SYNTHESIS OF GUANIDINE-FUNCTIONALIZED TERPENOIDS WITH RELEVANT BIOLOGICAL ACTIVITY AND THERAPEUTICAL POTENTIAL.

Project leaders

Marianna Carbone, Nicon Ungur

Agreement

MOLDOVA - ASM-not in force - Academy of Sciences of Moldova

Call

CNR/ASM 2015-2016

Department

Chemical sciences and materials technology

Thematic area

Chemical sciences and materials technology

Status of the project

New

Research proposal

Guanidine is one of the most widely used scaffold in the design and synthesis of new bioactive compounds. Numerous guanidine compounds from natural sources as well as those obtained through synthetic strategies and virtual design have gained much interest over the last few decades due to their therapeutic potential.1-3The guanidine group is categorized as organosuperbases whose basicity is magnified because of the resonance stabilization of the corresponding conjugated acid. Guanidine compounds are basic enough (pKa of their conjugated acids is around 12.5) to form intermolecular contacts mediated by H-bonding interactions. Their positive charge, resulting from guanidine protonation in a wide range of pH values, plays an important role in forming specific intermolecular interactions, comprising key-steps of many biological reactions including enzyme-mediated processes and interaction of hormones with their receptors. Thus, guanidine is a useful pharmacophore in medicinal chemistry. In nature the Y-shaped CN3 unit is mainly incorporated in peptide, polyketide, and aromatic structure whereas only a limited number of guanidine compounds possess a terpene carbon skeleton. Despite their low occurrence, guanidine terpenoid have shown interesting biological activities, standing out as promising lead structures suitable for development of potential drugs. Prenylated guanidines from higher plants, for example, display antitumor, anti-angiogenic, antimicrobial, insulin-like and anti-lipolytic properties.3 Recent studies have also indicated the ability of some of these compounds, e.g. nitensidine A, to modulate the activity of human ABCB1 (P-gp; P-glycoprotein), a transmembrane efflux pump belonging to ATP-binding cassette (ABC) transporter superfamily, which is involved in cancer multi drug resistance.4 A little number of terpenoid guanidine compounds including dotofide,5 a unique diacyl derivative, have been isolated also from marine sources. Surprisingly, few data on biological activity has been reported for these molecules most likely due to the difficulty to get enough amount of compounds for carrying out the biological assays. However, the synthesis of dotofide appeared in the literature very recently.6 The finding in a marine mollusk of a new linear sesquiterpene diacyl guanidine (our lab, unpublished data), prompted us to direct our interest toward the synthesis of this molecule, which is structurally related to dotofide, with the aim at confirming the chemical structure as well as at obtaining a suitable quantity for the biological activity evaluation. The project we propose here is focused firstly on the synthesis of this compound and, more in general, on the development of a new synthetic route to a series of guanidine-functionalized terpenoids. Starting from the synthesis of the naturally occurring linear sesquiterpene derivative that we have isolated, a small library of selected mono-, bi-, and tricyclic terpene acyl guanidine structures could be subsequently prepared for a pharmacological screening which will be direct mainly to the discovery of new antimicrobial agents.
The planned synthetic strategy involve the use of inexpensive terpene alcohols E,E-farnesol (for C-15 terpenes) and (-)-sclareol (for C-20 terpenes) as starting compounds. In particular, the choice of (-)-sclareol is based on the availability of this product, commercially obtained in Moldova from the wastes of Salvia sclarea essential oil production. The key step of the synthesis is the condensation of guanidine with an activated terpenoid carboxylic acid, opportunely prepared from the corresponding alcohol, by using a guanylating agent to provide the monoacyl guanidine.5,6 The preparation of the diacyl derivative will involve a subsequent conjugation step by forming the second amide function of guanidine by means the use of another terpenoid acyl residue.6,7 The proposed scheme involves the use of guanylating agents different from those utilized in the previously reported syntheses.6,7
The synthesized compounds will be identified on the base of both mass and spectroscopic data. The evaluation of the biological properties of the synthetic molecules will be carried out in the frame of existing collaborations between the research team at the Istituto di Chimica Biomolecolare (ICB) and group of pharmacologists from University of Naples.
This research programme is based on a fruitful scientific collaboration previously developed in the field of the synthesis of marine natural products between the two teams at ICB, in Pozzuoli, Italy and Institutul de Chimie (ASM) in Chisinau, Moldova. This collaborative activity is witnessed by several joint papers published on international journals.8-12
(1) M.K. Rauf, I. Din, A. Badshah Expert Opin. Drug. Discov. 2014, 9, 39-53. (2) F. Saczewski, L. Balewski Expert Opin. Ther. Patents 2013, 23, 965-995. (3) R. G. S. Berlinck, A. E. Trindade-Silva, M. F. C. Santos Nat. Prod. Rep. 2012, 29, 1382-1406. (4) Y. Tajima, Bolzani, A. Tamura, H. Nakagawa, O. Kadioglu, K. Satake, Y. Mitani, H. Murase, et al. Phytomedicine 2014, 21, 323-332. (5) A. Putz, S. Kehraus, G. Díaz-Agras, H. Wägele, G. M. König Eur. J. Org. Chem. 2011, (20), 3733-3737. (6) S. Serra, A. A. Cominetti, V. Lissoni. Nat. Prod. Commun. 2014, 9, 329-335. (7) E. Piers, M. Chong, K. Gustafson, R. J. Andersen. Can. J. Chem. 1984, 62, 1-5. (8) V. Kulcitki, N. Ungur, M. Gavagnin, M. Carbone, G. Cimino Tetrahedron Asym. 2004, 15, 423-428. (9) V. Kulcitki, N. Ungur, M. Gavagnin, M. Carbone, G. Cimino Eur. J. Org. Chem. 2005, 1816-1822. (10) N. Ungur, V. Kulcitki, M. Gavagnin, F. Castelluccio, G. Cimino Synthesis 2006, 14, 2385-2391. (11) V. Kulcitki, N. Ungur, M. Gavagnin, F. Castelluccio, G. Cimino Tetrahedron 2007, 63, 7617-7623. (12) M. Grinco, V. Kulcitki, N. Ungur, P.F. Vlad, M. Gavagnin, F. Castelluccio, G. Cimino Helv. Chim. Acta 2008, 91, 249-258.

Research goals

Our proposal aims at synthesizing a number of guanidine-functionalized terpenoids to be screened as antibacterial. In particular, two objectives will be pursued:
1) Elaboration of a synthetic strategy to prepare the new acyclic terpenoid diacyl guanidine recently isolated in our lab from a marine mollusk. The synthesis will allow to confirm the structure of this compound and to get suitable quantity for the biological screening.
2) Preparation of a series of structurally related molecules exhibiting both linear and cyclic terpenoidic framework and creation of a small library of linear, mono-, bi- and tricyclic guanidine-functionalized terpenes.
It is expected the synthesis of a number of diacyl guanidine analogs to be tested in antibacterial assays in order to develop a structure-activity relationship and, as a final goal, to select one or more optimal compounds exhibiting marked bactericidal activity.

Last update: 03/05/2025