Resveratrol derivatives: Synthesis and their biological activities

Resveratrol, a natural compound known especially for its antioxidant properties and protective action, opens the door for both it and its structural derivatives to be considered not only as chemopreventive but also as cancer chemotherapeutic agents. Due to the pharmacokinetic problems of resveratrol that demonstrate its poor bioavailability, the study of new derivatives is of interest. Thus, in this work ( E )-stilbenes derived directly from resveratrol and other cyclic analogues containing the benzofuran or indole nucleus have been synthesized. The synthesized compounds have been evaluated for their ability to affect tumor growth in vitro. Compounds 2 , 3 , 4 and 5 have shown cytotoxicity in human colon cancer (HT-29) and human pancreatic adenocarcinoma cells (MIA PaCa-2) higher than those of ( E )- resveratrol . The indolic derivative 13 , a cyclic analog of resveratrol, has shown in vitro cytotoxic activity 8 times higher than resveratrol against HT-29 cancer cells. The cyclic derivatives 8 , 9 and 12 showed a high inhibition of cell growth in HCT-116 (KRas mutant) at 20 μ M, while 13 shows moderate antiangiogenesis activity at 10 μ M


Introduction
Pharmaceutical studies suggested that the polyphenol resveratrol (3,4 ′ ,5-trihydroxy-trans-stilbene) present in some plants is one of the main wine-red grape components that protect from vascular, neurodegenerative diseases, atherosclerosis, oxidative stress and certain tumors due to antioxidant properties [1][2][3].The ability of resveratrol to prevent the occurrence of carcinomas was related to the inhibition of tumor cell cycle and induction of tumor cell death [4].Resveratrol, like other natural products, can act on different biological targets and present different biological effects and therefore is considered a multi-target drug.
Resveratrol exhibits poor solubility in water and also low oral bioavailability.Complexation with cyclodextrins or the formation of salts improve the aqueous solubility but the bioavailability does not increase [5].
In addition, resveratrol has a very short half-life (about 14 min when it was administered intravenously) due to its rapid metabolism.The presence of free hydroxyl groups facilitates conjugation with glucuronic acid and sulphatation via PAPS (phosphoadenosyl phosphosulfate) [6].
The study of resveratrol is on the rise as indicated by the 34,144 references and 2,833,781 bibliographic citations in SciFinder (July 2022), of which more than 80% are from the last 5 years.Although the clinical benefits of resveratrol have not been sufficiently demonstrated, the vast majority of publications refer to studies with prospective therapeutic applications.
Resveratrol is a stilbene that contains 2 hydroxyl groups on one of the phenyls and another hydroxyl group on the second benzene ring.Despite the fact that resveratrol and its analogues are normally in the Econfiguration ( 1 H NMR analysis J = 16.0-18.0Hz, ethene protons), both phenyl groups linked through an ethylene unit can give rise to the Z and E configurations.
Recently in the field of cancer, resveratrol has demonstrated its antimutagenic and phase II inducing capacity of hepatic enzymes detoxifying carcinogens (cytochrome P450 enzymes (CYPs)) [7].It has also been seen that it stimulates apoptosis or programmed cell death of tumor cells, thus helping to reduce tumor growth [8].According to the results of scientific studies, the P53 tumor suppressor protein could be considered the target for the apoptosis process since it would involve different phosphorylation enzymes and Bcl proteins [9].In other trials, resveratrol has been shown to activate the suppressor gene Rad 9 which induces the death of tumor cells.In this specific case, resveratrol has shown a reduction in lung and breast cancer at micromolar concentration in vitro and also in vivo test [10].Pradhan and col [11].report that resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by attacking primarily tumor-related macrophages.In short, it can be said that resveratrol affects all three phases of cancer development, initiation, promotion and progression, and also suppresses final steps such as angiogenesis and metastasis.
Currently, resveratrol continues to be of interest due to its multiple properties of therapeutic interest, especially its antitumor capacity.Previously, and due to its antioxidant nature, resveratrol was considered preventive against the development of cancer, today, there are research results that allow us to recognize its dose-dependent cytotoxic properties and can be considered chemopreventive and therapeutic agent [12].Because of its antitumor properties and its low toxicity even at high doses, resveratrol constitutes a good head for the design of new compounds.
Resveratrol has been well studied and its biological properties and even mechanisms of action are known, but there is virtually no information on other stilbenoids.On the one hand, and as in resultant the low bioavailability of resveratrol attributable to phenolic functions, we proposed the preparation of derivatives with protected hydroxyl groups or without these polar groups to improve activity as prodrugs by comparing it with to resveratrol itself (Fig. 1).
To improve bioavailability and its cytotoxic capacity, in this work, resveratrol derivatives have been prepared by alkylation of hydroxyl groups (compounds 2, 4 and 5) or acylation (compounds 6 and 7).Cyclic analogues of resveratrol have also been prepared, and their preparation and biological activities will be discussed.Compounds 2 and 4 had already been reported previously [bibliographic references 1e, 3b, 4c] but there are few data about them and here they were important to be able to make a comparative study of the biological activities.
In the design of new compounds from a model, in our case resveratrol, the formation of rings constitutes a classic approach to modulative pharmacomodulation.The preparation of cyclic analogues of resveratrol leads to an increase in the rigidity of the structure and constitutes an interesting method for the determination of the pharmacophore group of structures with a clear profile of biological activity.We focused on the synthesis of new structural resveratrol analogues replacing the central double bond by an unsaturated ring furan or pyrrole.In this work, the preparation of derivatives of the 2-arylbenzofuran type (compounds 8-11) by the introduction of an oxygen atom or of derivatives that contain the nucleus of 2-arylindoles that differ from resveratrol by the incorporation of an -NH-group that allows the formation of the heterocyclic ring (compounds 12-15) (Fig. 2) was carried out.
According to bibliographic data, the role of resveratrol against the Kras protein, as well as its antiangiogenesis properties are unknown.For this reason, our interest would be to determine the in vitro antitumor activity in colon cell lines as well as to determine the participation of Kras in the cytotoxic capacity of resveratrol.
Kras inhibition and angiogenesis studies have been carried out on the compounds selected and accepted by the Eli Lilly Laboratories OIDDs program (Open Innovation Drug Discovery Program).The OIDDs platform selected some of the compounds prepared in this work according to their structure to carry out in vitro biological tests against specific and concrete targets.This being the reason why the activity of each of the compounds against the different targets mentioned has not been indicated.

Chemistry
The synthetic routes for the preparation of resveratrol derivatives 2-7, 8-15 are shown in Schemes 1-4.
The polyalkylation of resveratrol with an excess of alkylating agents in basic medium allows access to alkylated derivatives such as 4 [14] and 5. Methylation using methyl iodide leads to 4 with quantitative yields while the reaction with 2-bromoethanol leads to a mixture of monoalkylated, dialkylated compounds and the trialkylated desired compound 7 being a minority (Scheme 2).Compounds 6 and 7 were prepared by acylation of resveratrol.Treatment of resveratrol with an excess of pivaloyl chloride makes it possible to obtain the triacylated derivative 6 with a yield of 66%.X-ray diffraction studies confirmed the structure proposed for derivative 6 and also confirms the proposed configuration E. (Fig. 3).In the same way, the treatment of resveratrol with lauroyl chloride in the presence of base allows access to the triacylated derivative 7 with a yield of 52% (Scheme 2).
A multistep and metal-free approach for the preparation of resveratrol analogues was proposed.Firstly, a condensation of the corresponding aldehyde 18 with the appropriate phenylacetic acid (19 or 20) under Perkin-type conditions using Ac 2 O and Et 3 N led to the intermediate arylcoumarins (21)(22) in moderate yield.The corresponding lactones (21)(22) were separately hydrolyzed and involved in an intramolecular cyclization reaction with 2 N HCl to afford the benzofurans (8 or 10) in moderate yield.The methoxyl groups of 8 were cleaved by treatment with BBr 3 at 0 • C affording 9 in satisfactory yield (Scheme 3).This process through the opening of the coumarin ring followed by decarboxylation in the presence of acid has a high trans selectivity and uses environmentally friendly conditions.

Determination cytotoxic activity
The in vitro cell proliferation of resveratrol (1) and synthetic resveratrol derivatives 2-7 was evaluated against two cancer cell lines, HT-29 (human colon adenocarcinoma) and MIA PaCa-2 (human pancreatic adenocarcinoma cells) by standard MTT assay (see the experimental section) and cytotoxicity values as IC 50 are shown in Table 1.L. Grau et al.The tested compounds show differences in activities with respect to resveratrol against the two tumor cell lines.The pentahydroxylated compound 3 shows activity comparable to that of resveratrol for HT-29 cells and a lower IC 50 value for MIA PaCa-2 cells (IC 50 = 96 ± 5 μM).
Trialcohol 5 surprisingly show greater cytotoxicity than expected in both types of cell lines.Regarding tumor cells HT-29 show a cytotoxicity 3 times higher than resveratrol (IC 50 = 23 ± 2 μM).Polyphenol 3 has cytotoxic activity comparable to resveratrol in the HT-29 cell line and higher in pancreatic cancer cells.The 3,4,5-trimethoxyphenol group of compound 3 can establish intramolecular hydrogen bonds that provide greater solubility in organic solvents than resveratrol favoring the passage of membranes.Polyphenol 3 and trialcohol 5 show practically the same log P values, however the IC 50 values are different, being markedly 5 more active than polyphenol 3 markedly in HT-29 cells.
Compound 2 shows the strongest cytotoxicity against colon carcinoma (HT-29) and pancreatic carcinoma (MIA PaCa-2) cells lines with IC 50 values of 12 ± 3 and 28 ± 4 μM respectively, being six and five times more active than resveratrol in the respective cell lines.The methoxylated-resveratrol 4 also shows significant cytotoxicity 5-and 4fold higher than resveratrol on HT-29 and MIA PaCa-2 cells, respectively.The pivaloyl ester 6, in these tests, showed a higher activity than that of resveratrol in both cell lines, showing that the triester has not been hydrolyzed to resveratrol (1) as might be expected.Triester 7, a more lipophilic compound, has less activity than resveratrol (1).The decrease in activity can be attributed to the low solubility and high stability of this derivative.Finally indicate that there is no direct relationship between lipophilicity and cytotoxicity of the seven compounds evaluated.But the results indicate that the compounds with logP between 2.29 and 3.85 are the ones that present greater cytotoxicity in vitro in HT-29 and MIA Paca-2 cells lines.
L. Grau et al. compound shows a 6-hydroxyl group and a 2,5-dimethoxyphenyl group in the carbon -two.The rest of the compounds of the indole series (compounds 12, 14 and 15) show a very weak cytotoxic activity.It should be noted that only compound 13 shows a hydroxyl group specifically in position 6, the rest do not contain free hydroxyl groups in any other position (Table 2).Derivative 12, a benzylated analog of 13, has a cytotoxic activity 24 times lower than that of compound 13, confirming the importance of having a hydroxyl group in the structure.
Regarding the cyclic derivatives with a benzofuran nucleus, the four compounds of the miniseries (compounds 8-11) show greater activity than the indolic derivatives with the exception of compound 13.It should be noted that all these compounds have a hydroxyl group at C-6.In addition, the two most active compounds 8 and 10 also show 2 methoxyl groups as substituents on the phenyl group at the position of the heterocyclic nucleus, like derivative 13, although in other positions.As far as lipophilicity is concerned, the results indicate that the most lipophilic compounds (compounds 12 and 15) are those with the least cytotoxic capacity against HT-29 cells in vitro.These results are of interest for the design of new compounds in order to be able to optimize the results.Thus, within these cyclic derivatives of resveratrol, compound 8 can be considered a hit for the design of new compounds with potential activity against HT-29 colon cancer cells.

Determination of KRas activity
The substituted benzofurans 8-9 and indoles 12-13 were selected by the Eli Lilly Laboratory (Indianapolis, USA) and submitted for biological testing to evaluate their therapeutical activities.
The KRas synthetic lethal phenotypic module measures survival in colon cancer cells with mutations that activate both Wnt and KRas oncogene signaling, based on the effect of synthetic lethality, to identify compounds that inhibit colon cancer formation with KRas mutations [16].The KRas mutation is detected in 35-42% of colon carcinoma and also in advanced adenomas [17].Many scientific works emphasize that the development of colon cancer is due to an activation of the two pathways, KRas and Wnt.It has also been shown that the two previous pathways can participate in the regulation of vascular endothelial growth factor [18,19].
Compounds 8, 9, 12 and 13 have been tested in in vitro assays and 8, 9 and 12 show significant growth inhibition of human colorectal HCT116 cancer cells (KRas mutant) at 20 μM (Table 3).IC 50 : Concentration that causes 50% inhibition in an MTT assay.Data are expressed as the mean ± SE from the dose-response curves of three independent experiments.P < 0.005, significant difference compared to the control.Log P (Partition Coefficient) was determined using ChemDraw 20.0.IC 50 : Concentration that causes 50% inhibition in an MTT assay.Data are expressed as the mean ± SE from the dose-response curves of three independent experiments.P < 0.005, significant difference compared to the control.Log P (Partition Coefficient) was determined using ChemDraw 20.0.
L. Grau et al.According to the results, the four tested resveratrol analogues have a low to moderate K-Ras activity depending on the cancer cell line.The benzofurans 8 and 9 have a moderate K-Ras activity on the RKO KRas SL cell line and low or no activity on the other cancer cell lines (Table 3).The trihydroxyphenyl group of 9 does not bring a better K-Ras activity compared to the trimethoxyphenyl group of 8, which suggests that neither the polarity nor the geometry of this moiety are decisive for its K-Ras activity.The arylindole 12 has an interesting K-Ras activity on HCT KRas SL, RKO KRasSL and SNU-C1 KRas SL cell lines.Compound 13 has a moderate K-Ras activity on Colo 320 KRas SL and SNU-C1 KRas SL.The difference of activity of 12 and 13 suggests that the benzyl group is important for the selectivity of these compounds between the different colon cell lines.These results show that the benzyl group produces an increase in lipophilicity and can modify behavior.The substituted indole 12 has nearly the same K-Ras activity on RKO Kras SL at high and low concentration, which suggests that its activity is not dose-dependent.Resveratrol tested under these conditions shows inhibitions of less than 15% (Table 3).No correlation was found between lipophilicity and the biological activity exhibited by these structural derivatives of resveratrol.

Determination of anti-angiogenesis activity
It appears that the process of angiogenesis is independent of the KRas gene status.But the process of tumor angiogenesis as well as the role of KRas arouse great interest in attempts to improve the treatment of colorectal cancer.The vascular endothelial growth factor (VEGF) pathway is critical for the regulation of angiogenesis, and research has focused on developing agents that selectively inhibit it [20].So, both the KRas protein and VEGF are considered good targets for the development of chemotherapeutic agents (Table 4).
Results of the four cyclic resveratrol analogues showed that only 13 has a significant anti-angiogenesis activity.None of them have a significant osteoporosis activity (Table 4).
According to the results obtained, it is clear that free hydroxyl groups would not be necessary to show activity on KRas-Wnt, since 8 and 9 show very similar results.
The K-Ras, antiangiogenesis and antiosteoporosis activity of these resveratrol analogues were compared with the activities shown by resveratrol (1) under the same conditions tested, which did not show activity in any of these targets.
Within the biological study carried out by Eli Lilly laboratories, compounds 8, 9, 12 and 13 were also tested against the target HNNMT and it should be noted that only compound 9 showed a significant inhibition of a cancer-associated metabolic to enzyme nicotinamide-Nmethyltransferase (HNNMT) (Inhibition of HNNMT = 77% at 10 μM, results not indicated in the Tables).This protein is a metabolic enzyme that catalyzes the transfer of methyl groups using S-adenosyl-L-methionine and its overexpression is associated with resistance to chemotherapy and radiotherapy and tumor aggressiveness [21].

Determination of CGRP antagonist activity
On the other hand, calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide produced by alternative splicing of the calcitonin gene [22].CGRP is widely distributed in the nervous system, particularly in anatomical structures possibly involved in the pathophysiology of migraine, including the trigeminus-vascular system.Over the last two decades, the body of clinical and basic science studies have established the pivotal role of CGRP in migraine [23].CGRP increases sensitivity to sensory stimuli at multiple levels, both in the central nervous and in the peripheral systems.In the brain, the wide distribution of CGRP and its receptors indicates several possible sites in which this peptide acts as a neuromodulator.Currently, CGRP has emerged as a therapeutic target for new treatments of migraine.This peptide is elevated in migraine and its antagonists have an application for migraine attacks.
The benzofurans 8 and 9 exhibit CGRP inhibitory activities at concentrations of 30 μM, without showing a significant difference between them.When it decreases to 12.5 μM (secondary test) only the analog with the trimethoxyphenyl group 8 shows a slight inhibitory activity, so that this nucleus is favored over trihydroxyphenyl nuclei, which could be attributed to the increase in lipophilicity (Table 5).Under these conditions, cyclic derivatives 8 and 9 show better results than resveratrol.

Determination of inhibition of tau protein
Tau protein is abundant in the central nervous system, while it is not as common in other parts of the body.It is mostly expressed in neurons, but has also been detected in astrocytes and oligodendrocytes.Tau belongs to the group of microtubule-associated proteins (MAPs) and their isomeric forms are the result of the alternative splicing of a single gene called MAPT (Microtubule Associated Protein Tau).The function of the Tau protein is to stabilize the microtubules present in the cells [24,25].
Los benzofurans 8 and 9 showed an inhibition of 58 and 55% of Tau protein respectively at concentrations of 40 μM (Table 6).As in the previous case, there is no difference between the phenolic compound and the methylated derivative with respect to the inhibition of the Tau protein.Tau are very rare prionoid microtubular proteins outside the central nervous system.Their main function is to stabilize the axonal microtubules through interaction with tubulin.However, when kinesin adheres to tau protein strips, the motor tends to come off the microtubule completely.In this way, tau protein helps regulate the balance of nerve cell trafficking, We do not have bioavailability results of the synthesized compounds, but it is expected that those compounds that have totally or partially methoxylated phenol groups have better bioavailability than resveratrol.

Conclusion
New resveratrol analogues 2-7 and 8-15 were successfully prepared.Arylbenzofurans were prepared by condensation of the aldehyde with the appropriate phenylacetic acid under Perkin-reaction conditions and subsequent hydrolysis and cyclization of the intermediate lactone, while indole derivatives were synthesized from 2-bromoarylethanone and the corresponding aniline under Bischler-Möhlau reaction conditions.The pharmacokinetic problems that condition the poor bioavailability of resveratrol limit its possible applications.For this reason, the study of analogous compounds that maintain a broad profile of therapeutic activities is of interest.The methylated derivatives (2, 4), the trialcohol or the triester 6 have shown a significant decrease in the growth of human colon cancer tumor cells (HT-29) and also of the pancreatic carcinoma cell line (MIA PaCa-2) and much higher than that caused by (E)-resveratrol.The benzofuran derivatives 8, 9 and the indolic derivative 12 have shown marked cytotoxic activity against HCT116 (KRas mutant) at 20 μM in vitro.While 13 showed a high antiangiogenesis character at 10 mM, benzofurans 8 and 9 exhibited inhibition of CGRP and Tau protein.The activity results obtained show that compounds and 9 show activity against different biological targets and could be considered potential candidates in cancer drug discovery for study and optimization.With the results that we have among the cyclic analogues derived from resveratrol, arylbenzofuran 8 presents a multitarget profile and could be considered a hit for the design of new compounds with potential activity against colon cancer.

General chemical synthesis
Melting points (mp) were obtained on an MFB-595010M Gallenkamp apparatus with digital thermometer in open capillary tubes and are reported without correction.IR spectra were obtained using FTIR Perkin-Elmer 1600 Infrared Spectrophotometer. 1 H and 13 C NMR spectra were recorded on a Brucker or Varian Gemini-300 and 400 (75.5 and 100.6 MHz respectively).Chemical shifts are reported in parts per million (ppm) relative to the central peak of the solvent: CDCl 3 (δ, 7.26 ( 1 H) and 77.16 ( 13 C)), CD 3 OD (δ, 3.31 (H) and 49.45 (C)), DMSO-d 6 (δ, 2.49 (H) and 39.51 (C)) as internal standards.The following abbreviations are used for the proton spectra multiplicities: s, singlet, d, doublet, t, triplet, q, quadruplet, m, multiplet.Coupling constants (J) are reported in Hertz (Hz).The reactions were monitored by thin-layer chromatography (TLC) analysis using silica gel (60 F254, Merck) plates.Compounds were visualized by UV irradiation.Column chromatography was performed with silica gel 60 (230-400 mesh, 0.040-0.063mm) and automatic column chromatography was performed with a CombiFlash R f system with UV-vis (PN 68-5230-008) detector and RediSep R f 4 and 12 g silica gel column.Elemental analysis C, H, N were realized at Serveis Cientifico-Tècnics UB on organic analyzer Thermo EA Flash 2000 (Thermo Scientific Apparatus).High-resolution mass spectra (HRMS) were performed on a LC/MSD-TOF (2006) (Agilent technologies) by the «Section of spectrometry of masses » at the University of Barcelona.All reagents were of high quality or were purified before use.Organic solvents were of analytical grade or were purified by standard procedures.Huh7: human hepatocyte cell lines.SP: Single Point.

-phenylene)bis) oxy))bis(ethan-1-ol) (5).
Resveratrol (1 g, 4.381 mmol, 1 eq) was introduced into a 100 mL capacity flask equipped with magnetic stirring and previously flamed under an argon atmosphere and dissolved in 30 mL acetone, then anhydrous potassium carbonate (3.6 g, 26.043 mmol, 12 eq) was added to the solution.The mixture was cooled with an external ice bath, then bromoethanol (3 mL, d = 1.763 g/mL, 42.274 mmol, excess) was added.The mixture was left to react at room temperature for 30 days, adding 0.3 mL (4.227 mmol) of alkylating agent every 3 days.Thin layer chromatography shows that after three days of reaction there was still mostly starting product and that monoalkylation product was formed.More alkylating agent (0.3 mL, d = 1.763 g/mL, 4.227 mmol) was added on reaction days 3, 5 and 14.On day 14 of the reaction, another six equivalents of potassium carbonate and 50 mL of ethanol were also added to improve the solubility of the mono-and dialkylated products and thus favor their reactivity.The solvent was evaporated to dryness on a rotary evaporator under vacuum and the residue obtained was dissolved in ethyl acetate and washed three times with an acidic aqueous solution (1 N HCl).The organic phase was dried over anhydrous sodium sulfate, which was subsequently filtered and the solvent was evaporated to dryness on a rotary evaporator.The residue obtained was purified by silica gel column chromatography using mixtures of hexane/ethyl acetate and ethyl acetate/methanol of increasing polarity as eluents.The compound 5 eluted with a polarity of 100% ethyl acetate and a white gummy solid is obtained (110 mg, 7% yield).R f : 0,095 (hexane/ethyl acetate (3:7)).mp: 100-102 • C (hexane/ethyl acetate).NMR 1 H (CDCl 3 , 400 MHz) δ( ppm (

E)-5-(4-(Pivaloyloxy)styryl)-1,3-phenylenebis(2,2-dimethylpropanoate) (6).
Resveratrol (1) (0.1 g, 0.438 mmol, 1 eq) suspended in 15 mL of dichloromethane was introduced into a 100 mL flask equipped with magnetic stirring.Anhydrous potassium carbonate (0.302 g, 2.190 mmol, 5 eq) was then added and cooled with an external water and ice bath.Pivaloyl chloride (0.324 mL, d = 0.979 g/mL, 5.256 mmol, 12 eq) was also added and the mixture allowed to react at room temperature for 16 h.After this time a reaction control was performed by thin layer chromatography and the starting product was observed but not the final product.The reaction crude showed a white precipitate corresponding to the unreacted starting material.In order to improve the solubility of resveratrol, anhydrous acetone (15 mL) and excess of triethylamine (5 mL, d = 0.726 g/mL, 35.87 mmol) were added and allowed to react for 24 h.The solvent was evaporated to dryness on a rotary evaporator with the aid of vacuum and the remaining residue was extracted with diethyl ether (3 × 15 mL) and distilled water (15 mL).The organic phases were combined and washed with 2 N NaOH (2 × 15 mL) and then dried over anhydrous Na 2 SO 4 , which was filtered and the solvent was evaporated to dryness.The crude reaction was purified by column chromatography on silica gel in CombiFlash® Rf using mixtures of hexane and ethyl acetate of increasing polarity as eluents.The final product, a white solid, eluted with a polarity of hexane/EtOAc (86:14).(0.289 mmol, 138 mg, 66% yield).R f : 0.55 (hexane/EtOAc ( 9 (E)-5-(4-(Dodecanoyloxy)styryl-1,3-phenylene didodecanoate (7).Resveratrol (0.1 g, 0.438 mmol, 1 eq) dissolved in 15 mL of acetone was introduced into a 50 mL flask equipped with magnetic stirring and previously flamed under argon atmosphere.Triethylamine (0.3 mL, d = 0.726 g/mL, 2.190 mmol, 5 eq) was added and allowed to react at room temperature for 10 min.It was then cooled with an external water and ice bath and dodecanoyl chloride (0.625 mL, d = 0.92 g/mL, 2.628 mmol, 6 eq) was added.The mixture was allowed to react at room temperature for four days.The white precipitate formed was filtered by gravity and the solvent was evaporated to dryness until a yellow oil is obtained.The NMR-1 H spectrum showed that the residue contains the final product but also dodecanoyl chloride.In order to remove it, it was washed with water and 2 N NaOH, but the product was not completely purified.Acid chloride could not be removed by hydrolysis as the ester of the final product was also unstable under these conditions.

OIDD Lilly tests
The Lilly tests (KRas inhibition and antiangiogenesis activities) were carried out according the procedures indicated in the OIDD-Lilly program (Open Innovation Drug Discovery -Eli Lilly) (https://openinnovati on.lilly.com)[27].

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Table 3
KRas inhibition by resveratrol 1 and analogues 8

Table 6
Inhibition of Tau protein of compounds 8 and 9.