Bioorg Med Chem Lett 2011 Mar 2;21(6):1578-81. Epub 2011 Feb 2.

Zelinsky Institute of Organic Chemistry RAS, Moscow, Russia.

Phenstatin and its derivatives with the modified ring A have been synthesized, using plant allylpolyalkoxybenzenes as a starting material. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antiproliferative activity. It was found that phenstatin ring A modifications yielded antimitotic compounds. The most effective myristicin derivative 7d (combretastatin A-2 analogue) was determined to be ca. 10 times more potent than phenstatin, displaying antimitotic tubulin-destabilizing activity at the same concentration range as combretastatins. In contrast to combretastatins, 7d featured the steric stability with potential for further design as anticancer agent.
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http://dx.doi.org/10.1016/j.bmcl.2011.01.124DOI Listing
March 2011

A Stereodivergent Approach for Accessing Both C2,8a-Syn and C2,8a-Anti Relative Stereochemical Manifolds in the Lepadin Family via a TiCL(4)-Promoted Aza-[3 + 3] Annulation.

Synthesis (Stuttg) 2009 Sep;2009(17):2905

Division of Pharmaceutical Sciences and Department of Chemistry, Wisconsin Center for Natural Products Research, School of Pharmacy, Rennebohm Hall, University of Wisconsin, Madison, WI 53705.

Details in developing a stereodivergent approach to the lepadin family and establishing an entry to both C2,8a-syn and C2,8a-anti relative stereochemical manifolds through a common intermediate are described here. This works paves a foundation for constructing all members of the lepadin family, which consists of three subsets based on an array of interesting relative configurations. These efforts underline the prominence of aza-[3 + 3] annulation as a unified strategy in alkaloid synthesis.
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http://dx.doi.org/10.1055/s-0029-1216920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819155PMC
September 2009

Total synthesis of (+)-lepadin F.

Org Lett 2008 Nov 27;10(21):4991-4. Epub 2008 Sep 27.

Division of Pharmaceutical Sciences and Department of Chemistry, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705, USA.

An enantioselective total synthesis of (+)-lepadin F is described. The synthetic sequence features an intermolecular aza-[3 + 3] annulation, homologation of a vinylogous amide via Eschenmoser's episulfide contraction, and a highly stereoselective hydrogenation essential for achieving the 1,3-anti relative stereochemistry at C2 and C8a.
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http://dx.doi.org/10.1021/ol802068qDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662136PMC
November 2008

Copper(II)-catalyzed amidations of alkynyl bromides as a general synthesis of ynamides and Z-enamides. An intramolecular amidation for the synthesis of macrocyclic ynamides.

J Org Chem 2006 May;71(11):4170-7

Division of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705, USA.

A general and efficient method for the coupling of a wide range of amides with alkynyl bromides is described here. This novel amidation reaction involves a catalytic protocol using copper(II) sulfate-pentahydrate and 1,10-phenanthroline to direct the sp-C-N bond formation, leading to a structurally diverse array of ynamides including macrocyclic ynamides via an intramolecular amidation. Given the surging interest in ynamide chemistry, this atom economical synthesis of ynamides should invoke further attention from the synthetic organic community.
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http://dx.doi.org/10.1021/jo060230hDOI Listing
May 2006
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