NUOVI APPROCCI ALLA SINTESI DI CANNABINOIDI OTTICAMENTE ATTIVI CON RILEVANTE ATTIVITA’ BIOLOGICA E POTENZIALE INTERESSE TERAPEUTICO

Responsabili di progetto

Margherita Gavagnincapoggiani, Veaceslav Kulcitki

Accordo

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

Bando

CNR/ASM 2011-2012

Dipartimento

Progettazione Molecolare

Area tematica

Scienze chimiche e tecnologie dei materiali

Stato del progetto

Nuovo

Proposta di ricerca

The plant Cannabis sativa produces over 421 chemical compounds, including about 80 terpeno-phenol compounds named phytocannabinoids that have not been detected in any other plant [1,2]. For obvious reasons, most attention has been paid to the most representative family member D9-tetrahydrocannabinol (D9-THC), which is the most psychotropic component [3]. However, recent developments suggest that non-psychotropic phytocannabinoids exert a wide range of pharmacological effects, many of which are of potential therapeutic interest [4]. Among these compounds, cannabichromene-type cannabinoids have captured the attention for their anti-inflammatory, analgesic, bone stimulant, antimicrobial, and antiproliferative activities, which made them a challenging target for the chemical synthesis [4-6]. To date, the synthetic methods reported in the literature for this class of cannabinoids allow only the preparation of racemic forms[5,6].   The current project aims at elaborating novel methods for the stereospecific chemical synthesis of cannabichromene-type cannabinoids in order to elucidate the stereochemical properties for cannabichromene and related compounds that are still undefined. The structural features of these compounds lie in the presence of two distinct structural parts of different biogenetical origin: the aromatic part, specifically a derivative of chromene, and the isoprenoidic part. The determination of the absolute stereochemistry of most representatives is not a trivial task and can be successfully solved only basing on a complex approach, including concurrent synthesis and degradation studies. In addition, the broadening of the structural features of prenylated cannabinoids, especially on varying the structure of isoprenic residue, can lead to novel substances with new and still unexplored properties.
Based on this preliminary information, we focus our project on the synthesis of cannabichromene (CBC) having  as the final goal the elaboration of a general procedure for the synthesis of a whole series of prenylated chromene cannabinoids. We intend to apply a combination of enantioselective and diastereoselective synthesis in order to access the desired prenylated chromenes in enantiomerically pure form. Subsequent degradation studies and stereochemical correlation methods will allow the determination of the absolute stereochemistry of these compounds. In the long run, generation of a library of prenylated chromenes will support Structure-Activity Relationship (SAR) studies for identification of novel compounds with prominent biological activity.
The evaluation of the biological properties of the synthetic molecules obtained during this study could be subsequently carried out in collaboration with pharmacologists working at ICB (Endocannabinoid Research Group), that are a very active group interested in the pharmacological studies of endo- and phytocannabinoids.
This research programme starts from a fruitful scientific collaboration previously developed in the field of the synthesis of marine natural products between the two teams applying the proposal at Istituto di Chimica Biomolecolare (CNR), in Pozzuoli, Italy and Institutul de Chimie (ASM) in Chisinau, Moldova. This collaborative activity is witnessed by several joint papers published on international journals [7-12]. 
 
[1]       Turner, C.E. (1980) Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J. Nat. Prod. 43, 169–234.
[2]       El-Sohly, M.A; Slade, D. (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78, 539-548.
[3]       Costa, B. (2007) On the pharmacological properties of D9-Tetrahydrocannabinol (THC). Chemistry & Biodiversity 4, 1664-1677.
[4]       Izzo, A.; Borrelli, F.; Capasso, R.; Di Marzo, V.; Mechoulam, R. (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 30, 515-527.
[5]       Razdan, R. (1981) The Total Synthesis of Cannabinoids. In: “The Total Synthesis of Natural Products”, Volume IV. Ed.:  ApSimon J. Wiley, New York, 185 –262.
[6]       Yong Rok Lee; Xue Wang (2005) Concise Synthesis of Biologically Interesting (±)-Cannabichromene, (±)-Cannabichromenic Acid, and (±)-Daurichromenic Acid. Bull. Korean Chem. Soc. 26, 1933-1936.
[7]       Ungur, N.; Kulcitki, V.; Gavagnin, M.; Castelluccio, F.; Vlad, P.F.; Cimino, G. (2002) Studies towards the synthesis of cheilanthane sesterterpenoids: superacidic cyclisation of methyl 13Z,17Z- and 13Z,17E-bicyclogeranylfarnesoates. Tetrahedron, 58, 10159-10165.
[8]       Kulcitki, V.; Ungur, N.; Gavagnin, M.; Carbone, M.; Cimino, G. (2004) Synthesis and absolute stereochemistry of marine nor-sesquiterpene austrodoric acid. Tetrahedron Asymmetry, 15, 423-428.
[9]       Kulcitki, V.; Ungur, N.; Gavagnin,M.; Carbone, M.; Cimino, G. (2005) Further synthetic studies towards the austrodorane skeleton: synthesis of austrodoral. Eur. J. Org. Chem., 1816-1822.
[10]     Ungur, N.; Kulcitki, V.; Gavagnin, M.; Castelluccio, F.; Cimino, G. (2006) Synthesis of optically active 14a- and 14b-cheilanthanic esters. Synthesis, 14, 2385-2391.
[11]     Kulcitki, V.; Ungur, N.; Gavagnin, M.; Castelluccio, F.; Cimino, G. (2007) Ring B-functionalisation of scalarane sesterterpenes by Radical Relay Halogenation. Tetrahedron, 63, 7617-7623.
[12]     Grinco, M.; Kulcitki, V.; Ungur, N.; Vlad, P.F.; Gavagnin, M.; Castelluccio, F.; Cimino, G. (2008) A biomimetic synthesis of sacculatane diterpenoids. Helv. Chim. Acta, 91, 249-258.

Obiettivi della ricerca

By using a disconnection approach, it is possible to reveal that the cannabichromene chirality given by the C-2 carbon atom of the chromene fragment derives from the isoprenic residue, namely from linalool, a component of different essential oils obtained industrially in Moldova. The aromatic part of CBC (olivetol) bears no chirality and is also a commercially available compound.
Apparently, the synthesis of CBC can be a very facile task and resides in the elaboration of an efficient method for the direct connection of these two fragments, followed by an intramolecular etherification. The main relevant problems of this transformation are connected to the difficulty of  generation the selective reactivity of the terminal double bond in linalool. The problem is given by the ability of the tertiary hydroxyl group of linalool to epimerise under both acidic and basic conditions, leading inevitably to racemisation. Bearing in mind this circumstances we have established the following project goals:
1.      Preparation of an organometallic derivative of olivetol as coupling partner for the terpenic fragment;
2.      Elaboration of a coupling procedure between organometallic fragment and different monoterpenic synthons;
3.      Elaboration of an enantioselective process for cyclization of the acyclic terpenoid olivetol condensed molecule into chromene structure. Synthesis of CBC;
4.      Design of degradation experiments and stereochemistry assignment.

Ultimo aggiornamento: 30/04/2025