Zanthoxylamide protoalkaloids based on N-phenylethyl cinnamamides: a series of natural and synthetic safe umami taste enhancing components assessed in silico and in vivo toxicity assays in zebrafish embryos

Significance 

Among 546 plant members of family Rutaceae, the genus Zanthoxylum is widely known. It is commonly used in cooking, as a spice, and also in alternative medicine for the treatment of carminative, dyspepsia, anthelmintic, stomachic disorders and fever. On the basis of these uses, scientists have selected these plants for phytochemical studies, isolating, characterized and evaluated a hundred secondary metabolites and alkaloids such as coumarins, flavonoids, limonoids, and volatile oils, identifying a series of leading compounds with antidiarrheal, antimicrobial, antileishmanial, anticholinesterase, antiprotozoal, larvicidal and antioxidant activities.

Indeed, genus Zanthoxylum contains a wide variety of amides, and those derived from L-phenylalanine and cinnamic acids are known as zanthoxylamide protoalkaloides. Armatamide, rubecenamide, lemairamin, rubemamine and zanthosine are the representative molecules of this family and recently the scientific community have become interested in their biological activities. Structure-taste relationship studies of cinnamamides against the umami taste (one of the five basic tastes together with sweetness, sourness, bitterness, and saltiness) have revealed that the 3,4-dimethoxycinnamic moiety is the responsible for modulating receptors associated with the umami taste in both in vitro and in vivo studies. Due to their outstanding umami properties, these protoalkaloids will be used in preparation of human food very soon, but before that, their toxicological profile needs to be studied and validated in vertebrate models related with humans like the zebrafish embryo model.

Recently, Dr. Carlos E. Puerto Galvis and Prof. Vladimir V. Kouznetsov (Industrial University of Santander, Colombia) developed a mild and efficient method for the synthesis, at gram-scale, of diverse zanthoxylamide protoalkaloids through the direct amidation between commercially available phenylethylamines and cinnamic acids, obtaining a series of 29 substituted N-phenylethyl cinnamamides using the tris-(2,2,2-trifluoroethyl) borate (B(OCH2CF3)3) as a catalyst in excellent yields.

Then, performing in silico computational methods against eight toxicity risks (mutagenic, hepatotoxicity, carcinogenicity, immunotoxicity, tumorigenic, cytotoxicity, reproductive effects and irritant), the authors found that the tested molecules exhibited moderate immunotoxicity and possible reproductive effects, while among different biological targets, these protoalkaloids showed a high affinity to the amine oxidase A (AOFA) and prostaglandin G/H synthase 1 (PGH1 receptors.

Finally, the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study for the synthesized zanthoxylamide protoalkaloids, and with the toxicity data of the selected reference compounds, an in vivo toxicity scale was established in which the average LC50 for the zanthoxylamide protoalkaloids fit in the safe region, indicating their low toxicity (LC50 values around 217 μM) on living organisms and their possible environmental impact.

Zanthoxylamide protoalkaloids based on N-phenylethyl cinnamamides: a series of natural and synthetic safe umami taste enhancing components assessed in silico and in vivo toxicity assays in zebrafish embryos - Medicine Innovates

About the author

Dr. Carlos E. Puerto Galvis was born in Duitama, Colombia. He obtained his B.Sc. from the Industrial University of Santander in 2010 and received his M. Sc. degree at the same institution in 2013 under the supervision of Prof. Vladimir V. Kouznetsov. In January of 2014 he began his Ph.D in the laboratory of Prof. Vladimir V. Kouznetsov and received its Ph.D degree in 2018 submitting a thesis on the total synthesis of isoquinoline alkaloids and their biological assessment in zebrafish embryos. In June 2019, he continued his career with Prof. Kouznetsov as postdoctoral researcher.

Research interests: transition-metal-catalyzed C–H functionalization and asymmetric transfer reactions towards the total synthesis of natural products and biologically active compounds, as well as the use of zebrafish embryo model to explore the toxicity and phenotypic changes induced by small molecules in order to study human diseases such as cancer, cardiac affections and digestive disorders.

About the author

Prof. Dr. Vladimir V. Kouznetsov studied Chemistry at the Russian Peoples Friendship University (Moscow), where he received his Laurea M.Sc. (1981) and Ph.D. (1986) degrees in Organic chemistry. In 1990-1992, he did postdoctoral studies at the University of Oviedo, Spain. He obtained his posthabilitation D.Sc. degree and was appointed as full Professor of the Russian Peoples Friendship University in 1994. In the same year, he started to work at the Industrial University of Santander (Bucaramanga, Colombia), where he is director of the Laboratory of Organic and Biomolecular Chemistry.

From this time, he had received various awards in Pharmacology, Oncology and Phytopharmaceutical science. In 2012 he received National Science Award, Colombian Association for the Advancement of Science. In 2014 he became Corresponding Member of the Colombian Academy of Exact, Physical and Natural Sciences.

Research interests: heterocyclic diversity-oriented synthesis, including natural product (alkaloids, phenolic metabolites) synthesis, green synthetic methodologies, interface between chemistry and biology.

Reference

Puerto Galvis, C. E., & Kouznetsov, V. V. Synthesis of zanthoxylamide protoalkaloids and their in silico ADME-Tox screening and in vivo toxicity assessment in zebrafish embryos. European Journal of Pharmaceutical Sciences, 127 (2019) 291-299. doi:10.1016/j.ejps.2018.10.028

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