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6. Tandem reaction sequences on a zirconocene template

Author

Stec, Jozef and Whitby, Richard

Subjects
547.05, QD Chemistry
Abstract

The novel research work described in this thesis covers three areas of organozirconium chemistry. The first area concerns the synthesis of rigid core structures containing the cis-bicyclo[3.3.0]oct-2-ene skeleton. Zirconocene mediated co-cyclisation of 1,6-enynes provides unsaturated 5-membered zirconacycles which are homologated to 6-membered zirconacycles by insertion of 1,1-dihalo-1-lithio species (dihalogenocarbenoids). Further rearrangement to a novel zirconium-alkenylidene complex driven by acetylides provided a powerful method for a rapid construction of novel bicyclic compounds with the potential for functionalization at multiple sites. Such obtained analogues provided an attractive template for structure-activity studies with respect to investigating the biological function of the human orphan nuclear receptors: LRH-1 and SF-1. Equivalent tandem insertion of 1,1-dihalo-1-lithio species and lithium acetylides into saturated zirconacycles resulted in the synthesis of novel bicyclo[3.3.0]octanes, though in many cases limited by a β-H elimination process. In the second area is presented research work relating to acyclic organozirconocene systems. Insertion of allenyl and propargyl carbenoids into organochlorozirconocenes and bisalkyl/-alkynyl zirconocenes led to 1,2-zirconate rearrangement with expulsion of the corresponding leaving group. Lewis acid promoted insertion of aldehydes and ketones into the resulting allenyl/propargyl zirconocene intermediate gave after hydrolysis a series of propargylic alcohols. Insertion of carbenoids derived from chiral propargyl tosylates into organochlorozirconocenes and further 1,2-metallate rearrangement gave the final alcohols as enantiomerically enriched products. The third area was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo[4.3.0]nonane unit with four contiguous stereocentres. Zirconocene mediated co-cyclisation of the appropriate precursor provided four possible diastereoisomers. It was proved that thermodynamic equilibration of the zirconacycle gives the desired bicyclic product as a major isomer. Although the target molecule was not realised, thorough work on Zr-based total synthesis of mucosin has been achieved and a viable route for successful completion of the synthesis has also been proposed.

Published
2010

14. Facile synthesis of the fungus-derived natural products: N,N′-dipalmitoleyl urea (C16:1) and N,N′-dioleyl urea (C18:1).

Author

Stec, Jozef and Pecic, Stevan

Subjects
NATURAL products, OXALYL chloride, UREA, INFLAMMATORY mediators, ORGANIC synthesis
Abstract

Oxalyl chloride is one of the most versatile reagents used in organic synthesis. Oxalyl chloride was employed in the convenient one-pot, two-step synthesis of the fungus-derived naturally occurring lipoids: N,N'-dipalmitoleyl urea (C16:1) and N,N'-dioleyl urea (C18:1). The two symmetrical diacyl urea-based natural products were previously identified as fungus-specific pathogen-associated molecules (PAMs), which act as inflammatory mediators during fungal infection. The highly lipophilic natural lipoids were efficiently synthesized from commercially available reagents in yields ranging from good to very good. [ABSTRACT FROM AUTHOR]

Published
2022
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17. Advancing the Therapeutic Potential of Indoleamides for Tuberculosis

Author

Lun, Shichun, primary, Tasneen, Rokeya, additional, Chaira, Tridib, additional, Stec, Jozef, additional, Onajole, Oluseye K., additional, Yang, Tian J., additional, Cooper, Christopher B., additional, Mdluli, Khisi, additional, Converse, Paul J., additional, Nuermberger, Eric L., additional, Raj, V. Samuel, additional, Kozikowski, Alan, additional, and Bishai, William R., additional

Published
2019
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18. The preclinical candidate indole-2-carboxamide improves immune responses to Mycobacterium tuberculosis infection in healthy subjects and individuals with type 2 diabetes

Author

Cao, Ruoqiong, primary, Islamoglu, Hicret, additional, Teskey, Garrett, additional, Gyurjian, Karo, additional, Abrahem, Rachel, additional, Onajole, Oluseye K., additional, Lun, Shichun, additional, Bishai, William, additional, Kozikowski, Alan P., additional, Fraix, Marcel P., additional, Sathananthan, Airani, additional, Zhong, Li, additional, Stec, Jozef, additional, and Venketaraman, Vishwanath, additional

Published
2019
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19. Controlling Extra- and Intramacrophagic Mycobacterium abscessus by Targeting Mycolic Acid Transport

Author

Viljoen, Albertus, Herrmann, Jean-Louis, Onajole, Oluseye K., Stec, Jozef, Kozikowski, Alan P., and Kremer, Laurent

Subjects
MmpL3, Mycobacterium abscessus, glycopeptidolipid, mycolic acid, macrophage, bacterial infections and mycoses, chemotherapy, Microbiology
Abstract

Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) causing serious infections especially among cystic fibrosis patients. Extremely limited therapeutic options against M. abscessus and a rise in infections with this mycobacterium require novel chemotherapies and a better understanding of how the bacterium causes infection. Different from most RGM, M. abscessus can survive inside macrophages and persist for long durations in infected tissues. We recently delineated differences in the infective programs followed by smooth (S) and rough (R) variants of M. abscessus. Unexpectedly, we found that the S variant behaves like pathogenic slow growing mycobacteria, through maintaining a block on the phagosome maturation process and by inducing phagosome-cytosol communications. On the other hand, R variant infection triggers autophagy and apoptosis, reminiscent of the way that macrophages control RGM. However, the R variant has an exquisite capacity to form extracellular cords, allowing these bacteria to rapidly divide and evade phagocytosis. Therefore, new chemotherapeutic interventions against M. abscessus need to efficiently deal with both the reservoir of intracellular bacilli and the extracellular cords. In this context, we recently identified two chemical entities that were very effective against both M. abscessus populations. Although being structurally unrelated these two chemotypes inhibit the activity of the essential mycolic acid transporter, MmpL3. In this Perspective, we aimed to highlight recent insights into how M. abscessus interacts with phagocytic cells and how the inhibition of mycolic acid transport in this pathogenic RGM could be an efficient means to control both intracellular and extracellular populations of the bacterium.

Published
2017
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21. Targeting Mycolic Acid Transport by Indole-2-carboxamides for the Treatment of Mycobacterium abscessus Infections

Author

Kozikowski, Alan P., primary, Onajole, Oluseye K., additional, Stec, Jozef, additional, Dupont, Christian, additional, Viljoen, Albertus, additional, Richard, Matthias, additional, Chaira, Tridib, additional, Lun, Shichun, additional, Bishai, William, additional, Raj, V. Samuel, additional, Ordway, Diane, additional, and Kremer, Laurent, additional

Published
2017
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27. Convenient One-Pot Two-Step Synthesis of Symmetrical and Unsymmetrical Diacyl Ureas, Acyl Urea/Carbamate/Thiocarbamate Derivatives, and Related Compounds.

Author

Hernandez, Anolan Garcia, Grooms, Gregory M., El-Alfy, Abir T., and Stec, Jozef

Subjects
UREA, THIOCARBAMATES, CHEMICAL derivatives, SULFONATION, CHEMICAL reagents
Abstract

A wide range of chemicals such as amides, hydrazides, amines, alcohols, carbazate, and sulfonate were reacted with acyl isocyanates generated by the reaction of primary amides with oxalyl chloride to give symmetrical and unsymmetrical diacyl urea derivatives, acyl ureas/carbamates/thiocarbamates, and related compounds. This method provides means for convenient one-pot, two-step synthesis of compounds bearing urea, carbamate, and other functional groups from cheap and commercially available starting reagents. It is expected that the results presented in this report will expand the medicinal chemist's toolbox. [ABSTRACT FROM AUTHOR]

Published
2017
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28. Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

Author

Stec, Jozef, primary, Vilchèze, Catherine, additional, Lun, Shichun, additional, Perryman, Alexander L., additional, Wang, Xin, additional, Freundlich, Joel S., additional, Bishai, William, additional, Jacobs, William R., additional, and Kozikowski, Alan P., additional

Published
2014
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29. Tandem reaction sequences on a zirconocene template

Author

Stec, Jozef. and Stec, Jozef.

Abstract

The novel research work described in this thesis covers three areas of organozirconium chemistry. The first area concerns the synthesis of rigid core structures containing the cis-bicyclo[3.3.0]oct-2-ene skeleton. Zirconocene mediated co-cyclisation of 1,6-enynes provides unsaturated 5-membered zirconacycles which are homologated to 6-membered zirconacycles by insertion of 1,1-dihalo-1-lithio species (dihalogenocarbenoids). Further rearrangement to a novel zirconium-alkenylidene complex driven by acetylides provided a powerful method for a rapid construction of novel bicyclic compounds with the potential for functionalization at multiple sites. Such obtained analogues provided an attractive template for structure-activity studies with respect to investigating the biological function of the human orphan nuclear receptors: LRH-1 and SF-1. Equivalent tandem insertion of 1,1-dihalo-1-lithio species and lithium acetylides into saturated zirconacycles resulted in the synthesis of novel bicyclo[3.3.0]octanes, though in many cases limited by a ?-H elimination process. In the second area is presented research work relating to acyclic organozirconocene systems. Insertion of allenyl and propargyl carbenoids into organochlorozirconocenes and bisalkyl/-alkynyl zirconocenes led to 1,2-zirconate rearrangement with expulsion of the corresponding leaving group. Lewis acid promoted insertion of aldehydes and ketones into the resulting allenyl/propargyl zirconocene intermediate gave after hydrolysis a series of propargylic alcohols. Insertion of carbenoids derived from chiral propargyl tosylates into organochlorozirconocenes and further 1,2-metallate rearrangement gave the final alcohols as enantiomerically enriched products. The third area was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo[4.3.0]nonane unit with four contiguous stereocentres. Zirconocene mediated co-cyclisation of the appropriate precursor provided four pos

Published
2010

30. Discrimination of Potent Inhibitors of Toxoplasma gondii Enoyl-Acyl Carrier Protein Reductase by a Thermal Shift Assay

Author

Afanador, Gustavo A., primary, Muench, Stephen P., additional, McPhillie, Martin, additional, Fomovska, Alina, additional, Schön, Arne, additional, Zhou, Ying, additional, Cheng, Gang, additional, Stec, Jozef, additional, Freundlich, Joel S., additional, Shieh, Hong-Ming, additional, Anderson, John W., additional, Jacobus, David P., additional, Fidock, David A., additional, Kozikowski, Alan P., additional, Fishwick, Colin W., additional, Rice, David W., additional, Freire, Ernesto, additional, McLeod, Rima, additional, and Prigge, Sean T., additional

Published
2013
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31. Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

Author

Stec, Jozef, primary, Fomovska, Alina, additional, Afanador, Gustavo A., additional, Muench, Stephen P., additional, Zhou, Ying, additional, Lai, Bo‐Shiun, additional, El Bissati, Kamal, additional, Hickman, Mark R., additional, Lee, Patty J., additional, Leed, Susan E., additional, Auschwitz, Jennifer M., additional, Sommervile, Caroline, additional, Woods, Stuart, additional, Roberts, Craig W., additional, Rice, David, additional, Prigge, Sean T., additional, McLeod, Rima, additional, and Kozikowski, Alan P., additional

Published
2013
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32. Preliminary Structure–Activity Relationships and Biological Evaluation of Novel Antitubercular Indolecarboxamide Derivatives Against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Author

Onajole, Oluseye K., primary, Pieroni, Marco, additional, Tipparaju, Suresh K., additional, Lun, Shichun, additional, Stec, Jozef, additional, Chen, Gang, additional, Gunosewoyo, Hendra, additional, Guo, Haidan, additional, Ammerman, Nicole C., additional, Bishai, William R., additional, and Kozikowski, Alan P., additional

Published
2013
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34. Novel N -Benzoyl-2-Hydroxybenzamide Disrupts Unique Parasite Secretory Pathway

Author

Fomovska, Alina, primary, Huang, Qingqing, additional, El Bissati, Kamal, additional, Mui, Ernest J., additional, Witola, William H., additional, Cheng, Gang, additional, Zhou, Ying, additional, Sommerville, Caroline, additional, Roberts, Craig W., additional, Bettis, Sam, additional, Prigge, Sean T., additional, Afanador, Gustavo A., additional, Hickman, Mark R., additional, Lee, Patty J., additional, Leed, Susan E., additional, Auschwitz, Jennifer M., additional, Pieroni, Marco, additional, Stec, Jozef, additional, Muench, Stephen P., additional, Rice, David W., additional, Kozikowski, Alan P., additional, and McLeod, Rima, additional

Published
2012
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35. Synthesis, Biological Evaluation, and Structure–Activity Relationships of N-Benzoyl-2-hydroxybenzamides as Agents Active against P. falciparum (K1 strain), Trypanosomes, and Leishmania

Author

Stec, Jozef, primary, Huang, Qingqing, additional, Pieroni, Marco, additional, Kaiser, Marcel, additional, Fomovska, Alina, additional, Mui, Ernest, additional, Witola, William H., additional, Bettis, Samuel, additional, McLeod, Rima, additional, Brun, Reto, additional, and Kozikowski, Alan P., additional

Published
2012
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39. Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

Author

Whitby, Richard J., primary, Stec, Jozef, additional, Blind, Raymond D., additional, Dixon, Sally, additional, Leesnitzer, Lisa M., additional, Orband-Miller, Lisa A., additional, Williams, Shawn P., additional, Willson, Timothy M., additional, Xu, Robert, additional, Zuercher, William J., additional, Cai, Fang, additional, and Ingraham, Holly A., additional

Published
2011
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41. Facile synthesis of the fungus-derived natural products: N,N '-dipalmitoleyl urea (C 16:1 ) and N,N '-dioleyl urea (C 18:1 ).

Author

Stec J and Pecic S

Subjects
Chemistry Techniques, Synthetic, Fungi, Biological Products, Urea
Abstract

Oxalyl chloride is one of the most versatile reagents used in organic synthesis. Oxalyl chloride was employed in the convenient one-pot, two-step synthesis of the fungus-derived naturally occurring lipoids: N,N' -dipalmitoleyl urea (C 16:1 ) and N,N' -dioleyl urea (C 18:1 ). The two symmetrical diacyl urea-based natural products were previously identified as fungus-specific pathogen-associated molecules (PAMs), which act as inflammatory mediators during fungal infection. The highly lipophilic natural lipoids were efficiently synthesized from commercially available reagents in yields ranging from good to very good.

Published
2022
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42. Tandem insertion of halocarbenoids and lithium acetylides into zirconacycles: a novel rearrangement to zirconium alkenylidenates by β-addition to an alkynyl zirconocene.

Author

Stec J, Thomas E, Dixon S, and Whitby RJ

Subjects
Catalysis, Molecular Structure, Stereoisomerism, Alkynes chemistry, Cyclopentanes chemistry, Lithium chemistry, Organometallic Compounds chemical synthesis, Organometallic Compounds chemistry, Zirconium chemistry
Abstract

Tandem insertion of 1,1-dihalo-1-lithio species (halocarbenoids) and lithium alkynides into zirconacyclopentenes and zirconcyclopentanes affords carbocyclic products in high yields via an unusual rearrangement that probably involves addition of an organolithium species to the β-position of a zirconium-alkyne complex to give an alkenylidene-zirconate species. A wide variety of cyclopentanoid organic structures are rapidly assembled in good yield using this multicomponent coupling. The main side reaction, which becomes exclusive in some cases, is β-hydride elimination of an intermediate cyclopentyl- or cyclopentenyl zirconocene., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2011
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