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Title:
PHENYLPROPANOID SACCHARIDE ESTERS, METHODS AND USES THEREOF
Document Type and Number:
WIPO Patent Application WO/2020/183442
Kind Code:
A2
Abstract:
The present disclosure relates to phenylpropanoid saccharide esters, methods for the synthesis of libraries of phenylpropanoid saccharide esters with different degree and place of substitution in the sugar core, and their use as antimicrobial agents, cytotoxic agents and/or antitumoral agents. The present disclosure relates to a compound for formula I wherein R1, R2, R3 and R4 are independently selected from each other; R1 is selected from H or COCH3, R2, R3 and R4 is selected from H, OCH3, OH, for use in a method for the treatment of a microbial infection, or for use in a method for the treatment of a fungal infection or for use in a method for the treatment of cancer.

Inventors:
MARKOVA-PETROVA KRASIMIRA TODOROVA (PT)
FERNANDES RODRIGUES FERREIRA ISABEL CRISTINA (PT)
COSTA CALHELHA MANUEL RICARDO (PT)
SOKOVIC MARINA (RU)
Application Number:
PCT/IB2020/052378
Publication Date:
September 17, 2020
Filing Date:
March 16, 2020
Export Citation:
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Assignee:
UNIV NOVA DE LISBOA (PT)
INST POLITECNICO DE BRAGANCA (PT)
INSTITUTE FOR BIOLOGICAL RES SINISA STANKOVIC (RU)
International Classes:
C07H13/04; A61K31/7024; A61K31/7028; A61P31/00; A61P31/04; A61P31/10; A61P33/00; A61P35/00; C07H13/08; C07H15/04
Foreign References:
Other References:
PANDA, P.M. APPALASHETTIZ.M.A. JUDEH: "Phenylpropanoid Sucrose Esters: Plant-Derived Natural Products as Potential Leads for New Therapeutics", CURR. MED. CHEM., vol. 18, 2011, pages 3234 - 3251
HARVEY, A.L.: "Natural products in drug discovery", DRUG DIS. TODAY, vol. 13, 2008, pages 894 - 900
SHEN, X. ET AL.: "Effects of Scrophularia ningpoensis Hemsl. on Inhibition of Proliferation, Apoptosis Induction and NF- B Signaling of Immortalized and Cancer Cell Lines", PHARMACEUTICALS, vol. 5, 2012, pages 189 - 208, XP055625508, DOI: 10.3390/ph5020189
KUMARA-SWAMY, K.C. ET AL.: "Mitsunobu and Related Reactions: Advances and Applications", CHEM. REV., vol. 109, 2009, pages 2551 - 2651, XP055023394, DOI: 10.1021/cr800278z
PETROVA, K.T. ET AL.: "Chemoselective synthesis of sucrose building blocks and their polymerization", CURR. ORG. CHEM., vol. 18, no. 13, 2014, pages 1788 - 1802
Attorney, Agent or Firm:
PATENTREE (PT)
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Claims:
C L A I M S

1. Compound for formula I

wherein

R1, R2, R3 and R4 are independently selected from each other;

R1 is selected from H or COCH3,

R2, R3 and R4 is selected from H, OCH3, OH, for use in a method for the treatment of a microbial infection, or for use in a method for the treatment of a fungal infection or for use in a method for the treatment of cancer.

2. Compound for use according to the previous claim, wherein R2 is selected from H or OCH3, pref- erably R2 is H.

3. Compound for use according to any of the previous claims, wherein R3 is selected from H or OH, preferably R3 is OH.

4. Compound for use according to any of the previous claims, wherein R1, R2, R3 and R4 are H.

5. Compound for use according to any of the previous claims 1-3, wherein R1 is Ac and R2, R3 and R4 are H.

6. Compound for use according to any of the previous claims 1-3, wherein R1 and R2 are H, R3 is OH and R4 is OCH3.

7. Compound for use according to any of the previous claims 1-3, wherein R1 is COCH3, R2 is H, R3 is OH and R4 is OCH3.

8. Compound for use according to any of the previous claims 1-3, wherein R1 and R2 are H, R3 and R4 are OH.

9. Compound for use according to any of the previous claims 1-3, wherein R1 is COCH3, R2 is H, R3 and R4 are OH.

10. Compound for use according to any of the previous claims 1-3, wherein R1, R2 and R4 are H and R3 is OH.

11. Compound for use according to any of the previous claims 1-3, wherein R1 is COCH3, R2 and R4 are H and R3 is OH.

12. Compound for use according to any of the previous claims 1-3, wherein R1 is H, R2 and R4 are OCH3, R3 is OH.

13. Compound for use according to any of the previous claims 1-3, wherein R1 is COCH3, R2 and R4 are OCH3, R3 is OH.

14. Compound for use according to any of the previous claims, wherein the microbial infection is caused by a Gram-positive bacterium.

15. Compound for use according to the previous claim, wherein the Gram-positive bacterium is se- lected from Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Micrococcus flavus, or combinations thereof, preferably from Staphylococcus aureus ATCC 6538, Listeria monocyto genes NCTC 7973, Micrococcus flavus ATCC 10240, or combinations thereof.

16. Compound for use according to any of the previous claims 1-13, wherein the microbial infection is caused by a Gram-negative bacterium.

17. Compound for use according to the previous claim, wherein the Gram-negative bacterium is se- lected from Pseudomonas aeruginosa, Escherichia coli, Salmonella typhimurium, Enterobacter cloacae, or combinations thereof, preferably from Pseudomonas aeruginosa ATCC 27853, Esche richia coli ATCC 35210, Salmonella typhimurium ATCC 13311, or combinations thereof.

18. Compound for use according to any of the previous claims 1-13, wherein the fungal infection is caused by Aspergillus fumigatus, Aspergillus versicolor, Aspergillus ochraceus, Aspergillus niger, Trichoderma viride, Penicillium funiculosum, Penicillium ochrochloron, Penicillium verrucosum var. cyclopium, or combinations thereof, preferably Aspergillus versicolor ATCC 11730, Aspergillus ochraceus ATCC 12066, Aspergillus niger ATCC 6275, Trichoderma viride 1AM 5061, Penicillium funiculosum ATCC 36839, Penicillium ochrochloron ATCC 9112, or combinations thereof.

19. Compound for use according to any of the previous claims 1-13, wherein the cancer is breast carcinoma, colon carcinoma or cervical carcinoma, preferably cervical carcinoma.

20. Compound for use according to any of the previous claims, wherein the compound is adminis- trated in the form of a tablet, capsule, granule, oral liquid preparation, or injection preparation.

21. Process for the synthesis of compound of formula I according to any of the previous claims

wherein R1, R2, R3 and R4 are independently selected from each other;

R1 is selected from H or COCH3,

R2, R3 and R4 is selected from H, OCH3, OH; the process comprises the following steps: dissolving sucrose in dimethylformamide; adding triphenylphosphine and an acid to the dissolved sucrose forming a mixture; adding diisopropyl azodicarboxylate to the mixture of sucrose, dimethylformamide, tri- phenylphosphine and acid, to obtain the compound of formula (I).

22. Process according to the previous claim, comprising a step of mixing diisopropyl azodicarboxylate, sucrose, dimethylformamide, triphenylphosphine and acid at 20-30 °C, for 24-35 h or comprising a step of transferring diisopropyl azodicarboxylate, sucrose, dimethylformamide, tri- phenylphosphine and acid to the microwave reactor with temperature control set at 145 °C and maximum of 300 W for 10-20 min.

23. Process according to any of the previous claims 21-22, wherein the acid is selected from cinnamic acid, ferulic acid, caffeic acid, p-coumaric acid or sinapic acid.

24. Process according to any of the previous claims 21-23, comprising a step of stirring the compound of formula (I) in a solution of pyridine and acetic anhydride, preferably an excess of acetic anhy- dride.

25. Process according to the previous claim, wherein the step of stirring the compound of formula (I) in a solution of pyridine and acetic anhydride is carried out at 20-30 °C, or wherein the step of stirring the compound of formula (I) in a solution of pyridine and acetic anhydride is carried out with microwave irradiation, in particular at 90 °C and 300W, for 1-10 minutes, preferably 5 minutes.

26. Process according to any of the previous claims 21-25, wherein the molar ratio of tri- phenylphosphine and sucrose is between 1.1-3.0 moles of triphenylphosphine per 1 mol of su- crose.

27. Process according to any of the previous claims 21-26, wherein the molar ratio of cinnamic acid and sucrose is between 1.1-3.0 moles of cinnamic acid per 1 mol of sucrose or wherein the molar ratio of ferulic acid and sucrose is between 1.1-3.0 moles of ferulic acid per 1 mol of sucrose or wherein the molar ratio of caffeic acid and sucrose is between 1.1-3.0 moles of caffeic acid per 1 mol of sucrose or wherein the molar ratio of p-coumaric acid and sucrose is between 1.1-3.0 moles of p-coumaric acid per 1 mol of sucrose or wherein the molar ratio of sinapic acid and sucrose is between 1.1-3.0 moles of sinapic acid per 1 mol of sucrose.

28. Process according to any of the previous claims 21-27, wherein the weight ratio of dimethylfor- mamide:sucrose is between 14-19.

29. Process according to any of the previous claims 21-28, wherein the molar ratio of diisopropyl azodicarboxylate and sucrose is between 1.1-3.0 moles of diisopropyl azodicarboxylate of diiso- propyl azodicarboxylate per 1 mol of sucrose.

30. Process according to any of the previous claims 21-29, comprising a step of cooling before the step of adding diisopropyl azodicarboxylate, preferably a step of cooling to 0 °C before the step of adding diisopropyl azodicarboxylate.

Description:
D E S C R I P T I O N

PHENYLPROPANOID SACCHARIDE ESTERS, METHODS AND USES THEREOF

TECHNICAL FIELD

[0001] The present disclosure relates to phenylpropanoid saccharide esters, methods for the synthesis of libraries of phenylpropanoid saccharide esters with different degree and place of substitution in the sugar core, and their use as antimicrobial agents, cytotoxic agents and/or antitumoral agents. The sim- plest sucrose ester is the 6-O-cinnamoyl sucrose ester, known under the trivial name Sibirioside A. Herein, it was synthesized for the first time in only one step from sucrose and cinnamic acid applying chemose- lective procedure.

[0002] The chemical structure of the synthesized sucrose ester and its unnatural analogue were con- firmed by optical rotation, m.p., NMR, and mass spectra. Their antibacterial, antifungal, cytotoxic and antioxidant activities were investigated. They exhibited strong inhibition against all bacteria tested, namely Staphylococcus aureus, Bacillus cereus, Micrococcus flavus, Listeria monocytogenes, Pseudomo nas aeruginosa, Salmonella typhimurium, Escherichia coli and Enterobacter cloacae and strong antifungal activity towards Aspergillus versicolor, Aspergillus ochraceus, Trichoderma viride and Penicillium ochro- chloron. They showed moderate antioxidant and antitumor potential against human breast, colon and cervical cell lines without hepatotoxicity.

[0003] The phenylpropanoid saccharide esters now disclosed can be obtained in larger quantities and at cheaper price comparing to the extracted one and thus could find application in various pharmacolog- ical compositions.

BACKGROUND

[0004] During the last decades, more than 150 phenylpropanoid sucrose esters have been isolated and identified from plants used in folk medicine since antiquity, which have been reported to possess antiox- idative properties, among other pharmacological activities. [1] Phenolic compounds and in particular cin- namoyl derivatives, abundant in vegetables and fruits ubiquitous in diet, have been reported to play an important role as chemopreventive agents. Exogenous antioxidants are nowadays considered a promising therapeutic approach in neurodegenerative diseases since they could play an important role in preventing or minimizing neuronal oxidative damage. Since conventional therapeutic have not been able to control the neurodegenerative diseases, the development of chemopreventive strategies is an urgent priority in public health. Diboside A (1,3,6'-tri-O-coumaroyl-6-O-feruloyl sucrose), isolated from the root of wild buckwheat was shown to inhibit the enzymatic starch digestion, which is the key to produce low glycemic index foods for diabetic patients. [0005] Successful approaches, by which lead compounds from natural sources have been developed into drugs have been described in a number of reviews. [2] Despite of the wide availability of the phe- nylpropanoid sucrose esters in many plant species, their potential significance as lead compounds and their rich chemistry, very few members of this family have been obtained synthetically so far. A closer look at their structures reveals that sucrose core is acylated primarily at four positions: the 6, 1', 3' and 6' hydroxyls. Consequently, selective acylation at these positions would provide a broad variety of deriva- tives. The syntheses reported have been based on protection-deprotection multi-step procedures. Thus, niruriside (1',2,4,6-tetra-O-acetyl-3',6'-O-cinnamoyl sucrose), which was a HIV REV/RRE binding inhibitor, was synthesized in 6 steps and 23 % overall yield starting from sucrose. Using a similar procedure, lapatho- side D (3',6'-O-coumaroyl sucrose) was obtained in 4 steps and 13 % overall yield; helonioside A (3',6'-di- O-feruloyl sucrose), 3',4',6'-tri-O-feruloyl sucrose and lapathoside C (6-O-feruloyl-3',6'-O-coumaroyl su- crose were synthesized and studied for their antitumor activity. Also, the synthesis of some glucose-phe- nolic esters has been reported, demonstrating the interest of these compounds.

[0006] However, the composition of active compounds in plants is highly variable and depends on plant species, plant age and physiochemical environment. The herbal extracts are mixtures of hundreds of com- pounds with varying content that bring along a lot of residues from the plant, which makes the quantifi- cation of the active substrates very difficult. As different molecules exist in a crude extract, a given activity may be a result of a synergistic interaction of two or more molecules that may disappear when sub-frac- tions are evaluated for efficacy. Moreover, false negative readouts may also occur more often, either because the active principle is present at low concentrations or because other constituents of the extract inhibit its activity. That is why, the use of crude extracts in discovery programs has been recently discour- aged.

GENERAL DESCRIPTION

[0007] The 6-O-cinnamoyl sucrose, with trivial name Sibirioside A, has been isolated from the herbs Veronicastrum sibiricum (L.) Pennell and Scrophularia ningpoensis Hemsl., widely distributed in China, and there has been a lot of interest in these plants pharmacological properties [4] and processing. The syn- thesis of Sibirioside A and its derivatives has not been achieved so far, which, combined with the milligram quantities isolated from plants in pure form, has prevented their use in pharmacology. In order to avoid lengthy protection/deprotection methodologies, normally followed in sucrochemistry, herein it is pro- posed a novel methodology to synthesize some of those naturally occurring and biologically active com- pounds based on chemoselective one-step procedure using Mitsunobu conditions. [5]

[0008] The Mitsunobu reaction is a convenient method for selective esterification, which performed with sucrose was proven to provide 6-O-monoesters. Several esters of sucrose, such as derivatives of fatty acids and 6-perfluoroalkanoates for biomedical uses have been prepared by this method, avoiding the need of protecting groups chemistry. Treatment of sucrose with phthalimide under Mitsunobu conditions afforded derivative, substituted at the primary 6- and 6'- positions and by using hydrazoic acid it was possible to obtain directly sucrose azides. Previously, we have utilized a similar reaction to generate a library of sucrose containing polymerizable monomers. To the best of our knowledge, the Mitsunobu re- action have never been applied to the synthesis of phenylpropanoid esters.

[0009] The present disclosure relates to a compound for formula I

wherein

R 1 , R 2 , R 3 and R 4 are independently selected from each other;

R 1 is selected from H or COCH 3 ,

R 2 , R 3 and R 4 is selected from H, OCH 3 , OH, for use in a method for the treatment of a microbial infection, or for use in a method for the treatment of a fungal infection or for use in a method for the treatment of cancer.

[00010] In an embodiment, R 2 may be selected from H or OCH 3 , preferably R 2 is H.

[00011] In an embodiment, R 3 may be selected from H or OH, preferably R 3 is OH.

[00012] In an embodiment, R 1 , R 2 , R 3 and R 4 may be H.

[00013] In an embodiment, R 1 may be Ac and R 2 , R 3 and R 4 may be H.

[00014] In an embodiment, R 1 and R 2 may be H, R 3 may be OH and R 4 may be OCH 3 .

[00015] In an embodiment, R 1 may be COCH 3 , R 2 may be H, R 3 may be OH and R 4 may be OCH 3 .

[00016] In an embodiment, R 1 and R 2 may be H, R 3 and R 4 may be OH.

[00017] In an embodiment, R 1 may be COCH 3 , R 2 may be H, R 3 and R 4 may be OH.

[00018] In an embodiment, R 1 , R 2 and R 4 are H and R 3 is OH. [00019] In an embodiment, R 1 may be COCH 3 , R 2 and R 4 may be H and R 3 may be OH.

[00020] In an embodiment, R 1 may be H, R 2 and R 4 may be OCH 3 , R 3 may be OH.

[00021] In an embodiment, R 1 may be COCH 3 , R 2 and R 4 may be OCH 3 , R 3 may be OH.

[00022] In an embodiment, the compound now disclosed may be for use in a method for the treatment of a microbial infection caused by a Gram-positive bacterium, preferably the Gram-positive bacterium is selected from Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Micrococcus flavus, or combinations thereof, preferably from Staphylococcus aureus ATCC 6538, Listeria monocytogenes NCTC 7973, Micrococcus flavus ATCC 10240, or combinations thereof.

[00023] In an embodiment, the compound now disclosed may be for use in a method for the treatment of a microbial infection caused by a Gram-negative bacterium, preferably the Gram-negative bacterium is selected from Pseudomonas aeruginosa, Escherichia coli, Salmonella typhimurium, Enterobacter cloacae, or combinations thereof, preferably from Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 35210, Salmonella typhimurium ATCC 13311, or combinations thereof.

[00024] In an embodiment, the compound now disclosed may be for use in a method for the treatment of a fungal infection caused by Aspergillus fumigatus, Aspergillus versicolor, Aspergillus ochraceus, Asper gillus niger, Trichoderma viride, Pen ici Ilium funiculosum, Penicillium ochrochloron, Penicillium verrucosum var. cyclopium, or combinations thereof, preferably Aspergillus versicolor ATCC 11730, Aspergillus ochraceus ATCC 12066, Aspergillus niger ATCC 6275, Trichoderma viride 1AM 5061, Penicillium funicu losum ATCC 36839, Penicillium ochrochloron ATCC 9112, or combinations thereof.

[00025] In an embodiment, the compound now disclosed may be for use in a method for the treatment of cancer, wherein the cancer is breast carcinoma, colon carcinoma or cervical carcinoma, preferably cer- vical carcinoma.

[00026] In an embodiment, the compound may be administrated in the form of a tablet, capsule, gran- ule, oral liquid preparation, or injection preparation.

[00027] The present disclosed also relates to a process for the synthesis of compound of formula I ac- cording to any of the previous claims

wherein R 1 , R 2 , R 3 and R 4 are independently selected from each other;

R 1 is selected from H or COCH 3 ,

R 2 , R 3 and R 4 is selected from H, OCH 3 , OH; the process comprises the following steps: dissolving sucrose in dimethylformamide; adding triphenylphosphine and an acid to the dissolved sucrose forming a mixture; adding diisopropyl azodicarboxylate to the mixture of sucrose, dimethylformamide, tri- phenylphosphine and acid, to obtain the compound of formula (I).

[00028] In an embodiment, the process may further comprise a step of mixing diisopropyl azodicarbox- ylate, sucrose, dimethylformamide, triphenylphosphine and acid at 20-30 ° , for 24-35 h or comprising a step of transferring diisopropyl azodicarboxylate, sucrose, dimethylformamide, triphenylphosphine and acid to the microwave reactor with temperature control set at 145 ° and maximum of 300 W for 10-20 min.

[00029] In an embodiment, the acid may be selected from cinnamic acid, ferulic acid, caffeic acid, p- coumaric acid or sinapic acid.

[00030] In an embodiment, the process may further comprise a step of stirring the compound of formula (I) in a solution of pyridine and acetic anhydride, preferably an excess of acetic anhydride.

[00031] In an embodiment, the step of stirring the compound of formula (I) in a solution of pyridine and acetic anhydride may be carried out at 20-30 ° , or the step of stirring the compound of formula (I) in a solution of pyridine and acetic anhydride may be carried out with microwave irradiation, in particular at 90 ° and 300W, for 1-10 minutes, preferably 5 minutes.

[00032] In an embodiment, the molar ratio of triphenylphosphine and sucrose may be between 1.1-3.0 moles of triphenylphosphine per 1 mol of sucrose. [00033] In an embodiment, the molar ratio of cinnamic acid and sucrose may be between 1.1-3.0 moles of cinnamic acid per 1 mol of sucrose or wherein molar ratio of ferulic acid and sucrose may be between 1.1-3.0 moles of ferulic acid per 1 mol of sucrose or wherein molar ratio of caffeic acid and sucrose may be between 1.1-3.0 moles of caffeic acid per 1 mol of sucrose or wherein molar ratio of p-coumaric acid and sucrose may be between 1.1-3.0 moles of p-coumaric acid per 1 mol of sucrose or wherein molar ratio of sinapic acid and sucrose may be between 1.1-3.0 moles of sinapic acid per 1 mol of sucrose.

[00034] In an embodiment, the weight ratio of dimethylformamide:sucrose may be between 14-19.

[00035] In an embodiment, the molar ratio of diisopropyl azodicarboxylate and sucrose may be between 1.1-3.0 moles of diisopropyl azodicarboxylate of diisopropyl azodicarboxylate per 1 mol of sucrose.

[00036] In an embodiment, the process may further comprise a step of cooling before the step of adding diisopropyl azodicarboxylate, preferably a step of cooling to 0 ° before the step of adding diisopropyl azodicarboxylate.

BRIEF DESCRIPTION OF THE DRAWINGS

[00037] For an easier understanding of the disclosure, attached there are figures which represent pre- ferred embodiments of the disclosure that, however are not intended to limit the scope of protection of the present disclosure.

[00038] Figure 1. 1 H NMR of 1 (a) with extensions (b) and (c).

[00039] Figure 2. 13 C NMR of 1.

[00040] Figure 3. DEPT of 1.

[00041] Figure 4. COSY of 1, wherein (a) represents the full spectrum and (b) represents extension of the sugar region.

[00042] Figure 5. HSQC of 1, wherein (a) represents the full spectrum and (b) represents extension of the sugar region.

[00043] Figure 6. Mass spectrum of 1, wherein (a) represents the full spectrum and (b) represents zoom range of the isotopic peak m/z 495.

[00044] Figure 7. 1 H NMR of 2 with extensions, wherein (a) represents the full spectrum, (b) represents extension of the aromatic region, (c) represents extension of the sugar region and (d) represents exten- sion of the acetyl groups region.

[00045] Figure 8. 13 C NMR of 2 with extensions, wherein (a) represents the full spectrum, (b) represents extension of the carbonyl carbons region, and (c) represents extension of the sugar carbons region.

[00046] Figure 9. DEPT of 2. [00047] Figure 10. COSY of 2 with extensions, wherein (a) represents the full spectrum and (b) represents extension of the sugar region.

[00048] Figure 11. HSQC of 2 with extensions, wherein (a) represents the full spectrum and (b) repre- sents extension of the sugar region.

[00049] Figure 12. HMBC of 2 with extensions, wherein (a) represents the full spectrum, (b) represents extension of the aromatic region, (c) represents extension of the sugar region and (d) represents exten- sion of the crosspeaks between the sugar protons and the carbonyl carbons.

[00050] Figure 13. Mass spectrum of 2, wherein (a) represents the full spectrum and (b) represents the zoom range of the isotopic peak m/z 789.

DETAILED DESCRIPTION

[00051] The present disclosure relates to phenylpropanoid saccharide esters and methods and uses thereof, wherein the method which would be selective for the 6-position of sucrose. Based on previous experiences, it was developed a method to achieve the desired product directly in one step using Mitsunobu conditions (Scheme 1).

[00052] The method now disclosed for the synthesis of phenylpropanoid saccharide esters was used to achieve the desired product directly in one step using Mitsunobu conditions comprises the following steps: dissolving sucrose in dry dimethylformamide (DMF), adding triphenylphosphine and an acid, said acid being selected from cinnamic acid, ferulic acid, caffeic acid, p-coumaric acid or sinapic acid, then cooling to 0-5 ° . Then diisopropyl azodicarboxylate (DIAD) was added slowly, and the mixture was stirred at room temperature, in particular at 20-30 ° , for 24-35 h or transferred to the microwave reactor with temperature control set at 145 ° and maximum of 300 W for 10-20 min. Compound 1, 3, 5, 7 or 9 was isolated by silicagel chromatography in 48 % yield at room temperature, in particular at 20-30 ° , or 46 % under microwave irradiation. Peracetylation of compound 1, 3, 5, 7 or 9 to obtain compound 2, 4, 6, 8 or 10, respectively, was performed by stirring 1, 3, 5, 7 or 9, in pyridine with excess of acetic anhydride overnight at room temperature, in particular at 20-30 ° , or under microwave irradiation, in particular at 90 ° and 300W, in which case the reaction was completed in 1-10 minutes, preferably in 5 min, and the outcome was quantitative.

[00053] The method described above was applied to obtain four other naturally occurring 6-O-phe- nylpropanoid sucrose esters (compounds 3, 5, 7, 9), presented in Table 1, and the respective peracety- lated derivatives (compounds 4, 6, 8, 10).

Synthesis of compounds without microwave reaction [00054] In an embodiment, the synthesis of compound 1 (6-O-cinnamoyl sucrose) was carried out as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DMF (15 to 20 ml per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and trans-cinnamic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. TLC (ethyl acetate/MeOH/water 5/2/1) showed the appearance of a new less polar compound after 24-35 h stirring at room temperature. After removal of DMF under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford the tar- get compound in 48 % yield as a white solid.

[00055] In an embodiment, the synthesis of compound 2 (1',2,3,3',4,4',6'-hepta-O-acetyl-6-O-cinnamoyl sucrose) was carried out as follows: Compound 1 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 1), and acetic anhydride was added (14 to 35 mol per 1 mol of 1). The mixture was stirred under Ar for 16-24 h, after that the solvent was distilled off, and the residue purified by flash column chromatography, eluent hexane/ethyl acetate 3/1, then 1/1, to afford the acetylated sucrose ester 2 in 98 % yield as a colourless solid.

[00056] In an embodiment, the synthesis of compound 3 (6-O-feruloyl sucrose) was carried out as fol- lows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DMF (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and ferulic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. TLC (ethyl ace- tate/MeOH/water 5/2/1) showed the appearance of a new less polar compound after 24-35 h stirring at room temperature. After removal of DMF under reduced pressure, the residue was purified by flash col- umn chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford the target compound in 46 % yield as a yellow solid.

[00057] In an embodiment, the synthesis of compound 4 (1',2,3,3',4,4',6'-hepta-O-acetyl-6-O-feruloyl sucrose) was carried out as follows: Compound 3 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 3), and acetic anhydride was added (14 to 35 mol per 1 mol of 3). The mixture was stirred under Ar for 16-24 h, after that the solvent was distilled off, and the residue purified by flash column chromatography, eluent hexane/ethyl acetate 3/1, then 1/1, to afford the acetylated sucrose ester 4 in 98 % yield as a yellow solid.

[00058] In an embodiment, the synthesis of compound 5 (6-O-caffeyl sucrose) was carried out as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DMF (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and caffeic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. TLC (ethyl acetate/MeOH/water 5/2/1) showed the appearance of a new less polar compound after 24-35 h stirring at room temperature. After removal of DMF under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford the tar- get compound in 45 % yield as a light brown solid.

[00059] In an embodiment, the synthesis of compound 6 (1',2,3,3',4,4',6'-hepta-O-acetyl-6-O-caffeyl su- crose) was carried out as follows: Compound 5 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 5), and acetic anhydride was added (14 to 35 mol per 1 mol of 5). The mixture was stirred under Ar for 16-24 h, after that the solvent was distilled off, and the residue purified by flash column chromatography, eluent hexane/ethyl acetate 3/1, then 1/1, to afford the acetylated sucrose ester 6 in 98 % yield as a light brown solid.

[00060] In an embodiment, the synthesis of compound 7 (6-O-p-coumaryl sucrose) was carried out as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DMF (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and p-coumaric acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. TLC (ethyl acetate/MeOH/water 5/2/1) showed the appearance of a new less polar compound after 24-35 h stirring at room temperature. After removal of DMF under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford the tar- get compound in 45 % yield as a brown solid.

[00061] In an embodiment, the synthesis of compound 8 (1',2,3,3',4,4',6'-hepta-O-acetyl-6-O-p- coumaryl sucrose) was carried out as follows: Compound 7 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 7), and acetic anhydride was added (14 to 35 mol per 1 mol of 7). The mixture was stirred under Ar for 16-24 h, after that the solvent was distilled off, and the residue purified by flash column chromatography, eluent hexane/ethyl acetate 3/1, then 1/1, to afford the acetylated sucrose ester 8 in 98 % yield as a brown solid.

[00062] In an embodiment, the synthesis of compound 9 (6-O-sinapoyl sucrose) was carried out as fol- lows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DMF (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and sinapic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. TLC (ethyl ace- tate/MeOH/water 5/2/1) showed the appearance of a new less polar compound after 24-35 h stirring at room temperature. After removal of DMF under reduced pressure, the residue was purified by flash col- umn chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford the target compound in 43 % yield as a red-brown solid. [00063] In an embodiment, the synthesis of compound 10 (1',2,3,3',4,4',6'-hepta-O-acetyl-6-O-sinapoyl sucrose) was carried out as follows: Compound 9 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 9), and acetic anhydride was added (14 to 35 mol per 1 mol of 9). The mixture was stirred under Ar for 16-24 h, after that the solvent was distilled off, and the residue purified by flash column chromatography, eluent hexane/ethyl acetate 3/1, then 1/1, to afford the acetylated sucrose ester 10 in 98 % yield as a red-brown solid.

Synthesis of compounds in a microwave reactor

[00064] In an embodiment, the microwave synthesis of compound 1 was carried out as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DM F (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and trans-cinnamic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. The reaction mixture was placed in the microwave cavity, and subjected to microwave irradiation (max 300W at constant temper- ature 145 ° ) for 10-20 min. After removal of DM F under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford 1 in the form of a white solid, yield: 46 %.

[00065] In an embodiment, the microwave synthesis of compound 2 is as follows: Compound 1 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 1), and acetic anhydride was added (14 to 35 mol per 1 mol of 1). The reaction mixture was placed in the microwave cavity, and subjected to MW irradiation (max 300W) at constant temperature (90 ° ) for 5 min. The method afforded, after removal of the solvent and purification by flash column chromatography (el- uent hexane/ethyl acetate 3/1, then 1/1), the corresponding acetylated sucrose derivative 2 in 98 % yield as a colourless solid.

[00066] In an embodiment, the microwave synthesis of compound 3 was performed as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DM F (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and ferulic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. The reaction mixture was placed in the microwave cavity, and subjected to microwave irradiation (max 300W at constant temperature 145 ° ) for 10-20 min. After removal of DM F under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford 3 in the form of a yellow solid, yield: 44 %.

[00067] In an embodiment, the microwave synthesis of compound 4 was performed as follows: Com- pound 3 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 3), and acetic anhydride was added (14 to 35 mol per 1 mol of 3). The reaction mixture was placed in the microwave cavity, and subjected to MW irradiation (max 300W) at constant temperature (90 ° ) for 5 min. The method afforded, after removal of the solvent and purification by flash column chromatography (eluent hexane/ethyl acetate 3/1, then 1/1), the corresponding acetylated sucrose de- rivative 4 in 98 % yield as a yellow solid.

[00068] In an embodiment, the microwave synthesis of compound 5 was performed as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DM F (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and caffeic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. The reaction mixture was placed in the microwave cavity, and subjected to microwave irradiation (max 300W at constant temperature 145 ° ) for 10-20 min. After removal of DM F under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford 5 in the form of a light brown solid, yield: 42 %.

[00069] In an embodiment, the microwave synthesis of compound 6 was performed as follows: Com- pound 5 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 5), and acetic anhydride was added (14 to 35 mol per 1 mol of 5). The reaction mixture was placed in the microwave cavity, and subjected to MW irradiation (max 300W) at constant temperature (90 ° ) for 5 min. The method afforded, after removal of the solvent and purification by flash column chromatography (eluent hexane/ethyl acetate 3/1, then 1/1), the corresponding acetylated sucrose de- rivative 6 in 98 % yield as a light brown solid.

[00070] In an embodiment, the microwave synthesis of compound 7 was performed as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DM F (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and p-coumaric acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. The reaction mixture was placed in the microwave cavity, and subjected to microwave irradiation (max 300W at constant temper- ature 145 ° ) for 10-20 min. After removal of DM F under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford 7 in the form of a brown solid, yield: 43 %.

[00071] In an embodiment, the microwave synthesis of compound 8 was performed as follows: Com- pound 7 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 7), and acetic anhydride was added (14 to 35 mol per 1 mol of 7). The reaction mixture was placed in the microwave cavity, and subjected to MW irradiation (max 300W) at constant temperature (90 ° ) for 5 min. The method afforded, after removal of the solvent and purification by flash column chromatography (eluent hexane/ethyl acetate 3/1, then 1/1), the corresponding acetylated sucrose de- rivative 8 in 98 % yield as a brown solid.

[00072] In an embodiment, the microwave synthesis of compound 9 was performed as follows: Sucrose (0.10 to 10.00 g, or 0.29 to 29.2 mmol) was dissolved in anhydrous DM F (14 to 19 g per 1 g of sucrose), then triphenylphosphine (1.1 to 3.0 mol per 1 mol of sucrose) and sinapic acid (1.1 to 3.0 mol per 1 mol of sucrose) were added at room temperature. After complete dissolution, the mixture was cooled to 0-5 ° and DIAD (1.1 to 3.0 mol per 1 mol of sucrose) was slowly introduced. The reaction mixture was placed in the microwave cavity, and subjected to microwave irradiation (max 300W at constant temperature 145 ° ) for 10-20 min. After removal of DM F under reduced pressure, the residue was purified by flash column chromatography, eluent ethyl acetate/acetone/water 100/100/1, then 10/10/1 to afford 9 in the form of a red-brown solid, yield: 39 %.

[00073] In an embodiment, the microwave synthesis of compound 10 was performed as follows: Com- pound 9 (purified or crude product) (0.1 to 10.0 g, or 0.21 to 21.2 mmol) was dissolved in pyridine (10-15 ml per 1 g of 9), and acetic anhydride was added (14 to 35 mol per 1 mol of 9). The reaction mixture was placed in the microwave cavity, and subjected to MW irradiation (max 300W) at constant temperature (90 ° ) for 5 min. The method afforded, after removal of the solvent and purification by flash column chromatography (eluent hexane/ethyl acetate 3/1, then 1/1), the corresponding acetylated sucrose de- rivative 10 in 98 % yield as a red-brown solid.

[00074] Analysis of 1 H NM R, 13 C NM R, COSY and HSQC spectra (see Figures 1-13) of the obtained com- pounds, in particular compounds 1 and 2, proved them to be the desired products.

[00075] In an embodiment, the 1 H NMR (400 Hz) and 13 C NMR (100 Hz) were recorded on Bruker ARX 400 spectrometer in CDCI 3 solutions. Chemical shift values (d) are expressed in parts per million and re- ported downfield from TMS (0.00 ppm). The J values are given in hertz. Melting point was determined on Electrothermal Melting Point Apparatus. Optical rotation was measured in methanol or chloroform solu- tion using an AA-1000 Polarimeter Optical Activity LTD (0.5 dm cell) at 589 nm. FTIR spectra were recorded on a Bruker Tensor 27 spectrometer in KBr dispersion. Microwave-assisted synthesis was performed as previously described. Flash chromatography was performed on silica gel (Merck, 200-400 mesh). Pyridine was distilled over KOH prior to use.

[00076] In an embodiment, in 1 H NMR, the characteristic peaks of the cinnamoyl ester group were ob- served with an integration corresponding of a monoester (Figure 1).

[00077] In an embodiment, in 13 C NMR it was possible to verify the presence of a carbonyl carbon at 168.9 ppm, the aromatic ring carbons between 133.9 and 128.3 ppm, and the two carbons connected by double bond at 146.5 and 116.8 ppm (Figures 2,3). Since C-2' of the sucrose core was the only quaternary carbon present, its characteristic shift at 103.7 ppm was observed, while the anomeric carbon peak of the glucose unit was at 91.9 ppm. The peaks for the other sucrose core - C-H were between 81.4 and 69.8, while the three primary CH 2 peaks appeared between 63.7 and 61.4 ppm. The attribution of the peaks, based on COSY and HSQC spectra (Figures 4,5) was in agreement with the one previously reported, but in contrast with these publications herein was used the conventional nomenclature of sucrose denoting the positions of the glucose ring 1-6 and the ones of the fructose ring 1'-6'.

Scheme 1. Synthesis of 6-O-cinnamoyl sucrose 1 and 1',2,3,3',4,4',6'-hepta-O-acetyl-6-O-cinnamoyl su- crose 2.

[00078] In an embodiment, the characterization of 1 is as follows: m.p.: 109-110 ° , [a] D 25 = +38.7 (c=1.02, OH). 1 HNMR: d H (400 M HZ, D 2 O): 7.76 (1H, d, J CH=CH = 16.1 Hz, Ar -CH=), 7.66 (2H, m, Ar -H, o-), 7.49 (3H, m, Ar -H, m,p-), 6.59 (1H, 2d, J CH=CH = 16.1 Hz, COO -CH=), 5.42 (1H, d, J 1-2 =3.6 Hz, H 1 ), 4.53 (1H, d, J 6a-6b =11.5 Hz, H 6a ), 4.43-4.35 (1H, m, H 6b ), 4.22 (1H, d, J 3'-4' = 8.7 Hz, H 3 ,), 4.17-4.11 (1H, m, H 5 ), 4.04 (1H, t, J 3'-4'-5' =8.5 HZ, H 4' ), 3.92-3.86 (1H, m, H 5' ), 3.83-3.75 (3H, m, H 6' , H 3 ), 3.66 (2H, d, J H-H = 12.0 Hz, H 1' ), 3.60 (1H, dd, J 1-2 =3.6 HZ, J 2-3 =9.8 HZ, H 2 ), 3.49 (1H, t, J 3-4.5 =9.7 Hz, H 4 ). 13 CNM R: d C (100 MHz, D 2 O): 168.9 (-COO- ), 146.5 (Ar-CH=), 133.9 (Ar-quaternary), 131.0 (Ar-p), 129.1 (Ar-m), 128.3 (Ar-o), 116.8 (-COO-CH=), 103.7 (C 2' ), 91.9 (C 1 ), 81.4 (C 5' ), 76.4 (C 3' ), 74.2 (C 4' ), 72.3 (C 3 ), 70.9 (C 2 ), 70.4 (C 5 ), 69.8 (C 4 ), 63.7 (C 6 ), 62.7 (C 6' ), 61.4 (C 1' ); ESI-MS (m/z): 495 [M+Na] + .

[00079] In an embodiment, the characterization of 2 is as follows: m.p.: 47-49 ° , [a] D 25 = +64.63 (c=0.96, CHCI 3 ), 1 HNM R: d H (400 M HZ, CDCI 3 ): 7.72 (1H, d, J CH=CH = 16.0 Hz, Ar -CH=), 7.58-7.54 (2H, m, Ar -H, o-), 7.41- 7.36 (3H, m, Ar -H, m,p-), 6.52 (1H, d, J CH=CH = 16.0 Hz, COO -CH=), 5.72 (1H, d, J 1-2 =3.7 Hz, H 1 ), 5.48-5.44 (2H, m, H 3 , H 3' ), 5.38 (1H, t, J 3'-4'-5' =5.7 Hz, H 4' ), 5.13 (1H, t, J 3-4-5 = 9.6 Hz, H 4 ), 4.90 (1H, dd, J 1-2 =3.7 Hz, J 2 - 3 =10.4 Hz, H 2 ), 4.39-4.29 (5H, m, H 5 , H 6' , H 6 ), 4.23-4.19 (3H, m, H 5' , H 1' ), 2.19 (3H, s, CH 3 O), 2.11 (3H, s, CH 3 O), 2.10 (6H, s, 2CH 3 O), 2.08 (3H, s, CH 3 O), 2.06 (3H, s, CH 3 O), 2.02 (3H, s, CH 3 O). 13 CNM R: d c (100 MHz, CDCI 3 ): 170.5 (CH 3 CO), 170.1 (3CH 3 CO), 169.9 (CH 3 CO), 169.7 (CH 3 CO), 169.5 (CH 3 CO), 166.5 (-COO-), 145.7 (Ar-CH=), 134.4 (Ar-quaternary), 130.4 (Ar-p), 128.9 (Ar-m), 128.3 (Ar-o), 117.4 (-COO-CH=), 104.1 (C 2' ), 90.0 (C 1 ), 79.2 (C 5' ), 75.8 (C 3 , ), 75.1 (C 4' ), 70.3 (C 2 ), 69.7 (C 3 ), 68.6 (C 5 ), 68.5 (C 4 ), 63.6 (C 6' ), 62.9 (C 1' ), 62.0 (C 6 ), 20.6 (7CH 3 CO); ESI-MS ( m/z ): 789 [M+Na] + .

[00080] In an embodiment, the characterization of compound 3 is as follows: m.p.: 92-94 ° , [a] D 25 = +31.2 (c=0.91, CH 3 OH). 1 HNMR: d H (400 MHZ, D 2 O): 7.55 (1H, d, J CH=CH = 15.6 Hz, Ar -CH=), 7.06 (1H, s, Ar- H2, o-), 7.01 (1H, d, J ArH5-ArH6 = 8.4 Hz, Ar -H5, m-), 6.52 (1H, d, J ArH5-ArH6 = 8.2 Hz, Ar -H6, o-), 6.15 (1H, d, J CH=CH = 15.6 Hz, COO -CH=), 5.31 (1H, d, J 1-2 =3.6 Hz, H 1 ), 4.11 (1H, d, J 3 -4 =8.8 Hz, H 3 , ), 3.95 (1H, t, J 3'-4'-5' =8.6 Hz, HA'), 3.82-3.65 (10H, m, H 3 , H 5 , H 5' , H 6 , H 6' , OCH 3 ), 3.57 (2H, s, H 1' ), 3.45 (1H, dd, J 1-2 =3.8 Hz, J 2-3 =9.8 Hz, H 2 ), 3.36 (1H, t, J 3-4-5 =9.4 HZ, H A ). 13 CNMR: d c (100 MHZ, D 2 O): 171.0 (-COO-), 149.1 (Ar-C3,C4), 148.9 (Ar- CH=), 127.6 (Ar-Cl), 126.4 (Ar-C5), 119.3 (Ar-C6), 110.5 (Ar-C2), 109.2 (-COO-CH=), 105.3 (C 2' ), 93.7 (C 1 ), 83.8 (C 5' ), 79.5 (C 3 , ), 75.7 (C 4' ), 74.6 (C 3 ), 74.4 (C 5 ), 73.2 (C 4 ), 71.4 (C 2 ), 64.1 (C 6 ), 63.4 (C 6' ), 62.3 (C 1' ), 55.8 (OCH 3 ); ESI-MS (m/z): 541 [M+Na] + .

[00081] In an embodiment, the characterization of compound 4 is as follows: [a] D 25 = +63.87 (c=0.88, CHCl 3 ), 1 HNMR: d H (400 MHz, CDCI 3 ): 7.65 (1H, d, J CH=CH = 15.6 Hz, Ar -CH=), 7.56 (1H, s, Ar -H2, o-), 7.48 (1H, d, J ArH5-ArH6 = 8.4 Hz, Ar -H5, m-), 6.51 (1H, d, J ArH5-ArH6 = 8.2 Hz, Ar -H6, o-), 6.15 (1H, d, J CH=CH = 15.6 Hz, COO- CH=), 5.72 (1H, d, J 1-2 =3.6 HZ, H 1 ), 5.49-5.44 (2H, m, H 3 , H 3 , ), 5.37 (1H, t, J 3'-4'-5' =8.7 Hz, H 4' ), 5.13 (1H, t, J 3.4. 5 =9.6 Hz, H 4 ), 4.90 (1H, dd, J 1-2 =4.0 Hz, J 2-3 =10.4 Hz, H 2 ), 4.39-4.29 (5H, m, H 5 , H 6' , H 6 ), 4.23-4.19 (3H, m, Hs-, Hr), 3.86 (3H, s, O CH 3 ), 2.19 (3H, s, CH 3 O), 2.11 (3H, s, CH 3 O), 2.10 (6H, s, 2CH 3 O), 2.09 (3H, s, CH 3 O), 2.07 (3H, s, CH 3 O), 2.03 (3H, s, CH 3 O). 13 CNMR: d c (100 MHz, CDCI 3 ): 170.5 (CH 3 CO), 170.2 (3CH 3 CO), 169.9 (CH 3 CO), 169.8 (CH 3 CO), 169.4 (CH 3 CO), 166.6 (-COO-), 149.0 (Ar-C3,C4), 148.8 (Ar-CH=), 127.4 (Ar-Cl), 126.3 (Ar-C5), 119.3 (Ar-C6), 109.1 (-COO-CH=), 103.1 (C 2' ), 90.8 (C 1 ), 79.5 (C 5' ), 75.9 (C 3 , ), 75.0 (C 4' ), 70.6 (C 2 ), 69.8 (C 3 ), 68.7 (C 5 ), 68.5 (C 4 ), 63.4 (C 6' ), 63.0 (C 1' ), 62.2 (C 6 ), 56.9 (OCH 3 ), 20.7 (7CH 3 CO); ESI-MS (m/z): 835 [M+Na] + .

[00082] In an embodiment, the characterization of compound 5 is as follows: m.p.: 89-93 °C, [a] D 25 = +29.8 (c=0.81, CH 3 OH). 1 HNMR: d H (400 M HZ, D 2 O): 7.53 (1H, d, J CH=CH = 15.9 Hz, Ar -CH=), 7.15 (1H, s, Ar- H2, o-), 7.02 (1H, d, J ArH5-ArH6 = 8.1 Hz, Ar -H5, m-), 6.86 (1H, d, J ArH5-ArH6 = 8.0 Hz, Ar -H6, o-), 6.26 (1H, d, J CH=CH = 15.9 Hz, COO -CH=), 5.30 (1H, d, J 1-2 =3.5 Hz, H 1 ), 4.12 (1H, d, J 3' -4' =9.8 Hz, H 3 , ), 3.96 (1H, t, J 3'-4'-5' =9.6 Hz, H 4' ), 3.82-3.65 (7H, m, H 3 , H 5 , H 5' , H 6 , H 6' ), 3.55 (2H, s, H 1' ), 3.47 (1H, dd, J 1-2 =3.6 Hz, J 2-3 =9.8 Hz, H 2 ), 3.34 (1H, t, J 3-4- 5 =9.7 Hz, H 4 ). 13 CNM R: d c (100 MHz, D 2 O): 167.0 (-COO-), 146.7 (Ar-C4), 146.1 (Ar-C3), 145.9 (Ar-CH=), 128.6 (Ar-Cl), 124.4 (Ar-C6), 118.0 (Ar-C5), 116.7 (-COO-CH=), 115.5 (Ar-C2), 115.0 (C 2' ), 100.1 (C 1 ), 85.9 (C 5' ), 79.9 (C 3 , ), 76.7 (C 4' ), 74.8 (C 3 ), 74.6 (C 5 ), 74.0 (C 4 ), 72.5 (C 2 ), 64.2 (C 6 ), 62.4 (C 6 ), 61.2 (C 1' ); ESI-MS (m/z): 527 [M+Na] + . [00083] In an embodiment, the characterization of compound 6 is as follows: [a] D 25 = +65.92 (c=0.76, CHCI 3 ), 1 HN M R: d H (400 M HZ, CDCI 3 ): 7.63 (1H, d, J CH=CH = 15.9 Hz, Ar -CH=), 7.23 (1H, s, Ar -H2, o-), 7.20 (1H, d, J ArH5-ArH6 = 8.1 Hz, Ar -H5, m-), 6.87 (1H, d, J ArH5-ArH6 = 8.0 Hz, Ar -H6, o-), 6.28 (1H, d, J CH=CH = 15.9 Hz, COO- CH=), 5.68 (1H, d, JI- 2 =3.5 HZ, HI), 5.50-5.43 (2H, m, H 3 , H 3 , ), 5.38 (1H, t, J 3'-4'-5' =8.8 Hz, H 4' ), 5.12 (1H, t, J 3.4. 5 =9.7 Hz, H 4 ), 4.91 (1H, dd, J 1-2 =4.0 Hz, J 2-3 =10.2 Hz, H 2 ), 4.40-4.30 (5H, m, H s , H 6' , H 6 ), 4.25-4.20 (3H, m, Hs', Hr), 2.20 (3H, s, CH 3 O), 2.10 (3H, s, CH 3 O), 2.09 (6H, s, 2CH 3 O), 2.08 (3H, s, CH 3 O), 2.06 (3H, s, CH 3 O), 2.02 (3H, s, CH 3 O). 13 CNMR: d c (100 M HZ, CDCI 3 ): 170.7 (CH 3 CO), 170.3 (3CH 3 CO), 170.0 (CH 3 CO), 169.7 (CH 3 CO), 169.2 (CH 3 CO), 166.5 (-COO-), 147.7 (Ar-C4), 147.3 (Ar-C3), 146.0 (Ar-CH=), 128.3 (Ar-Cl), 124.1 (Ar-C6), 119.1 (Ar-C5), 116.5 (-COO-CH=), 115.1 (Ar-C2), 104.0 (C 2' ), 93.1 (C 1 ), 82.3 (C 5' ), 76.0 (C 3 , ), 75.4 (C 4' ), 70.9 (C 2 ), 69.2 (C 3 ), 68.8 (C 5 ), 68.4 (C 4 ), 63.7 (C 6' ), 63.1 (C 1' ), 62.6 (C 6 ), 20.7 (7CH 3 CO); ESI-MS (m/z): 821 [M+Na] + .

[00084] In an embodiment, the characterization of compound 7 is as follows: m.p.: 112-116 °C, [a] D 25 = +23.8 (c=1.12, CH 3 OH). 1 HNMR: d H (400 MHz, D 2 O): 7.54 (1H, d, J CH=CH = 15.6 Hz, Ar -CH=), 7.37 (2H, d, J ArH2- ArH3 = 8.2 Hz, Ar -H2,H6, o-), 6.63 (2H, d, J ArH2-ArH3 = 8.2 Hz, Ar -H3, H5, m-), 6.18 (1H, d, J CH=CH = 15.8 Hz, COO- CH=), 5.30 (1H, d, J 1-2 = 3.2 Hz, H 1 ), 4.43-4.15 (2H, m, H 6 ), 4.09 (1H, d, J 3 -- 4 - = 8.7 Hz, H 3 , ), 4.01-3.98 (1H, m, Hs ), 3.92 (1H, t, J 3' -4' -5' = 8.6 Hz, H 4' ), 3.81-3.65 (4H, m, H 3 , H s , H 6' ), 3.54 (2H, s, H 1 ' ), 3.48 (1H, dd, J 1-2 = 3.5 Hz, J 2 - 3 = 9.9 Hz, H 2 ), 3.36 (1H, t, J 3-4-5 = 9.6 Hz, H 4 ). 13 CNM R: d c (100 MHz, D 2 O): 166.8 (-COO-), 156.7 (Ar- C4), 145.2 (Ar-CH=), 129.6 (Ar-C2, C6), 125.8 (Ar-Cl), 116.5 (-COO-CH=), 115.7 (Ar-C3, C5 ), 110.0 (C 2' ), 98.1 (C 1 ), 84.9 (C 5' ), 79.1 (C 3 , ), 75.6 (C 4' ), 74.7 (C 3 ), 74.5 (C 5 ), 73.9 (C 4 ), 72.2 (C 2 ), 64.7 (C 6 ), 63.4 (C 6 ), 61.8 (C 1' ); ESI-MS (m/z): 511 [M+Na] + .

[00085] In an embodiment, the characterization of compound 8 is as follows: [a] D 25 = +63.53 (c=0.98, CHCI 3 ), 1 HNMR: d H (400 M HZ, CDCI 3 ): 7.59 (1H, d, J CH=CH = 15.6 Hz, Ar -CH=), 7.47 (2H, d, J ArH2-ArH3 = 8.2 Hz, Ar -H2,H6, o-), 6.71 (2H, d, J ArH2-ArH3 = 8.2 Hz, Ar -H3, H5, m-), 6.27 (1H, d, J CH=CH = 15.8 Hz, COO -CH=), 5.78 (1H, d, JI- 2 =3.5 HZ, HI), 5.52-5.44 (2H, m, H 3 , H 3 , ), 5.40 (1H, t, J 3' -4' -5' = 8.9 Hz, H 4' ), 5.13 (1H, t, J 3-4.5 = 9.8 Hz, H 4 ), 4.90 (1H, dd, JI- 2 =3.5 HZ, J 2-3 =9.9 HZ, H 2 ), 4.42-4.28 (5H, m, H s , H 6 -, H 6 ), 4.26-4.18 (3H, m, H 5' , Hr), 2.18 (3H, s, CH 3 O), 2.11 (3H, s, CH 3 O), 2.10 (6H, s, 2CH 3 O), 2.08 (3H, s, CH 3 O), 2.05 (3H, s, CH 3 O), 2.01 (3H, s, CH 3 O). 13 CN M R: d c (100 M HZ, CDCI 3 ): 170.6 (CH 3 CO), 170.3 (4CH 3 CO), 169.9 (CH 3 CO), 169.6 (CH 3 CO), 166.7 (-COO-), 157.8 (Ar-C4), 145.5 (Ar-CH=), 130.7 (Ar-C2, C6), 127.9 (Ar-Cl), 116.2 (-COO-CH=), 115.4 (Ar-C3, C5), 104.2 (Cr), 92.4 (C 1 ), 81.8 (C 5' ), 76.7 (C 3 , ), 74.3 (C 4 ), 72.7 (C 2 ), 71.3 (C 3 ), 69.6 (C 5 ), 67.4 (C 4 ), 62.7 (C 6 ), 61.7 (C 1' ), 60.2 (C 6 ), 21.2 (7CH 3 CO); ESI-MS (m/z): 805 [M+Na] + .

[00086] In an embodiment, the characterization of compound 9 is as follows: m.p.: 75-78 °C, [a] D 25 = +40.2 (c=1.01, CH 3 OH). 1 HNM R: d H (400 M HZ, D 2 O): 7.57 (1H, d, J CH=CH = 15.9 Hz, Ar -CH=), 7.01 (2H, s, Ar -H, o-), 6.39 (1H, d, J CH=CH = 15.9 Hz, COO -CH=), 5.32 (1H, d, J 1-2 =3.5 Hz, H 1 ), 4.45-4.23 (2H, m, H 6 ), 4.12 (1H, d, J 3'-4' = 9.7 Hz, Hr), 3.94 (1H, t, J 3'-4 -5' =9.6 Hz, H 4' ), 3.82-3.60 (5H, m, H 3 , H 5 , H 5' , H 6' ), 3.55 (2H, s, H 1 ' ), 3.50 (1H, dd, J 1-2 =3.4 HZ, J 2-3 = 10.1 Hz, H 2 ), 3.78 (1H, t, J 3-4.5 = 9.5 Hz, H 4 ), 3.25 (6H, s, O CH 3 ). 13 CNM R: d c (100 MHz, D 2 O): 167.8 (-COO-), 148.3 (Ar-m), 145.5 (Ar-CH=), 136.8 (Ar-p), 127.9 (Ar-quaternary), 116.5 (-COO-CH=), 109.1 (Ar-o), 104.2 (C 2' ), 94.9 (C 1 ), 81.5 (C 5' ), 76.1 (C 3 ,), 74.3 (C 4 ), 72.9 (C 3 ), 71.9 (C 2 ), 70.1 (C 5 ), 69.2 (C 4 ), 64.7 (C 6 ), 62.8 (C 6' ), 62.4 (C 1' ), 56.4 (OCH 3 ); ESI-MS ( m/z ): 571 [M+Na] + .

[00087] In an embodiment, the characterization of compound 10 is as follows: m.p.: 34-39 °C, [a] D 25 = +62.33 (c=0.88, CHCI 3 ), 1 HNMR: d H (400 MHz, CDCI 3 ): 7.56 (1H, d, J CH=CH = 16.1 Hz, Ar -CH=), 7.00 (2H, s, Ar- H, o-), 6.40 (1H, d, JCH=CH = 16.0 Hz, COO -CH=), 5.71 (1H, d, J 1-2 =3.6 Hz, H 1 ), 5.50-5.45 (2H, m, H 3 , H 3' ), 5.40 (1H, t, J 3'-4'-5' =8.8 HZ, H 4' ), 5.15 (1H, t, J 3-4.5 = 8.9 Hz, H 4 ), 4.95 (1H, dd, J 1-2 =3.5 Hz, J 2.3 = 9.9 Hz, H 2 ), 4.41-4.32 (5H, m, H 5 , H 6' , H 6 ), 4.25-4.17 (3H, m, H 5' , H 1' ), 3.85 (6H, s, OCH 3 ), 2.18 (3H, s, CH 3 O), 2.13 (3H, s, CH 3 O), 2.09 (6H, s, 2CH 3 O), 2.07 (3H, s, CH 3 O), 2.06 (3H, s, CH 3 O), 2.00 (3H, s, CH 3 O). 13 CNM R: d c (100 MHz, CDCI 3 ): 170.6 (CH 3 CO), 170.0 (3CH 3 CO), 169.6 (3CH 3 CO), 166.7 (-COO-), 148.1 (Ar-m), 145.3 (Ar-CH=), 136.5 (Ar- p), 126.9 (Ar-quaternary), 116.8 (-COO-CH=), 109.0 (Ar-o), 104.5 (C 2' ), 91.1 (C 1 ), 79.8 (C 5' ), 75.7 (C 3 , ), 75.3 (C 4' ), 70.1 (C 2 ), 69.5 (C 3 ), 68.9 (C 5 ), 68.2 (C 4 ), 63.8 (C 6' ), 62.5 (C 1' ), 62.1 (C 6 ), 56.0 (OCH 3 ), 20.7 (7CH 3 CO); ESI- MS (m/z): 865 [M+Na] + .

[00088] Table 1: Structures of Sibirioside A (6-O-cinnamoyl sucrose) 1, Arillatose B (6-O-feruloyl sucrose) 3, 6-O-caffeyl sucrose 5, Acretoside (6-O-p-coumaryl sucrose) 7 and Sibiricose A2 (6-O-sinapoyl sucrose) 9 and the corresponding peracetylated derivatives 2, 4, 6, 8 and 10.

[00089] In an embodiment, the antibacterial activity screening was performed as follows. For antibacte- rial activity screening, the Gram-positive bacteria Staphylococcus aureus (ATCC 6538), Bacillus cereus (clinical isolate), Listeria monocytogenes (NCTC 7973), and Micrococcus flavus (ATCC 10240), and the Gram-negative bacteria Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 35210), Salmo- nella typhimurium (ATCC 13311), and Enterobacter cloacae (human isolate), were used. The antibacterial assay was carried out by a microdilution method as previously described.

[00090] The synthesized sucrose esters 1 and 2 exhibited high antibacterial activity against all bacterial species tested (Table 2), with MIC in the range of 18 - 150 mg/mL, and MBC in the range of 150 - 300 mg/mL. Higher activity was achieved for compound 1 than 2. Comparing the results obtained for the syn- thetic compounds with the ones for the commercial antibiotic streptomycin (40.0 to 260.0 mg/mL), it was noticed that the synthesized samples exhibited stronger antibacterial activity in the cases of the most bacteria tested. Compounds 1 and 2 expressed higher inhibitory activity than streptomycin against all Gram (+) bacteria and higher both inhibitory and bactericidal potentials than streptomycin towards Gram (-) bacteria. Both compounds exhibited higher antibacterial effect than ampicillin (18.0 - 150.0 mg/mL ver- sus 250.0 - 740.0 mg/mL). Minimum bactericidal concentrations for compounds 1 and 2 were in the range of 150.0 - 300.0 mg/mL, while streptomycin completely stopped bacterial growth at 90.0 - 520.0 mg/mL and ampicillin at 370.0 - 1240.0 mg/mL. Both tested compounds showed much better activity than antibi- otics, as much as few times higher.

Table 2. Antibacterial activity of compounds 1 and 2, mg/mL.

[00091] In an embodiment, the antifungal activity screening was performed as follows. For antifungal activity screening, Aspergillus fumigatus (human isolate), Aspergillus versicolor (ATCC 11730), Aspergillus ochraceus (ATCC 12066J, Aspergillus niger (ATCC 6275), Trichoderma viride (1AM 5061), Penicillium funic- ulosum (ATCC 36839J, Penicillium ochrochloron (ATCC 9112) and Penicillium verrucosum var. cyclopium (food isolate), were used. Commercial fungicides, bifonazole (Srbolek, Belgrade, Serbia) and ketoconazole (Zorkapharma, Sabac, Serbia), were used as positive controls (1-3000 mg/mL). The antifungal activity assay was performed by a modified microdilution technique according to a previous description.

[00092] The tested compounds showed very strong antifungal potential (Table 3) and again the com- pound 1 was the more active one. Inhibitory activity was in the range of 2 - 375 mg/mL, while fungicidal effect was ranged from 4.5 - 750 mg/mL. The commercial antifungal agent, bifonazole, showed MIC at 100 - 200 mg/mL and MFC at 200 - 250 mg/mL. Ketoconazole showed M IC ranging 200 - 2500 mg/mL and M FC at 300 - 3500 mg/mL. Compounds 1 and 2 showed higher activity than both mycotics tested, except for compound 2 which exhibited lower potential against P. verrucosum.

[00093] The results showed that the growth of the various types of bacteria tested responded differently to the synthetic compounds. This indicates that it may have different modes of action on the different species or that the metabolism of some bacteria is able to overcome the effect of the compound or adapt to it. It is known that Gram (+) bacterial species are more susceptible to antimicrobial agents than Gram (-) bacteria, and that fungi are more susceptible than bacteria in general. Thus, the susceptibility of micro- organisms to external agents depends not only on their properties, but also on the microorganism itself.

Table 3. Antifungal activity of compound 1 and 2, mg/mL.

Table 3. Antibacterial activity of compounds 1-10 (MIC and MBC in mM)

[00094] In an embodiment, the antioxidant activity of compounds 1 and 2 was performed as follows. DPPH (2,2-dipheny-1-picrylhydrazyl) radical-scavenging activity and lipid peroxidation inhibition were the in vitro assays used for the evaluation of the antioxidant activity. Briefly, DPPH radical scavenging activity was evaluated using an ELX800 microplate Reader (Bio-Tek Instruments, Inc., Winooski, VT, USA), and calculated as a percentage of DPPH discoloration using the formula: [(A DPPH - A C )/A DPPH ] × 100, where Ac is the absorbance of the solution containing the compound at 515 nm, and ADPPH is the absorbance of the DPPH solution. Inhibition of lipid peroxidation using thiobarbituric acid reactive substances (TBARS) was evaluated by the lipid peroxidation inhibition in porcine brain homogenates where the colour intensity of the malondialdehyde-thiobarbituric acid (MDA-TBA) was measured by its absorbance at 532 nm; the in- hibition ratio (%) was calculated using the following equation: [(A-B)/A] ´ 100%, where A and B were the absorbance of the control and the compound solution, respectively. EC 50 values (compound concentration that achieved 50 % of antioxidant activity) were determined and trolox was used as standard.

[00095] The synthesized compounds did not show very high antioxidant activity, but it was higher than the cinnamic acid that, up to 100 mg/mL, did not show any activity in the assays performed (Table 5).

Table 5. Antioxidant activity of compounds 1 and 2, mg/mL.

[00096] In an embodiment, antitumor activity and hepatotoxicity were carried out as follows. Five hu- man tumor cell lines were used: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), HCT-15 (colon carcinoma), HeLa (cervical carcinoma) and FlepG2 (hepatocellular carcinoma). GI 50 values (compound concentration that inhibited 50 % of the net cell growth) were determined and ellipticine was used as standard.

[00097] The synthesized compounds 1 and 2 showed activity against human breast, colon and cervical carcinoma cell lines, being the latter the most susceptible one (Table 6). Up to 400 mg/mL, they did not present any activity towards lung and hepatocellular carcinoma cell lines. GI 50 values obtained were higher (lower cytotoxic activity) than the ones of the standard ellipticine. Nevertheless, it should be noted that the tested compounds did not show toxicity for non-tumor cells (porcine liver cells primary culture; PLP2), while the standard proved to be strongly hepatotoxic (2.96 mg/mL).

[00098] In summary, the synthesized compounds exhibited higher antibacterial activity than ampicillin against all Gram (-) bacteria. The compounds tested (1 or 2) possess wide spectrum of activities, depend- ing on bacterial and fungal species. They showed a moderate cytotoxic and antioxidant potential, but without hepatotoxicity. As the synthesized product could be obtained in large quantities and at cheaper price comparing to the extracted one, it can find exciting applications in pharmacological compositions.

[00099] Table 6. Cytotoxicity and hepatotoxicity of the compounds 1-10 (GI 50 values in mM)

[000100] GI50 values correspond to the compound concentration achieving 50% of growth inhibition in human tumor cell lines or in liver primary culture PLP2.

[000101] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skills in the art will foresee many possibilities to modifications thereof.

[000102] Furthermore, where ranges are given, endpoints are included. Furthermore, it is to be under- stood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is also to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range.

[000103] The above described embodiments are combinable. The following claims further set out partic- ular embodiments of the disclosure. REFERENCES

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