Viewpoint pubs.acs.org/chemneuro
The Critical Role of Organic Chemistry in Drug Discovery David P. Rotella Sokol Professor of Chemistry and Biochemistry Sokol Institute of Pharmaceutical Life Sciences Department of Chemistry and Biochemistry, Montclair State University, Montclair, New Jersey 07043, United States ABSTRACT: Small molecules remain the backbone for modern drug discovery. They are conceived and synthesized by medicinal chemists, many of whom were originally trained as organic chemists. Support from government and industry to provide training and personnel for continued development of this critical skill set has been declining for many years. This Viewpoint highlights the value of organic chemistry and organic medicinal chemists in the complex journey of drug discovery as a reminder that basic science support must be restored. KEYWORDS: AZT, small molecules, drug discovery, organic chemistry
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recall the excitement in the 1970s and 1980s associated with synthesis of taxol, prostaglandins, leukotrienes, and asymmetric aldol methodology, to cite just a few examples. A number of faculty, graduate students, and postdoctoral researchers who developed solutions to these questions applied their skills in the discovery of new medications including some of the molecules highlighted in Figure 1. More recently, organic chemists have developed efficient methodology to activate C−H bonds and fluorinate organic molecules to permit more facile access to complicated molecules of therapeutic interest. Novel methods for organocatalytic synthesis permit us to selectively obtain enantiomers that display interesting biological activity. It is a testament to the value of these discoveries that they are now considered mainstream. The funding provided to the scientists who carried out the research was sine qua non.1−3 Like any investment, the return was not immediate; fortunately it was and remains substantial. To commit to such a long-term objective, patience and recognition of value are required and these traits are scarce in both government and industry. The challenges inherent in drug discovery require continuing investment by public and private organizations in the basic disciplines involved. Organic chemistry is a critical science where this investment has been declining for some time, in favor of increased attention to applied research such as translational medicine and biomarker development.1−3 Interestingly, both of these fields require molecules to answer questions. Those molecules are often provided by medicinal chemists who were originally trained as organic chemists. In my view, it is time to adjust this imbalance to provide support for the next generation of synthetic medicinal chemists. It has reached dangerously low levels and this has serious consequences. One simple example is the significant decrease in graduate fellowships from 18 to 3 over the period from 2006 to 2016 provided by the divisions of organic chemistry and medicinal chemistry within the American Chemical Society.4 This is directly related to refocusing of industrial resources elsewhere. Academicians are well aware of the substantial
mall molecule drugs and drug candidates represent the majority of new chemical entities (NCEs) in use or under study worldwide.1−3 These molecules are made available in part by virtue of the skill and ingenuity of medicinal and process chemists who synthesize the compounds. Countless lives have been and continue to be extended and saved with immeasurable gain to society, the families and friends of the people treated with drugs such as atorvastatin (1), ledipasvir (2), imantinib (3), AZT (4), and linezolid (5) [Figure 1]. The complexity of these structures varies in terms of stereochemistry, functional groups, and framework; such features are related to the target for each molecule. However, one should never conflate molecular complexity with therapeutic value. AZT was the first drug useful in the treatment of HIV infection, and imantinib was the first kinase inhibitor approved to treat chronic myeloid leukemia. Each demonstrated that difficult to treat diseases could be addressed with small molecules and represented the leading edge of fields that remain vibrant today. The synthesis of each molecule was first carried out on a small scale (probably milligrams) in the laboratory, followed much later by development of safe, efficient, and scalable methods to provide kilograms of active pharmaceutical ingredient (API) that was incorporated into dosage forms for administration to patients. It is critical to point out that an early step in the complex process of drug discovery was the synthesis of a molecule that tested a hypothesis faced by the project team. This required a medicinal chemist to use organic chemistry training and experience to conceive of a compound and then employ appropriate reactions to furnish the desired target and synthesize a suitable number of derivatives to optimize the spectrum of properties associated with drug like candidates. Later on, process chemists use their expertise to devise a safe, practical, and economical route to reliably deliver the large quantities of API needed for clinical development and manufacture of the approved drug. Clearly without the benefit of synthetic organic chemistry and the scientists who first made them, these life changing drugs would not have been discovered. Biologically active molecules will continue to provide strong impetus for discovery of new chemical reactions, due to the value implicit in providing a molecule for study. Many of us © XXXX American Chemical Society
Received: August 31, 2016 Accepted: September 1, 2016 A
DOI: 10.1021/acschemneuro.6b00280 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience
Viewpoint
Figure 1. Representative life changing small molecule drugs.
change in focus and decreased funding provided by NSF and NIH for organic chemistry research. The analytical and problem solving skills developed in disciplines such as organic chemistry are central features in the field of drug discovery. The benefits derived from an increase in basic science support from government and industry will be returned many times over for generations to come because in this instance, unlike other investments, past performance is a clear indicator of future results.
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AUTHOR INFORMATION
Notes
The author declares no competing financial interest.
REFERENCES
(1) Lindsley, C. W. (2016) Lost in Translation: The death of basic science. ACS Chem. Neurosci. 7, 1024. (2) Teitelbaum, M. S. (2014) Falling Behind: Boom, Bust and the Global Race for Scientific Talent, Princeton University Press, Princeton, NJ. (3) Stephan, P. (2012) How Economics Shape Science. President and Fellows of Harvard College, Boston, MA. (4) For information on the ACS divisions mentioned, see www. organicdivision.org and www.acsmedchem.org.
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DOI: 10.1021/acschemneuro.6b00280 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
