It was recently demonstrated that an IDR- (Inverted Direct Response) HSQC-TOCSY data set could be... more It was recently demonstrated that an IDR- (Inverted Direct Response) HSQC-TOCSY data set could be decomposed into a negatively phased direct response spectrum and a positively phased relayed response spectrum that could then be subjected to unsymmetrical indirect covariance processing for the removal of artifacts due to response overlap in the proton NMR spectrum of the molecule. Using experimentally discrete HSQC and HMBC data sets, it is shown that unsymmetrical indirect covariance processing of the pair of NMR spectra affords a presentation containing long-range carbon-carbon connectivity information. The method is demonstrated using strychnine as a model compound. The resulting data are largely free of artifacts although artifacts can arise due to proton response overlap, as previously reported.
Described herein are applications of the latest version of the StrucEluc expert software system, ... more Described herein are applications of the latest version of the StrucEluc expert software system, enhanced to use 2D NMR data, to the structure elucidation of 60 recently isolated natural products. In this study, selected molecules containing between 15 and 65 skeletal atoms and having molecular masses ranging from 200 to 900 amu have been investigated. The correct structure was determined unambiguously for 58 of these molecules. The structures for 75% of the data sets were determined in less than one minute, while 90% of the analyses required no more than 30 minutes. The strategy of structure elucidation by this expert system is described, and several examples are discussed. These illustrate that StrucEluc is a powerful and versatile analytical tool for the structure elucidation of natural products.
Computers in chemistry V 0380 Structure Elucidator: A Versatile Expert System for Molecular Struc... more Computers in chemistry V 0380 Structure Elucidator: A Versatile Expert System for Molecular Structure Elucidation from 1D and 2D NMR Data and Molecular Fragments -(ELYASHBERG, M. E.; BLINOV, K. A.; WILLIAMS*, A. J.; MOLODTSOV, S. G.; MARTIN, G. E.; MARTIROSIAN, E. R.; J. Chem. Inf. Comput. Sci. 44 (2004) 3, 771-792; Moscow Dep., Adv. Chem. Dev., Inc., Moscow 117513, Russia; Eng.) -Lindner 30-208
Recently, through the use of 2D NMR methods and cryogenic NMR probe technology in conjunction wit... more Recently, through the use of 2D NMR methods and cryogenic NMR probe technology in conjunction with computer-assisted structure elucidation (CASE) methods, the structures of some chemical degradation products of this family of alkaloids have also been reported. We now report the characterization of a novel indoloquinoline dimeric alkaloid, quindolinocryptotackieine, through the extensive utilization of CASE methods. The NMR data presented here were collected over a decade earlier before the elucidation of the structure was possible, since manual analysis did not present a conclusive structure, whereas CASE produced a series of structures from which the structure could be verified. The original mass spectrometric (MS) data collected for the sample were problematic. Contemporary MS data were instead recollected from remaining small quantities of this alkaloid using modern instrumentation. The re-collected data gave a usable molecular ion and several key fragment ions that were diagnostically useful.
Identification of degradants of pharmaceuticals is a necessary challenge of the drug development ... more Identification of degradants of pharmaceuticals is a necessary challenge of the drug development process following the subjection of candidate molecules to a variety of physico-chemical stresses. It would be desirable to be able to conduct such studies on a minimal amount of material. As a prototypical study, the isolation and identification of degradants of a sample of the complex indoloquinoline alkaloid, cryptospirolepine, was undertaken after prolonged storage in DMSO solution using a combination of cryogenic NMR probe technology and CASE (Computer-Assisted Structure Elucidation) programs. None of the starting alkaloid remained after storage; a chromatogram of the DMSO solution demonstrated the presence of >25 components in the mixture. The two most abundant degradation products were identified as the known alkaloid cryptolepinone (~35%) and an unprecedented rearrangement product, DP-2, (~16%).
Computers in chemistry V 0380 Fuzzy Structure Generation: A New Efficient Tool for Computer-Aided... more Computers in chemistry V 0380 Fuzzy Structure Generation: A New Efficient Tool for Computer-Aided Structure Elucidation (CASE). -(ELYASHBERG, M. E.; BLINOV, K. A.; MOLODTSOV, S. G.; WILLIAMS*, A. J.; MARTIN, G. E.; J. Chem. Inf. Model. (J. Chem. Inf. Comput. Sci.) 47 (2007) 3, 1053-1066; Moscow Dep., Adv. Chem. Dev., Inc., Moscow 117513, Russia; Eng.) -Lindner 33-228
GHSQC-TOCSY experiments allow sorting of proton-proton connectivity information as a function of ... more GHSQC-TOCSY experiments allow sorting of proton-proton connectivity information as a function of (13)C chemical shift. GHSQC-TOCSY is a relatively insensitive 2D NMR experiment. Given two coherence transfer experiments, A --> B and A --> C, it is possible to indirectly determine B <--> C. Unsymmetrical indirect covariance processing of a (1)H- (13)C GHSQC and a GCOSY spectrum afforded a GHSQC-COSY spectrum, with an information content analogous to a GHSQC-TOCSY experiment. However, GHSQC-TOCSY is of significantly lower sensitivity and the data require considerably more time to acquire than either of the component experiments. Investigators needing access to GHSQC-TOCSY type data can, in principle, access it from more readily acquired 2D NMR data. Strychnine ( 1) was used as a model compound to illustrate this capability.
In this article we describe a fast and accurate method of 13C NMR chemical shift prediction. The ... more In this article we describe a fast and accurate method of 13C NMR chemical shift prediction. The high speed of chemical shift calculation described is achieved using a simple structure description scheme based on individual atoms rather than functional groups. The systematic choice of an appropriate encoding scheme and the usage of partial least squares regression on a large training set has resulted in a robust and fast algorithm. The approach provides accuracy comparable with other well known approaches but demonstrates accelerated calculation speeds of up to a thousand times faster.
Background: This article coincides with the 40 year anniversary of the first published works devo... more Background: This article coincides with the 40 year anniversary of the first published works devoted to the creation of algorithms for computer-aided structure elucidation (CASE). The general principles on which CASE methods are based will be reviewed and the present state of the art in this field will be described using, as an example, the expert system Structure Elucidator.
This paper considers the strategy of the StrucEluc expert system application for structure elucid... more This paper considers the strategy of the StrucEluc expert system application for structure elucidation of new natural products when there is a lack of connectivity information that is characteristic of protondeficient molecules. It is shown that in this case, a database search for fragments using a 13 C NMR spectrum as input allows an investigator to fill gaps in the recorded data. Algorithms and programs have been developed that allow fragments found in the library and/or proposed by the user to be embedded in the molecular connectivities diagrams built on the basis of 2D NMR data analysis. We demonstrate the structure determination of three alkaloids from the cryptolepine series using the principles of construction and application of a user fragment library. The approach described appears to be the most efficient means of structure elucidation for natural products with 2D NMR spectra characterized by sparse responses.
Utilization of long-range (1)H--(15)N heteronuclear chemical shift correlation has continually gr... more Utilization of long-range (1)H--(15)N heteronuclear chemical shift correlation has continually grown in importance since the first applications were reported in 1995. More recently, indirect covariance NMR methods have been introduced followed by the development of unsymmetrical indirect covariance processing methods. The latter technique has been shown to allow the calculation of hyphenated 2D NMR data matrices from more readily acquired nonhyphenated 2D NMR spectra. We recently reported the use of unsymmetrical indirect covariance processing to combine (1)H--(13)C GHSQC and (1)H--(15)N GHMBC long-range spectra to yield a (13)C--(15)N HSQC-HMBC chemical shift correlation spectrum that could not be acquired in a reasonable period of time without resorting to (15)N-labeled molecules. We now report the unsymmetrical indirect covariance processing of (1)H--(13)C GHMBC and (1)H--(15)N IMPEACH spectra to afford a (13)C--(15)N HMBC-IMPEACH spectrum that has the potential to span as many as six to eight bonds. Correlations for carbon resonances long-range coupled to a protonated carbon in the (1)H--(13)C HMBC spectrum are transferred via the long-range (1)H--(15)N coupling pathway in the (1)H--(15)N IMPEACH spectrum to afford a much broader range of correlation possibilities in the (13)C--(15)N HMBC-IMPEACH correlation spectrum. The indole alkaloid vincamine is used as a model compound to illustrate the application of the method.
Utilization of long-range 1 H-15 N heteronuclear chemical shift correlation has continually grown... more Utilization of long-range 1 H-15 N heteronuclear chemical shift correlation has continually grown in importance since the first applications were reported in 1995. More recently, indirect covariance NMR methods have been introduced followed by the development of unsymmetrical indirect covariance processing methods. The latter technique has been shown to allow the calculation of hyphenated 2D NMR data matrices from more readily acquired non-hyphenated 2D NMR spectra. We recently reported the use of unsymmetrical indirect covariance processing to combine 1 H-13 C GHSQC and 1 H-15 N GHMBC long-range spectra to yield a 13 C-15 N HSQC-HMBC chemical shift correlation spectrum that could not be acquired in a reasonable period of time without resorting to 15 N-labeled molecules. We now report the unsymmetrical indirect covariance processing of 1 H-13 C GHMBC and 1 H-15 N IMPEACH spectra to afford a 13 C-15 N HMBC-IMPEACH spectrum that has the potential to span as many as 6 to 8 bonds. Correlations for carbon resonances long-range coupled to a protonated carbon in the 1 H-13 C HMBC spectrum are transferred via the long-range 1 H-15 N coupling pathway in the 1 H-15 N IMPEACH spectrum to afford a much broader range of correlation possibilities in the 13 C-15 N HMBC-IMPEACH correlation spectrum. The indole alkaloid vincamine is used as a model compound to illustrate the application of the method.
Described herein are applications of the latest version of the StrucEluc expert software system, ... more Described herein are applications of the latest version of the StrucEluc expert software system, enhanced to use 2D NMR data, to the structure elucidation of 60 recently isolated natural products. In this study, selected molecules containing between 15 and 65 skeletal atoms and having molecular masses ranging from 200 to 900 amu have been investigated. The correct structure was determined unambiguously for 58 of these molecules. The structures for 75% of the data sets were determined in less than one minute, while 90% of the analyses required no more than 30 minutes. The strategy of structure elucidation by this expert system is described, and several examples are discussed. These illustrate that StrucEluc is a powerful and versatile analytical tool for the structure elucidation of natural products.
A software program for the automated structure elucidation of complex organic molecules using an ... more A software program for the automated structure elucidation of complex organic molecules using an expert system and utilizing 2D homo-and heteronuclear correlation 1 H, 13 C and 15 N NMR spectroscopy is described. The methodology is illustrated on the basis of the automated structure determination of strychnine and some other examples.
Table 1S. Typical structure-outliers with their MAE values and maximum errors dmax. Symbols dQ, d... more Table 1S. Typical structure-outliers with their MAE values and maximum errors dmax. Symbols dQ, dA and dN are related to QM, HOSE and NN methods correspondingly.
It was recently demonstrated that an IDR- (Inverted Direct Response) HSQC-TOCSY data set could be... more It was recently demonstrated that an IDR- (Inverted Direct Response) HSQC-TOCSY data set could be decomposed into a negatively phased direct response spectrum and a positively phased relayed response spectrum that could then be subjected to unsymmetrical indirect covariance processing for the removal of artifacts due to response overlap in the proton NMR spectrum of the molecule. Using experimentally discrete HSQC and HMBC data sets, it is shown that unsymmetrical indirect covariance processing of the pair of NMR spectra affords a presentation containing long-range carbon-carbon connectivity information. The method is demonstrated using strychnine as a model compound. The resulting data are largely free of artifacts although artifacts can arise due to proton response overlap, as previously reported.
Described herein are applications of the latest version of the StrucEluc expert software system, ... more Described herein are applications of the latest version of the StrucEluc expert software system, enhanced to use 2D NMR data, to the structure elucidation of 60 recently isolated natural products. In this study, selected molecules containing between 15 and 65 skeletal atoms and having molecular masses ranging from 200 to 900 amu have been investigated. The correct structure was determined unambiguously for 58 of these molecules. The structures for 75% of the data sets were determined in less than one minute, while 90% of the analyses required no more than 30 minutes. The strategy of structure elucidation by this expert system is described, and several examples are discussed. These illustrate that StrucEluc is a powerful and versatile analytical tool for the structure elucidation of natural products.
Computers in chemistry V 0380 Structure Elucidator: A Versatile Expert System for Molecular Struc... more Computers in chemistry V 0380 Structure Elucidator: A Versatile Expert System for Molecular Structure Elucidation from 1D and 2D NMR Data and Molecular Fragments -(ELYASHBERG, M. E.; BLINOV, K. A.; WILLIAMS*, A. J.; MOLODTSOV, S. G.; MARTIN, G. E.; MARTIROSIAN, E. R.; J. Chem. Inf. Comput. Sci. 44 (2004) 3, 771-792; Moscow Dep., Adv. Chem. Dev., Inc., Moscow 117513, Russia; Eng.) -Lindner 30-208
Recently, through the use of 2D NMR methods and cryogenic NMR probe technology in conjunction wit... more Recently, through the use of 2D NMR methods and cryogenic NMR probe technology in conjunction with computer-assisted structure elucidation (CASE) methods, the structures of some chemical degradation products of this family of alkaloids have also been reported. We now report the characterization of a novel indoloquinoline dimeric alkaloid, quindolinocryptotackieine, through the extensive utilization of CASE methods. The NMR data presented here were collected over a decade earlier before the elucidation of the structure was possible, since manual analysis did not present a conclusive structure, whereas CASE produced a series of structures from which the structure could be verified. The original mass spectrometric (MS) data collected for the sample were problematic. Contemporary MS data were instead recollected from remaining small quantities of this alkaloid using modern instrumentation. The re-collected data gave a usable molecular ion and several key fragment ions that were diagnostically useful.
Identification of degradants of pharmaceuticals is a necessary challenge of the drug development ... more Identification of degradants of pharmaceuticals is a necessary challenge of the drug development process following the subjection of candidate molecules to a variety of physico-chemical stresses. It would be desirable to be able to conduct such studies on a minimal amount of material. As a prototypical study, the isolation and identification of degradants of a sample of the complex indoloquinoline alkaloid, cryptospirolepine, was undertaken after prolonged storage in DMSO solution using a combination of cryogenic NMR probe technology and CASE (Computer-Assisted Structure Elucidation) programs. None of the starting alkaloid remained after storage; a chromatogram of the DMSO solution demonstrated the presence of >25 components in the mixture. The two most abundant degradation products were identified as the known alkaloid cryptolepinone (~35%) and an unprecedented rearrangement product, DP-2, (~16%).
Computers in chemistry V 0380 Fuzzy Structure Generation: A New Efficient Tool for Computer-Aided... more Computers in chemistry V 0380 Fuzzy Structure Generation: A New Efficient Tool for Computer-Aided Structure Elucidation (CASE). -(ELYASHBERG, M. E.; BLINOV, K. A.; MOLODTSOV, S. G.; WILLIAMS*, A. J.; MARTIN, G. E.; J. Chem. Inf. Model. (J. Chem. Inf. Comput. Sci.) 47 (2007) 3, 1053-1066; Moscow Dep., Adv. Chem. Dev., Inc., Moscow 117513, Russia; Eng.) -Lindner 33-228
GHSQC-TOCSY experiments allow sorting of proton-proton connectivity information as a function of ... more GHSQC-TOCSY experiments allow sorting of proton-proton connectivity information as a function of (13)C chemical shift. GHSQC-TOCSY is a relatively insensitive 2D NMR experiment. Given two coherence transfer experiments, A --> B and A --> C, it is possible to indirectly determine B <--> C. Unsymmetrical indirect covariance processing of a (1)H- (13)C GHSQC and a GCOSY spectrum afforded a GHSQC-COSY spectrum, with an information content analogous to a GHSQC-TOCSY experiment. However, GHSQC-TOCSY is of significantly lower sensitivity and the data require considerably more time to acquire than either of the component experiments. Investigators needing access to GHSQC-TOCSY type data can, in principle, access it from more readily acquired 2D NMR data. Strychnine ( 1) was used as a model compound to illustrate this capability.
In this article we describe a fast and accurate method of 13C NMR chemical shift prediction. The ... more In this article we describe a fast and accurate method of 13C NMR chemical shift prediction. The high speed of chemical shift calculation described is achieved using a simple structure description scheme based on individual atoms rather than functional groups. The systematic choice of an appropriate encoding scheme and the usage of partial least squares regression on a large training set has resulted in a robust and fast algorithm. The approach provides accuracy comparable with other well known approaches but demonstrates accelerated calculation speeds of up to a thousand times faster.
Background: This article coincides with the 40 year anniversary of the first published works devo... more Background: This article coincides with the 40 year anniversary of the first published works devoted to the creation of algorithms for computer-aided structure elucidation (CASE). The general principles on which CASE methods are based will be reviewed and the present state of the art in this field will be described using, as an example, the expert system Structure Elucidator.
This paper considers the strategy of the StrucEluc expert system application for structure elucid... more This paper considers the strategy of the StrucEluc expert system application for structure elucidation of new natural products when there is a lack of connectivity information that is characteristic of protondeficient molecules. It is shown that in this case, a database search for fragments using a 13 C NMR spectrum as input allows an investigator to fill gaps in the recorded data. Algorithms and programs have been developed that allow fragments found in the library and/or proposed by the user to be embedded in the molecular connectivities diagrams built on the basis of 2D NMR data analysis. We demonstrate the structure determination of three alkaloids from the cryptolepine series using the principles of construction and application of a user fragment library. The approach described appears to be the most efficient means of structure elucidation for natural products with 2D NMR spectra characterized by sparse responses.
Utilization of long-range (1)H--(15)N heteronuclear chemical shift correlation has continually gr... more Utilization of long-range (1)H--(15)N heteronuclear chemical shift correlation has continually grown in importance since the first applications were reported in 1995. More recently, indirect covariance NMR methods have been introduced followed by the development of unsymmetrical indirect covariance processing methods. The latter technique has been shown to allow the calculation of hyphenated 2D NMR data matrices from more readily acquired nonhyphenated 2D NMR spectra. We recently reported the use of unsymmetrical indirect covariance processing to combine (1)H--(13)C GHSQC and (1)H--(15)N GHMBC long-range spectra to yield a (13)C--(15)N HSQC-HMBC chemical shift correlation spectrum that could not be acquired in a reasonable period of time without resorting to (15)N-labeled molecules. We now report the unsymmetrical indirect covariance processing of (1)H--(13)C GHMBC and (1)H--(15)N IMPEACH spectra to afford a (13)C--(15)N HMBC-IMPEACH spectrum that has the potential to span as many as six to eight bonds. Correlations for carbon resonances long-range coupled to a protonated carbon in the (1)H--(13)C HMBC spectrum are transferred via the long-range (1)H--(15)N coupling pathway in the (1)H--(15)N IMPEACH spectrum to afford a much broader range of correlation possibilities in the (13)C--(15)N HMBC-IMPEACH correlation spectrum. The indole alkaloid vincamine is used as a model compound to illustrate the application of the method.
Utilization of long-range 1 H-15 N heteronuclear chemical shift correlation has continually grown... more Utilization of long-range 1 H-15 N heteronuclear chemical shift correlation has continually grown in importance since the first applications were reported in 1995. More recently, indirect covariance NMR methods have been introduced followed by the development of unsymmetrical indirect covariance processing methods. The latter technique has been shown to allow the calculation of hyphenated 2D NMR data matrices from more readily acquired non-hyphenated 2D NMR spectra. We recently reported the use of unsymmetrical indirect covariance processing to combine 1 H-13 C GHSQC and 1 H-15 N GHMBC long-range spectra to yield a 13 C-15 N HSQC-HMBC chemical shift correlation spectrum that could not be acquired in a reasonable period of time without resorting to 15 N-labeled molecules. We now report the unsymmetrical indirect covariance processing of 1 H-13 C GHMBC and 1 H-15 N IMPEACH spectra to afford a 13 C-15 N HMBC-IMPEACH spectrum that has the potential to span as many as 6 to 8 bonds. Correlations for carbon resonances long-range coupled to a protonated carbon in the 1 H-13 C HMBC spectrum are transferred via the long-range 1 H-15 N coupling pathway in the 1 H-15 N IMPEACH spectrum to afford a much broader range of correlation possibilities in the 13 C-15 N HMBC-IMPEACH correlation spectrum. The indole alkaloid vincamine is used as a model compound to illustrate the application of the method.
Described herein are applications of the latest version of the StrucEluc expert software system, ... more Described herein are applications of the latest version of the StrucEluc expert software system, enhanced to use 2D NMR data, to the structure elucidation of 60 recently isolated natural products. In this study, selected molecules containing between 15 and 65 skeletal atoms and having molecular masses ranging from 200 to 900 amu have been investigated. The correct structure was determined unambiguously for 58 of these molecules. The structures for 75% of the data sets were determined in less than one minute, while 90% of the analyses required no more than 30 minutes. The strategy of structure elucidation by this expert system is described, and several examples are discussed. These illustrate that StrucEluc is a powerful and versatile analytical tool for the structure elucidation of natural products.
A software program for the automated structure elucidation of complex organic molecules using an ... more A software program for the automated structure elucidation of complex organic molecules using an expert system and utilizing 2D homo-and heteronuclear correlation 1 H, 13 C and 15 N NMR spectroscopy is described. The methodology is illustrated on the basis of the automated structure determination of strychnine and some other examples.
Table 1S. Typical structure-outliers with their MAE values and maximum errors dmax. Symbols dQ, d... more Table 1S. Typical structure-outliers with their MAE values and maximum errors dmax. Symbols dQ, dA and dN are related to QM, HOSE and NN methods correspondingly.
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Papers by Kirill Blinov