Based on experience, fused ring systems on an unknown structure tend to conjure up variations of odd connections. The possibilities can seem endless.
The diagram, shown below, samples a subset of fused ring systems for a given dataset. It is important to note that although certain systems may be more appealing to the eye, it is imperative for an elucidator to evaluate each variation prior to accepting or rejecting the proposed candidate.
Drug Trials commence with in vitro and in vivo experiments on nonhuman subjects and observing the effects of the candidate drug(s). These are commonly referred to as the pre-clinical trials. Once safe and effective thresholds have been set, the candidate drug(s) can be administered to human subjects and thus begin the clinical trials. The clinical trials are divided into various Phases I, II, III, IV.
In a concerted effort, preformulation studies look at the candidate’s solubility, stability, crystal properties, etc. to optimize the method of delivery. As testing nears completion (or soon after the Drug Design stage is complete), an application for a new drug is submitted to an internal regulatory board and a patent is filed.
Drug Trials commence with in vitro and in vivo experiments on nonhuman subjects and observing the effects of the candidate drug(s). These are commonly referred to as the pre-clinical trials. Once safe and effective thresholds have been set, the candidate drug(s) can be administered to human subjects and thus begin the clinical trials. The clinical trials are divided into various Phases I, II, III, IV.
In a concerted effort, preformulation studies look at the candidate’s solubility, stability, crystal properties, etc. to optimize the method of delivery. As testing nears completion (or soon after the Drug Design stage is complete), an application for a new drug is submitted to an internal regulatory board and a patent is filed.
The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.
In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.
The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.
In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.
Following the diagram presented in Part 1, the Drug Discovery stage begins with the identification of a target site that is linked to a disease. (Note: some researchers refer to this as the pre-Drug Discovery stage.)
The main goal behind the Drug Discovery stage is to identify or envision a hit compound(s) that can offer some potential for activity at the target site. A hit compound(s) is uncovered from an array of resources such as: natural products, de novo, high-throughput screening, biotechnology, serendipity, searching across structural libraries, past experiences on similar targets, etc. The hit compound(s) is validated, and barring any toxicity issues, the compound is transitioned from hit to lead compound for the next stage of the development process Drug Design.
The Innovation website presents a similar description on drug development in industry. It also includes a nice movie summarizing the development.
Following the diagram presented in Part 1, the Drug Discovery stage begins with the identification of a target site that is linked to a disease. (Note: some researchers refer to this as the pre-Drug Discovery stage.)
The main goal behind the Drug Discovery stage is to identify or envision a hit compound(s) that can offer some potential for activity at the target site. A hit compound(s) is uncovered from an array of resources such as: natural products, de novo, high-throughput screening, biotechnology, serendipity, searching across structural libraries, past experiences on similar targets, etc. The hit compound(s) is validated, and barring any toxicity issues, the compound is transitioned from hit to lead compound for the next stage of the development process Drug Design.
The Innovation website presents a similar description on drug development in industry. It also includes a nice movie summarizing the development.
Many new medicinal drugs produced by pharmaceutical companies follow a very similar pathway starting from the inception of the project idea and ending at the shelves of a pharmacy. Each stage in the development of the drug involves various types of chemists, each lending their expertise at synthesizing, extracting, analyzing and testing the new drug.
The following diagram presents a simplified summary in the development of a medicinal drug. The general stages are 1. Drug Discovery, 2. Drug Design, 3. Drug Trials and 4. Drug Manufacturing/Process.
Many new medicinal drugs produced by pharmaceutical companies follow a very similar pathway starting from the inception of the project idea and ending at the shelves of a pharmacy. Each stage in the development of the drug involves various types of chemists, each lending their expertise at synthesizing, extracting, analyzing and testing the new drug.
The following diagram presents a simplified summary in the development of a medicinal drug. The general stages are 1. Drug Discovery, 2. Drug Design, 3. Drug Trials and 4. Drug Manufacturing/Process.
There are many ways to teach the process of elucidating unknown structures. Offering a student a visual guide, such as seeing firsthand a spectral dataset, can enhance the learning process and better equip the student on future work.
Presented below is a typical elucidation question from a university test. The numerical values have been extracted from a 1H NMR spectrum and the student is basically left to focus on elucidating the unknown.
There are many ways to teach the process of elucidating unknown structures. Offering a student a visual guide, such as seeing firsthand a spectral dataset, can enhance the learning process and better equip the student on future work.
Presented below is a typical elucidation question from a university test. The numerical values have been extracted from a 1H NMR spectrum and the student is basically left to focus on elucidating the unknown.
After a long and arduous attempt at an elucidation, it is quite common to be left with more than one candidate structure. In some cases collecting more data is not an option and an exhaustive database/literature search turns up nothing useful, the alternative approach is to synthesize the proposed candidates and then compare the spectral data to the original unknown.
The example below shows three proposed candidate structure differing in the attachment of the hexopyranoside group. The high degree of similarity between the candidates and the high number of quaternary carbons (11 per structure) makes it very difficult to narrow the list to one candidate.
When data is limited and thus cannot assist in eliminating two out of the three candidates, then the only option left is to synthesize the candidates and compare the spectral data.
After a long and arduous attempt at an elucidation, it is quite common to be left with more than one candidate structure. In some cases collecting more data is not an option and an exhaustive database/literature search turns up nothing useful, the alternative approach is to synthesize the proposed candidates and then compare the spectral data to the original unknown.
The example below shows three proposed candidate structure differing in the attachment of the hexopyranoside group. The high degree of similarity between the candidates and the high number of quaternary carbons (11 per structure) makes it very difficult to narrow the list to one candidate.
When data is limited and thus cannot assist in eliminating two out of the three candidates, then the only option left is to synthesize the candidates and compare the spectral data.
The approach behind solving a structure elucidation problem is very similar to attempting a math problem or working on a jigsaw puzzle. This similar mental framework shares a basis, but not limited to, on understanding the basic rules that define the problem, and in some cases the creativity and flexibility to redefine the problem.
When presented with a set of data, an elucidator can recognize that the data is valid and logical, address any problematic areas and explore a strategy to fix or solve it without making too many assumptions. Although various problem solving techniques exist, ultimately, it is experience that goes a long way.
The following reference addresses some of the underlying issues described in this blog: J.E. Davidson and R.J. Sternberg. The Psychology of Problem Solving. Cambridge University Press, 2003.
The approach behind solving a structure elucidation problem is very similar to attempting a math problem or working on a jigsaw puzzle. This similar mental framework shares a basis, but not limited to, on understanding the basic rules that define the problem, and in some cases the creativity and flexibility to redefine the problem.
When presented with a set of data, an elucidator can recognize that the data is valid and logical, address any problematic areas and explore a strategy to fix or solve it without making too many assumptions. Although various problem solving techniques exist, ultimately, it is experience that goes a long way.
The following reference addresses some of the underlying issues described in this blog: J.E. Davidson and R.J. Sternberg. The Psychology of Problem Solving. Cambridge University Press, 2003.
I would like to begin the new year with a weblog that summarizes the components of an elucidation process. Each component, shown as a Venn diagram below, can blend in with the next until a conclusion is reached. The goal for the elucidator is to exhaust all aspects of each possible component thus ensuring that nothing is overlooked.
Dereplication/Database/Library search
Publish/Report/Present/Store
I would like to begin the new year with a weblog that summarizes the components of an elucidation process. Each component, shown as a Venn diagram below, can blend in with the next until a conclusion is reached. The goal for the elucidator is to exhaust all aspects of each possible component thus ensuring that nothing is overlooked.
Dereplication/Database/Library search
Publish/Report/Present/Store
The message behind an old carpenter’s adage ‘measure twice, cut once’ can be applied to the process of structure elucidation as ‘verify twice, publish once’. Committing the time to double check a candidate structure against the experimental data can save a lot of hassles and embarrassment from a mistake being published/presented/stored/reported. Without picking on a specific case, journals are littered with examples of incorrect structures.
As the holidays approach, Philosophy to Chemistry to Elucidation blogging will be taking a short break and will resume in the new year. In the meantime, the following link is an interesting read on the importance of shape within the field of Chemistry: Angew. Chem. Int. Ed. Engl. 30 (1991)1-16.
The message behind an old carpenter’s adage ‘measure twice, cut once’ can be applied to the process of structure elucidation as ‘verify twice, publish once’. Committing the time to double check a candidate structure against the experimental data can save a lot of hassles and embarrassment from a mistake being published/presented/stored/reported. Without picking on a specific case, journals are littered with examples of incorrect structures.
As the holidays approach, Philosophy to Chemistry to Elucidation blogging will be taking a short break and will resume in the new year. In the meantime, the following link is an interesting read on the importance of shape within the field of Chemistry: Angew. Chem. Int. Ed. Engl. 30 (1991)1-16.
For synthetic reactions where rearrangement, derivatization, or cyclization has occurred, a common task is to compare the NMR spectra between the starting material and the product. The similar peaks indicate a structural region where change has not occurred whereas the unique peaks indicate a region where change has occurred. Arguably, this becomes a peak mapping task as opposed to structure elucidation which is geared towards the unique pieces.
A cyclization reaction for the starting material, N-(2,6-dimethylphenyl)-N2,N2-dimethylalaninamide is shown below. The dotted circle represents the unknown region of the product. The CH3 groups circled in red indicate the similar regions between the starting material and the product.
The unknown product, N,N-dimethyl-1-(8-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-yl)ethanamine, is shown below. The blue circle indicates the point of the cyclization and thus the area where an elucidator must piece together the experimental data to complete the structure.
