A New Hybrid Molecule Based on (5 Z ,9 Z )-icosa-5,9-dienoic Acid and Monocarbonyl Derivatives of Curcuminoids †

: Efﬁcient methods for the synthesis of previously undescribed hybrid compounds based on monocarbonyl derivatives of curcumin and 5 Z ,9 Z -dienoic acid with yields of 58–66% are presented. The key monomer, (5 Z ,9 Z )-icosa-5,9-dienoic acid, was prepared using the stereoselective cross-cyclomagnesiation reaction of aliphatic and oxygen-containing 1,2-dienes catalyzed by Cp 2 TiCl 2 .


Introduction
Over the past years, a strategy has been actively developed for obtaining molecular hybrids containing pharmacophore groups of known biologically active compounds in their structures. The rationale for this approach is based on the supposed synergistic interaction of two pharmacologically active components with the intended target, which can significantly increase the effectiveness of the compounds obtained [1,2].
It is believed that the use of hybrid molecules minimizes the risk of interactions between different drugs when used together, and each component of the hybrid is able to balance the side effects of the other and avoid potential drug resistance [3][4][5][6][7].
Since ancient times, curcumin has been of great interest to researchers, exhibiting a variety of pharmacological activities. However, the high metabolic instability, poor absorption and bioavailability of natural curcumin are deterrents to its active use in pharmacology and medicinal chemistry. In this regard, new synthetic analogs are being developed; for example, by changing the number of carbon atoms in the middle linker chain, monocarbonyl derivatives of curcuminoids have been obtained, which exhibit high antitumor and antibacterial properties, while having low toxicity and greater bioavailability compared to curcumin [8][9][10][11][12].
A large number of hybrid compounds based on curcuminoids have been synthesized, which show high cytotoxic, neuroprotective, antibacterial, and antiviral activities in vitro and in vivo, while maintaining low toxicity. It should be noted that the activity of hybrid compounds is much higher than the activity of the original derivatives. Moreover, this approach allows the improvement of the bioavailability of compounds and transport through the membranes of cell organelles, as well as protecting active substances from enzymatic degradation [13][14][15][16][17][18].
A low-step stereoselective method for the preparation of natural and synthetic 5Z,9Zdienoic fatty acids has recently been developed [23]. The studies performed have shown Chem. Proc. 2022, 12, 45 2 of 5 that the unsaturated acids synthesized by us, and new derivatives obtained on their basis, demonstrate antitumor activity in vitro against a number of tumor cell lines [24][25][26][27][28].
In the development of our research, taking the above into account, we decided to implement the idea of synthesizing new hybrid molecules based on biologically active (5Z,9Z)-icosa-5,9-dienoic acid and curcumin monocarbonyl derivatives.

Results and Discussion
The synthetic strategy for obtaining the target hybrid molecules included preliminary synthesis of (5Z,9Z)-icosa-5,9-dienoic acid 4 based on the use of original Ti-catalyzed intermolecular cross-cyclomagnesiation of aliphatic and O-containing 1,2-dienes with Grignard reagents.
A low-step stereoselective method for the preparation of natural and synthetic 5Z,9Zdienoic fatty acids has recently been developed [23]. The studies performed have shown that the unsaturated acids synthesized by us, and new derivatives obtained on their basis, demonstrate antitumor activity in vitro against a number of tumor cell lines [24][25][26][27][28].
In the development of our research, taking the above into account, we decided to implement the idea of synthesizing new hybrid molecules based on biologically active (5Z,9Z)-icosa-5,9-dienoic acid and curcumin monocarbonyl derivatives.

Results and Discussion
The synthetic strategy for obtaining the target hybrid molecules included preliminary synthesis of (5Z,9Z)-icosa-5,9-dienoic acid 4 based on the use of original Ti-catalyzed intermolecular cross-cyclomagnesiation of aliphatic and O-containing 1,2-dienes with Grignard reagents.

Scheme 1. Synthesis of hybrid molecules.
The structure of the resulting compounds 6 was established using combined experimental methods, including one-dimensional ( 1 H, 13 C) and two-dimensional heteronuclear correlation NMR experiments (HSQC, HMBC), as well as mass spectrometry (HRMS).

Materials and Methods
Reactions were carried out in an inert atmosphere. Solvents were dried (diethyl ether over Na, dichloromethane over P2O5) and freshly distilled before use. Commercial 5hexyn-1-ol and Cp2TiCl2 (Aldrich) were used without preliminary purification. The individuality and purity of the synthesized compounds were controlled using TLC on Silufol UV-254 plates; anisic aldehyde in acetic acid was used as a developer. One-( 1 H, 13 C) and Scheme 1. Synthesis of hybrid molecules.
The structure of the resulting compounds 6 was established using combined experimental methods, including one-dimensional ( 1 H, 13 C) and two-dimensional heteronuclear correlation NMR experiments (HSQC, HMBC), as well as mass spectrometry (HRMS).

Materials and Methods
Reactions were carried out in an inert atmosphere. Solvents were dried (diethyl ether over Na, dichloromethane over P 2 O 5 ) and freshly distilled before use. Commercial 5-hexyn-1-ol and Cp 2 TiCl 2 (Aldrich) were used without preliminary purification. The individuality and purity of the synthesized compounds were controlled using TLC on Silufol UV-254 plates; anisic aldehyde in acetic acid was used as a developer. One-( 1 H, 13  General procedure of Steglich esterification. Vanillin (4.2 mmol, 1 eq.), in an argon atmosphere, was dissolved in dry methylene chloride (50 mL), then (5Z,9Z)-icosa-5,9-dienoic acid 4 (5 mmol, 1.2 eq.) and DMAP (5 mmol, 1.2 eq.) were added. The reaction mixture was cooled to 0 • C, and for 30 min, dropwise DIC (4.2 mmol, 1 eq.) dissolved in methylene chloride (10 mL) was added. The resulting reaction mass was stirred at room temperature (8 h) and the reaction was controlled using TLC. The resulting precipitate was filtered, the solvent was evaporated and the remaining product was purified by column chromatography (SiO 2 , eluent PE:EA = 8:1).
4-formyl-2-methoxyphenyl-(5Z,9Z)-icosa-5,9-dienoate (5). 1  General procedure for the synthesis of hybrid molecules. To conjugate 5 (10 mmol, 2 equiv.) dissolved in 10 mL of ethanol (96%), ketone (5 mmol, 1 equiv.) was added and stirred for 15 min at room temperature. Then, a solution of sodium hydroxide (0.4 g) in water (10 mL) was added dropwise and the reaction mixture was stirred for 48 h at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, water (20 mL) was added to the reaction mass and extracted with methylene chloride (3*50 mL). The organic layer was dried over MgSO 4 and the product was isolated by column chromatography (SiO 2 , eluent PE:EA = 4:1).

Conclusions
As a result of this research, hybrid molecules based on biologically active monocarbonyl derivatives of curcumin and (5Z,9Z)-icosa-5,9-dienoic acid were synthesized for the