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A Template-Based Approach for Guiding and Refining The molecules Communication A Template-Based Approach for Guiding and Refining the Development of Cinnamon-Based Phenylpropanoids as Drugs Ngoc Uy Nguyen and Brendan David Stamper * Pacific University School of Pharmacy, 222 S.E. 8th Avenue #451, Hillsboro, OR 97123, USA; nguy7353@pacificu.edu * Correspondence: stamperb@pacificu.edu; Tel.: +1-503-352-7287 Academic Editors: Giuseppe Caruso, Nicolò Musso and Claudia Giuseppina Fresta Received: 22 September 2020; Accepted: 9 October 2020; Published: 11 October 2020 Abstract: Background: Structure-activity relationships describe the relationship between chemical structure and biologic activity and are capable of informing deliberate structural modifications to a molecule in order enhance drug properties. Methods: Here, we present a subtle, yet unique twist on structure-activity relationships in which a collective biologic activity was measured among five cinnamon constituents with a shared phenylpropanoid template (cinnamic acid, cinnamaldehyde, chlorogenic acid, caffeic acid, and ferulic acid). This template-based approach utilized publicly available transcriptomic data through the Gene Expression Omnibus (GEO) to identify a fundamental biologic effect; in essence, a phenylpropanoid template effect. Results: The recurrent identification of cytokine-cytokine receptor interaction and neuroactive ligand receptor pathways in each individual treatment condition strongly supports the fact that changes in gene expression within these pathways is a hallmark of the phenylpropanoid template. With a template effect identified, future structural modifications can be performed in order to overcome pharmacokinetic barriers to clinical use (i.e., traditional structure-activity relationship experiments). Moreover, these modifications can be implemented with a high degree of confidence knowing that a consistent and robust template effect is likely to persist. Conclusion: We believe this template-based approach offers researchers an attractive and cost-effective means for evaluating multicomponent natural products during drug development. Keywords: phenylpropanoids; cinnamic acids; cinnamon; natural products; gene expression; drug development; DAVID 1. Introduction In recent years, there has been a renewed interest in the utilization and evidence-based use of natural products in conventional medicine practices [1]. Major challenges with natural product-based drug development not only include organizing the pharmacologic and toxicologic activity of individual molecules within a complex mixture, but also understanding how these multiple constituents interact with one another in potentially synergistic or antagonistic ways. Take cinnamon as an example. Resinous compounds (e.g., cinnamic acid cinnamyl acetate, and cinnamaldehyde), essential oils (e.g., eugenol, borneol, and terpinolene), as well as coumarin and procyanidins are thought to contribute to the therapeutic potential of cinnamon [2]. The structural diversity of these compounds might suggest that the potential therapeutic applications associated with cinnamon constituents varies greatly, thus making delineation of cinnamon’s pharmacologic activity quite complex. However, despite the array of diverse molecular structures, cinnamon constituents are purported to possess remarkably similar and broad therapeutic benefits. For example, cinnamic acid derivatives have been shown to possess anti-inflammatory, antioxidant, anti-microbial, and neuroprotective activities [3–5]. Molecules 2020, 25, 4629; doi:10.3390/molecules25204629 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 8 Molecules 2020, 25, 4629 2 of 8 derivatives have been shown to possess anti-inflammatory, antioxidant, anti-microbial, and Inneuroprotective this study, we soughtactivities to investigate [3–5]. In howthis five study, cinnamon we sought constituents to investigate with a phenylpropanoid how five cinnamon template (cinnamicconstituents acid, with ferulic a phenylpropanoid acid, cinnamaldehyde, template caffeic (cinnamic acid, and acid, chlorogenic ferulic acid, acid) cinnamaldehyde, affected gene expression, caffeic andacid, to and consider chlorogenic whether theiracid) shared affected phenylpropanoid gene expression, template and contributed to consider to awhether shared potential their shared use in pharmacotherapyphenylpropanoid (Figuretemplate1). contributed It is also worth to a noting shared that potential the utility use of in natural pharmacotherapy product-based (Figure medicines 1). It isis oftentimesalso worth hamperednoting that by the poor utility pharmacokinetic of natural product properties.-based Even medicines though is some oftentimes phenylpropanoids hampered by contain poor polarpharmacokinetic and ionizable properties. groups, many Even are quitethough lipophilic some andphenylpropanoids sparingly water-soluble contain such polar as certainand ionizable cinnamic acidgroups, derivatives, many are stilbenoids, quite lipophilic and flavonoids. and sparingly In addition water to potential-soluble absorptionsuch as certain issues, cinnamic complications acid associatedderivatives, with stilbenoids, metabolism and must flavonoids. also beconsidered In addition as to many potential natural absorption products areissues, susceptible complications to both intestinalassociated and with/or metabolism hepatic metabolism. must also Forbe considered example, gutas many microbiota natural are products capable are of cleavingsusceptible glycosidic to both bondsintestinal and and/or transforming hepatic orally metabolism. administered For example, xenobiotics gut [microbiota6]. Furthermore, are capable many of natural cleavi product-basedng glycosidic moleculesbonds and also transforming undergo metabolic orally administered modifications xenobiotics in the liver [6]. or kidneyFurthermore, once absorbed many natural [7]. The product overall- impactbased molecules is that certain also structuralundergo metabolic features and modifications metabolic susceptibilities in the liver or may kidney result once in lowabsorbed bioavailability [7]. The andoverall an inabilityimpact is to that sustain certain suitable structural therapeutic feature serums and concentrations.metabolic susceptibilities For this reason, may manyresult clinicalin low trialsbioavailability involving and a natural an inability product-based to sustain molecule suitable or therapeutic a combination serum product concentrations. require participants For this reason, to take largermany dosesclinical to trials achieve involving minimally a natural effective product concentrations.-based molecule Further complicatingor a combination matters product is the factrequire that manyparticipants trials end to take with larger inconclusive doses to results achieve [8]. minimally Without a effective stable parent concentrations. compound thatFurther possesses complicating positive pharmacokineticmatters is the fact parameters, that many it cantrials be end challenging with inconclusive for natural results product-based [8]. Without medicines a stable to progress parent throughcompound the that drug possesses development positive pipeline. pharmacokinetic parameters, it can be challenging for natural product-based medicines to progress through the drug development pipeline. Figure 1. Molecular structures for ( a) cinnamaldehyde, ( b) cinnamic acid, ( c)) caffeic caffeic acid, (d) ferulic acid, and (e) chlorogenic acid.acid. Rather thanthan evaluating evaluating individual individual agents agents for activity,for activity, this workthis soughtwork sought to identify to identify a robust a template robust etemplateffect first, effect which first, could which then could be modifiedthen be modified to improve to improve pharmacokinetic pharmacokinetic parameters. parameters. Based onBased the facton the that fact the that phenylpropanoid the phenylpropanoid template template exists within exists all within five of theseall five cinnamic of these acid-like cinnamic derivatives, acid-like wederivatives, sought to we examine sought to whatto examine extent the to phenylpropanoidwhat extent the template phenylpropanoid guides pharmacologic template guides effects. Inpharmacologic other words, effects. by deconstructing In other words, five molecules by deconstructing to their phenylpropanoid five molecules to template, their phenylpropanoid we might reveal importanttemplate, we characteristics might reveal based important on their characteristic foundationals structuralbased on design.their foundational If common characteristicsstructural design. could If becommon identified, characteristics reverse engineering could be couldidentified, then bereverse utilized engineering to improve could the potency then be and utilized pharmacokinetic to improve profilethe potency of the and template, pharmacokinetic thus allowing profile researchers of the template, to simplify thus theallowing complexities researchers associated to simplify with the specificcomplex characteristicsities associated of eachwith individualthe specific compound. characteristics Ultimately, of each this individual study hopes compound. to present Ultimately, a potential approachthis study tohopes overcome to present the a barriers potential that approach have prevented to overcome natural the barriers product that derivatives have prevented from reaching natural clinical utility using cinnamon’s phenylpropanoid template as a case study. Molecules 2020, 25, 4629 3 of 8 In order to accomplish this objective, a direct comparison between cinnamon constituents was performed using
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