Synthesis of guanidine-functionalized terpenoids with relevant biological activity and therapeutical potential.

Joint research project

Project leaders: Marianna Carbone, Nicon Ungur
Agreement: MOLDOVA - ASM-not in force - Academy of Sciences of Moldova
Call: CNR/ASM biennio 2018-2019 2018-2019
Department: Chemical sciences and materials technology
Thematic area: Chemical sciences and materials technology
Status of the project: Extended
Report for renewal: final-report-asm-cnr-carbone-ungur-signed-1.pdf

Research proposal

The research program here proposed is intended as the continuation of the previous project "Synthesis of guanidine-functionalized terpenoids with relevant biological activity and therapeutical potential" which has been focused on the studies of chemical and biological properties of guanidine containing compounds.
Guanidine chemistry is a flourishing area of research with a very promising future in different application fields. The ability of guanidine to form hydrogen bonds, its planarity and high basicity are some of its predominant characteristics that make it one of the most versatile functional group in chemistry as well as in biological science. Compounds containing this system have found application as catalysts, fertilizers, insecticidals, biomaterials, but mainly in pharmaceutical sector where guanidine is considered a useful pharmacophore. Several reports have appeared in the literature dealing with the biological properties of guanidine-containing compounds, such as those published by Saczecwski and Balewski in 2009 and 2013 [1-2].
The previous research joint program was focused on the synthesis of a guanidine natural product, the actinofide, isolated by our group from a marine shell-less mollusk, as well as on the evaluation of its biological properties. Its structure has inspired the synthesis of a series of analogs whose bioactivities were also investigated [3].
Actinofide belongs to a specific class of guanidine containing compounds, the acylguanidine family. These compounds are particularly interesting being less basic bioisosteres of alkyl guanidines. The basicity of the acylguanidines (pKa values around 8) is 45 orders of magnitude lower than that of the corresponding alkylguanidines improving in most cases the pharmacokinetics and pharmacodynamics on various biological targets.
Actinofide is also a rare example of naturally occurring guanidine terpenoid being in nature the guanidine unit mainly incorporated in peptide, polyketide, and aromatic structures. Despite their low occurrence, guanidine terpenoids have shown interesting biological activities, standing out as promising lead structures suitable for development of potential drugs [4]. One of the earliest reported examples of natural compound incorporating a guanidine unit on a terpene framework was galegine from the higher plants Verbena encelioides and Galega officinalis. This natural product provided the template for the synthesis of metformin and stimulated interest in the synthesis of other biguanidine-type antidiabetic drugs.
Therefore, starting by the results of the previous studies on actinofide and its synthetic analogs [3], the proposed extension of the project aims at enlarge our collection of acylguanidine compounds by both continuing the bioprospecting program on marine environment and elaborating synthetic strategy to prepare natural product-inspired guanidine compounds with potential applications for human health. In this contest, we intend also evaluate the bioisosteric guanidine-acylguanidine exchange as an approach to improve the biological profile of selected alkylguanidine secondary metabolites.
The development of this research program will be assured by the complementary expertise of the two research group involved in this project, as well as by the collaborations existing between ICB researchers and biologist and pharmacologists belonging to other national and international research institutions. Indeed this project will be part of a wider research program focused on the valorization and exploitation of natural source with regards to the marine environment aimed at identify new "hits" of interest for the pharmaceutical, food and cosmetic industry.
[1] Saczewski F., Balewski L (2009) Expert. Opin. Ther. Pat. 19, 1417-1448. [2] Saczewski F., Balewski L (2013) Expert. Opin. Ther. Pat. 23, 965-995. [3] Carbone M., Ciavatta M. L., Mathieu V., Ingels A., Kiss R., Pascale P., Mollo E., Ungur N.,. Guo Y.W, Gavagnin M. (2017) J. Nat. Prod. 2017 DOI: 10.1021/acs.jnatprod.6b00941. [4] Tajima Y., Nakagawa H., Tamura A., Kadioglu O., Satake K., Mitani Y., Murase H., Regasini L.O., Bolzani V.d.S., Ishikawa T., Fricker G., Efferth T. (2014) Phytomedicine 21, 323-332.

Research goals

This project involves skills in the isolation, identification and synthesis of natural compounds, as well as in the evaluation of biological properties. In particular the research activities will target three main goals:
1 ) Design and synthesis of a number of acylguanidine terpenoids including both linear and cyclic skeleton. Within this objective, the incorporation of guanidine functional group on terpene included in the marine natural products ICB-collection will be considered. A huge number of terpenes have been isolated from marine organisms at ICB and among them will be selected those in which the guanidine group could be easily introduced.
2) Synthesis of the corresponding alkyl derivative for each acylguanidine obtained, including the previously reported actinofide and its analogs, in order to compare their activities.
3) Isolation of new guanidine marine natural products by exploring the secondary metabolism of marine invertebrates belonging to taxonomic group known to contain this class of metabolites.
In the frame of these three objectives, the evaluation of the biological properties of the synthetized compounds will be performed by screening the antiproliferative effects on selected cancer cell lines as well as by testing zebrafish embryo toxicity. Embryos of the zebrafish Danio rerio are excellent animal models for studying the effects of small molecules on early development and on toxicity, thus allowing effective in vivo evaluations of potential drugs.

Last update: 23/04/2024