Part3: Tailored Functionalization Of Natural Phenols To Improve Biological Activity

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5. Lipidic Phenols

Lipidic phenols (or phenolic lipids, also called phenolipids) are phenols substituted with lipophilic chains, that confer to the molecule amphiphilic characteristics. An important phenolic lipid is α-tocoferol[330]; however, this compound alone deserves a review, so it has not been included.

The importance of natural lipidic phenols has been underestimated for a long time [331]. However, their excellent antioxidant, antigenotoxic, and cytostatic properties are now established [332], together with their bioactivity in influencing biological pathways involved in Alzheimer's disease pathogenesis 333]. Anti-inflammatory and anti-arthritis activities were also reported for lipidic phenols extracted from cashew nut(Anacardium occidentale) [334].

Because of the importance of such a class of compounds, several synthetic lipidic phenols have been proposed in recent decades to further extend their biological applications.

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5.1. Biocatalyzed Syntheses of Lipidic Phenols

Lipases are the enzymes of choice to perform transesterification reactions to obtain modified or synthetic lipids, with functional or pharmaceutical applications [335,336]. A large number of esters from catechol and fatty acids were prepared to stir a suspension of catechol in ethyl ester of a fatty acid [337].

Semisynthetic lipidic phenols were prepared by transesterifications reactions of phenolic acids with flaxseed oil [338,339], olein [340], fish liver oil [341], and krill oil [342]. The reactions, performed in organic solvents or in a solvent-free system [343,344], were catalyzed by Novozym 435 isolated by Candida Antarctica(Scheme 33).

More recently, yields improved using supercritical carbon dioxide as the reaction medium [345]. The prepared mixtures of lipidic phenols were tested for antioxidant activity. The obtained radical scavenging activity ranged from moderate to good, but it was always lower than that of α-tocopherol. Moreover, being obtained from mixtures, the results could not be attributed to a single compound.

Conversely, pure phenolic lipids of varying chain-length fatty acids were prepared with ferulic acid [346]. The synthesis involved a bio-catalyzed step (by Nosozyme)(Scheme 34).

The antioxidant activity investigation gave mixed results because the radical scavenging assay showed no improvement with respect to ferulic acid, while autoxidation of linoleic acid in a micellar system showed some improvement, attributed to increased solubility.

Chemo-enzymatic synthesis of phosphatidylcholines containing phenolic acid and fatty acids was reported [347], with one of the active derivatives, 1-(4-hydroxy-3,5-dimethoxy)cinnamoyl-2-acyl-sn-glycerol-3-phosphocholine, showing excellent antioxidant activity.

A different approach was to obtain lipidic phenols from a phenol and free fatty acids or the corresponding esters, with immobilized lipase from Candida Antarctica as the biocatalyst [348]. The antioxidant activity of tyrosol was increased upon acylation, but no correlation was found with the number of double bonds in the fatty acyl group (Scheme 35).

Some esters were synthesized from natural phenols and α-lipoic acid in a reaction catalyzed by Novozym 435(the immobilized lipase B from Candida Antarctica)in a butanone-hexane mixture [349]. The antioxidant activity was determined not only by radical scavenging assay but also by measuring the inhibition of the oxidation in a tuna fish oil emulsion. The ester 2-(3,4-dihydroxyphenyl)ethyl-5-(1,2-dithiolan-3-yl)pentanoate, obtained from tyrosol and α-lipoic acid, followed by aromatic hydroxylation (Scheme36), showed excellent antioxidant activity in both tests and, according to the authors, it may be used as pro-drug, because, upon hydrolysis, it releases compounds which are non-toxic or even healthy.

Later, it was found that 2-S-lipoyl caffeic acid methyl ester was an inhibitor of tyrosinase from human melanoma cells [350].

The goal to prepare a single lipidic phenol, avoiding troublesome separation of a complicated mixture, was achieved by a multi-step strategy involving both chemical and enzymatic catalysis. Immobilized lipase from Candida Antarctica(CAL-B)was used in an organic medium [351] (Scheme 37).

After characterization, the prepared 1-[11-(ferulyloxy)undecanoyl)glycerol under-went antimicrobial, antioxidant and cytotoxic studies. The antimicrobial activity was moderate, the antioxidant activity was excellent and activity against some cancer cell lines was promising, so the authors predicted potential cosmetic and biomedical applications.

Transesterification reaction using Candida Antarctica lipase B was performed, treating 4-hydroxyphenyl acetic acid with triolein and with fish oil, obtaining synthetic substances that have both antioxidant and antibacterial activity [352].

5.2. Chemical Syntheses of Lipidic Phenols

Lipidic phenols were prepared as esters, either from phenols with long-chain carboxylic acids or from phenolic acids. Selected examples of synthetic lipidic phenols are reported in Table 1.

Anacardic acid, from fresh and dry cashew nuts of Anacardium occidentale, was trans-formed into isobenzofuranones, as illustrated in Scheme 38, with an alcohol(A) or keto (K)functionality in the long-chain [360].

Both isobenzofuranones A and K, as well as the acyclic precursor, were moderate to significantly active in cytotoxicity screening with different human cancer cell lines.

A good antioxidant ability to stabilize olive oil was observed with a family of phenolic fatty acid esters, prepared from 3,4-dihydroxy benzoyl alcohol (protocatechuic alcohol) or hydroxytyrosol and fatty acids. The reaction was performed in anhydrous THF, in the presence of a carbodiimide and DMAP[361]. All twenty compounds were investigated as potential antioxidants in refined olive oil. The length of the alkyl chain attached to the phenyl ring seems to influence the activity.

Following the finding that 5-alkyl- and 5-alkylresorcinols, isolated from the mush-room Merulius incarnates, inhibited methicillin-resistant Staphylococcus aureus [362], a good synthetic method was necessary, because they are not readily available, but are important for analytical, metabolic, and bioactivity studies. A general method, based on the Wittig reaction, was developed [363] to overcome the problem of alkyl chain introduction into the aromatic ring. The problem was solved by reacting long-chain alkanols, when available, with semi-stabilized benzylphosphoniumyilids or, alternatively 3,5-dimethoxybenzenecarbaldehyde with alkyl phosphonium ylids. The procedure delivered 5-alkylresorcinols with alkyl chains up to 25 C atoms. The reaction was performed in water or a water-DMSO mixture, with MW irradiation, in pressurized or in an open vessel. One example for each route is shown in Scheme 39.

Moderate to good in vitro antioxidant activity was shown by 1,2-dibutanoyloxy-2-(4-hydroxy-3-methoxyphenyl)ethyl butanoate, a lipidic phenol obtained from ferulic acid [354].

2-Methyl-5-[(2Z)-non-2-en-1-yl]benzene-13-diol and 5-[(2Z)-non-2-en-1-yl]benzene-1,2,3-triol were prepared as synthetic derivatives of the natural5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol (climacostol), a defence chemical in protozoan Climacostomum virens[355]. The structural modifications in the aromatic ring (a methyl and a hydroxylgroup, respectively) increased the toxicity.

Long-chain alkyl hydroxycinnamates were prepared from the corresponding monoesters of malonic acid and benzaldehyde derivatives by Knoevenagel condensation [364]. The observed antioxidant activity followed the order caffeic esters > sinapic esters >ferulic esters.

12-Hydroxy-9-octadecanoic acid (ricinoleic acid) was transformed in (Z)-methyl-12-aminooctadeca-9-enoate and then reacted with phenolic acids, forming the corresponding amides [356]. The investigated antioxidant activity indicated that modification of phenolic acids with lipophilic moieties improves their antioxidant and anticancer properties.

It is worth signaling a conceptually different type of lipidic phenols, namely the phenyl sulfonyl furoxan derivatives of caffeic and other phenolic acids [357]. Besides good antioxidant activities in vivo, these compounds showed anticoagulant and vasodilatation effects that were attributed to the NO-releasing ability.

Caffeic or 3,4-dimethylcaffeic acids were reacted with malic acid and then coupled with monoglycerides of fatty acids with chain lengths ranging from 8 to 18 C atoms [359]. The combinations of phenolic and fatty acids gave a series of six amphiphilic compounds that were tested for activity. They proved to be non-toxic and gave stable oil-in-water emulsions, with potential for food, pharmaceutical, and cosmetic industry applications, according to the authors.

6. Polyphenols

Natural polyphenols constitute a numerous and largely distributed group of bioactive molecules in edible plants, with bioactivities ranging from cardiovascular protection to prevention of cancer [365-368].

Polyphenols are characterized by the presence of a benzo-fused heteroaromatic ring of the pyrene or Pyridium type. They are usually named by a semi-systematic nomenclature, based on the parent heterocycle. Thus, benzopyrene derivatives with a phenyl substituent are named flavones, while phenol substituted benzophenones are indicated as flavones The structures of parent compounds and their phenyl derivatives are collected in Figure 9.

The synthesis of natural and semi-synthetic highly oxidized bioactive polyphenols was reviewed in 2008, discussing advances and challenges [369]. Alternatively, more efficient and sustainable production may come from microbial cell factories, as reviewed in 2018 [370].

Chemical transformations of natural phenols might lead to more effective species if structural features at the basis of biological activity are understood. Thus, results of chemical modifications for representative polyphenols are reported in the following.

6.1.Phenols from Chroman

Catechin is a polyphenol of the flavanol family that can be found in green tea. Derivatives reported in Figure 10 were prepared from racemic catechin(tetra methoxy, pentaacetoxy, and cyclic)[371]. Catechin and the derivatives were tested for antimicrobial activity against root-colonizing fungi, which was maintained, although with lower efficiency, in the less polar compounds.

The antioxidative radical scavenging of (+)-catechin, probed against the galvinoxyl radical, is enhanced upon reaction with ninhydrin [374].

To address the problem of increasing resistance of microorganisms, studies were aimed at preparing and testing synthetic derivatives of catechin. The systematic etherification of the 3-hydroxyl groups with linear alkyl chains of different lengths or with substituted benzyl groups gave a library of 3-O-alkyl analogs of catechin [372] that were used to test the antifungal activity as a function of the structure. Compounds with longer chains(C14-C16)exhibited weaker activities than compounds with C8-C12 chains.

Moreover, varying the -OH functionality in 3, twelve derivatives of(-)-catechin were prepared [373]. Only three compounds showed antibacterial and antifungal activity higher than that of the standard drugs (neomycin and miconazole). Molecular docking studies agreed with experimental results.

Brazilin and the oxidized analog brazilein (Figure 11)are chromane derivatives found in plants(Caesalpinia sappan L.), known for their anti-inflammatory properties. Novel synthetic derivatives were prepared to explore their antitumor activity. The synthesis of Brazilians [375] was achieved starting from 1,3-dihydroxybenzene (resorcinol) and 3-chloropropanoic acid, with the formation of the key intermediate 7-hydroxy-4-chromanone. The synthesized Brazilians (Figure 1l) were tested for anti-inflammatory effects against a number of human cancer cell lines, but only some of the synthetic derivatives showed some improvement with respect to the unsubstituted brazilein.

6.2. Phenols from Chromen

Coumarin (2H-chromen-2-one), the most common derivative of chromen, and substituted coumarins are found in green plants, where they exert different actions [377].

Considering the versatility of reactions leading to coumarin heterocyclessystem [378, a number of substituted coumarins were synthesized and promising activity was found with coumarin-fused 14A-thiazepines, synthesized starting from 4-hydroxycoumarins(Scheme 40)[379].

Coumarins and benzocoumarins substituted with a hydroxyl group in 7-or 8- positions were prepared and tested in vitro for a number of biological activities [380]. Generally, they delivered potent superoxide anion scavengers and inhibited in vitro lipid peroxidation; on the other hand, they did not show significant lipoxygenase inhibitory activity.

6.3.Phenols from Chromon

Quercetin (3,3'4',5,7-pentahydroxyflavone) is a flavonol largely present in plants, foods, and beverages, often together with fisetin (3,3'4',7-tetrahydroxyflavone).

The interest in quercetin was prompted by its anti-cancer, anti-inflammatory, and antioxidant roles. Particular relevance is offered by the anti-hypertensive effect [381]. Many synthetic derivatives were prepared with the aim to obtain anti-cancer candidates that might overcome quercetin problems:(i)low solubility in water,(ii)low bioavailability, and (ii) fast degradation. Studies on biological activity were not sufficient to assess the actual effectiveness of those derivatives, although some of them seemed promising [382]. On the other hand, simple complexation with Cu(I) gave a Cu(quercetin)(bipy) complex with enhanced antioxidant properties compared to free quercetin [383].

The interest in the therapeutic properties of quercetin and derivatives is not limited to cytotoxicity, as can be seen by the number of patents reported between 2010 and 2015 [384]. Selected meaningful examples are collected in Table 2.

Most of such derivatives involved transformations at all the hydroxyl groups, with the modification at the C-3-hydroxyl group resulting in enhancement of anticancer activity. Moreover, the bioactivity was significantly increased by nanotechnology.

The problem of scarce solubility in water of flavonoids polyphenols was addressed considering derivatives with hydrophilic substituents, such as sulfate [385].

A different approach was to prepare conjugates of sugars with flavonoid being the aglycone. Glucose, galactose, and rhamnose were used, inter alia.

Enzymatic synthesis was successful in modifying natural compounds yielding not only more soluble but also more efficient species in medicinal [386] or cosmeceutical[387]applications.

It is interesting that rutin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranosyloxy]-4H-chromen-4-one)was further transformed by enzymatic transesterification reaction into mono- and di-acetate derivatives (Scheme 41)with maintained anti-oxidant properties and more efficient ability to penetrate the cell membrane of murine macrophages [388]. Moreover, acetoxy-substituted rutins were not toxic to mammalian cells and the enzyme could be reused.

The importance of sugar-substituted flavonoids is exemplified by myricitrin (myricetin-3-O-α-L-rhamnopyranoside), whose anti-oxidant activity had a protective effect against DNA damage [389].

A novel flavonoid scaffold was prepared to introduce salicylate and trimethoxybenzene groups in flavonoids [390]. All the compounds were evaluated for antiproliferative activity against three human tumor cells showing moderate to good activity.

6.4.Phenols from 2,3-dihydrochromon

Among flavanones, secondary metabolites of plants with a broad spectrum of biological activities, pinstriping (5-hydroxy-7-methoxy-flavanone)received interest because it is the major component in the rhizome of fingerroot (Kaempferia pandurata), used in Southeast Asian cooking, known to have several pharmacological activities, among which the antimicrobial one is promising.

Allylation and prenylation of pinostrobin were performed using MW irradiation (Mitsunobu and metathesis reactions, Claisen and Cope rearrangements)(Scheme 42), giving compounds that were tested against a number of cancer cell lines [391]. The derivatives were more reactive than pinostrobin, a result that the authors attributed to a better interaction with the biological targets, due to the increased lipophilicity provided by alkenyl substituents.

Pinostribin was prenylated under simple SN2 conditions(Scheme 43), giving a mixture of products, most of which lost the flavanone structure. They were separated and tested for antimicrobial activity [392], showing a moderate effect. Interestingly, several prenylated coumarins and quercetins were isolated from the root bark of Broussonefia papyrifera as metabolites with, in some cases, cytotoxic activity [393].

Astilbin, a sugar derivative of the flavanol taxifolin, is extracted from herbal medicinal plants, commonly used in traditional Chinese medicine. However, for their possible pharmaceutical use, the astilbin available from extraction is not sufficient. An efficient process to obtain astilbin from taxifolin relied on microbial fermentation in genetically-engineered Escherichia coli (Scheme 44) [394].

A cascade biocatalytic system was developed to prepare the 4'-O-glucoside derivatives of naringenin (5,7-dihydroxy flavanone), a flavonoid with several bioactive effects, found in grapes and oranges [395]. The method relies on regenerating uridine diphosphate from sucrose and reusing it, performing also preparative scale production. By the same method, quercetin 7-O-a-L-rhamnoside was obtained.

Interestingly, myricitrin (myricetin-3-O-α-L-rhamnopyranoside)[389] and naringenin, present in extracts of Cynara cardunculus, a powerful natural herbicide, exhibited phytotoxic effects on the leaves of Trifolium incarnatum, opening the way to natural herbicides, a field increasingly important due to the increasing resistance of weeds to commonly used ones[396]. 

7. Curcumin and Curcuminoids

Curcumin, [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dionel, a yellow pigment isolated from turmeric(Curcuma longa Linn), is a multifunctional compound that, at least from reading the literature of the past twenty years, seems a sort of panacea for all the illness of modern society, cancer and Alzheimer's disease included. Phenolic-OH groups ensure the anti-oxidant properties, whereas the extensive conjugation due to the ketoenol equilibrium (Scheme 45)is the basis of photodynamic activity.

Several recent reviews discuss the aspects of biological activity [397-400] and possible medical applications [70,292,401-404] of curcumins and derivatives. Important aspects, such as new delivery methods and synergistic effects with other compounds, were also discussed, together with the mechanism of action [405]. An increasing interest is devoted to curcumin-based drugs against neurodegenerative diseases [406], especially Alzheimer's[407] and cancer [408].

The quest for new curcumin derivatives is motivated by (i) the necessity of increasing the material availability, and (i) the necessity of meliorating the solubility in an aqueous solution.

Notably, just treating curcumin with Cu(II), a Cu(curcumin)(bipy) complex was isolated and it was a better antioxidant and DNA binding compared to free curcumin while being less toxic, on the basis of its antifungal properties [383]. It was also reported that silver-curcumin nanoconjugates, prepared by a sonochemical method, were tested on skin cell lines and for antibacterial activity against Escherichia coli. Results indicated that silver nanoparticles were made biocompatible by curcumin, while they make curcumin more photostable and more active as an antibacterial [409].

We discuss curcumin derivatives according to structural changes. 

7.1. Minor Structural Changes

Small structural changes can alter the efficiency of curcumin bioactivity. For example, introducing one methyl group in position 2or two methyl groups, as in 2,7-dimethylcurcumin, enhanced anti-angiogenesis activity and suppression of tumor growth [410]were observed, together with increased anti-inflammatory activity[411] and stability against enzymatic reduction [412], with respect of curcumin.

Diacetylcurcumin, easily prepared by acetylation of the parent compound, showed excellent antibacterial activity [413] and it was effective in antiarthritic activity in mice (Table 3) [414].

The anti-oxidant activity of curcumin was compared with that of dimethoxy metabolites and of hydrogenated derivatives [415]. Results indicated that the saturated derivatives (tetrahydro-, hexahydro- and octahedron-coumarins) have increased antioxidant activity with respect to coumarin (Table 3).

The derivative obtained by the introduction of prenyl substituents in both aromatic rings was tested against oxidative stress[416](Table 3), showing equal or better antioxidant properties with respect to curcumin.

A more drastic substitution was performed, introducing electron-withdrawing substituents into benzene rings, or even condensing heterocycles (Table 3)[417].

7.2. Substituents in the UInsaturated Chain

Most the synthetic derivatives come from the introduction of substituents in position 4, thus affecting curcumin tautomeric equilibrium.Important bioactivity linked to the keto-enol equilibrium is the interaction with amyloid β(A)aggregation, present in Alzheimer's disease. An extensive investigation of keto-enol tautomeric equilibria in substituted curcumins was performed [432-434]. Recently, it was reported that 4,4-disubstituted curcumin (Figure 12), where the keto form is the only possible one, binds non-fibrillar soluble Aβ oligomers, becoming, as the authors state," a first-generation compound targeting Aβ oligomers"[435].

Fluorinated curcumin derivatives showed significant inhibition of the thioredoxin-interacting protein (TXNIP), which is associated with multiple diseases [418].

A number of curcumin derivatives substituted by acid or ester groups in position4 were prepared [436](Figure 13). Acidity, lipophilicity, and kinetic stability were determined, together with free radical scavenging activity, in order to evaluate any relationship between structure and activity. The ester derivatives exhibited selectivity against colon carcinoma cells, probably as a result of their higher lipophilicity thank curcumin.

A different approach was the introduction of an unsaturated moiety in position 4 (Table 3), by Knovenagel reaction with benzenecarbaldehyde,4-hydroxybenzaldehyde, and 4-hydroxy-3-methoxy-benzaldehyde (vanillin)419]. Obtained derivatives were tested for anti-malaria activity against P. falciparum, and the vanillin derivative was considerably potent.4-Benzylidene curcumins, prepared from 2-hydroxybenzenecarbaldehyde [420]and 4-benzylidenecurcumins, were investigated as anti-oxidant agents and both were effective in attenuating the cataract in cultured rat lenses.

7.3. Modification of the β-dicarbonyl Moiety

Eighteen new derivatives, still featuring the hepta-1,6-dien-3,5-dione structure of curcumin, but with one of the carbonyl groups incorporated into the cycloheptanone moiety, were synthesized by a versatile synthetic strategy [421]. One example of substituted tropinone is reported in Table 3. The authors are confident that the family of dicarbonyl curcumins with the tropane ring will have important activity since the simple monocarbonyltropanones were cytotoxic towards breast cancer cells.

A library of curcumin derivatives was obtained upon reaction with one or two equivalents of sulfonamides(chosen among sulfa drugs)(Scheme 46)[437]. Antibacterial and antifungal activities were evaluated against Gram-positive and Gram-negative microorganisms, with good results.

3,4-Dihydropyrimidin-2(1H)-one and thione analogs of curcumin (Table 3) were synthesized in good yield by a one-pot multi-component cyclo condensation under MW irradiation [425]. Antibacterial and antioxidant studies were performed in vitro with results considered by the authors"moderate" in the former case and"excellent" in the latter.

A pyrazole derivative of curcumin was prepared to try to incorporate in the same molecule the structural features of curcumin and of asteroid-like compound(cyclohexyl bisphenol A)[422]. The compound was found to be neuroprotective in cell culture assays, also against intracellular and extracellular amyloid. Moreover, it was found to possess memory-enhancing properties in a rat object recognition test [423].

7.4. Partial Replacement of the β-dicarbonyl Moiety

Partial replacing of the β-dicarbonyl moiety of curcumin was considered useful to overcome the problem of its unsatisfactory stability. A series of mono-carbonyl analogs of curcumin, synthesized from the opportunely substituted benzaldehyde and a cycloalkane [438-440]. The stability of the substituted cyclopentanones and cyclohexanones was enhanced in vitro. The cytotoxic activity was also higher with cyclohexanones, with remarkable importance of substituents electronic effects (Scheme 47).

The aminocarbonyl curcumin analogs were tested against pro-inflammatory cytokines, exhibiting a more potent inhibitory ability than curcumin.

Symmetrical bis(arylidene)ketones were prepared by reacting cycloalkanones with substituted benzaldehydes, in an acid-catalyzed aldolic condensation. Most of the synthesized compounds showed inhibition of ovarian cancer cell growth, even with cells resistant to cisplatin [441].

Several synthetic aminocarbonyl curcumin analogs were tested against Trichomonas vaginalis (considered the"most common non-viral sexually transmitted infection in the world")[442];15-diphenylpenta-1,4-diene-3-one,15-bis(2-chlorophenyl)Penta-1.4-diene-3-one and 2,6-bis(2-chlorobenzylidene)cyclohexanone presented significant antiparasitic activity at effective concentrations lower than that of curcumin.

More recently, a first, but very promising, the result was obtained with (2E,6E)-2,6-bis(2(trifluoromethyl)benzylidene)cyclohexanone, which was found to heal the diabetic wounds in mice [426] (Table 3).

A dozen curcumin aminocarbonyl analogs were synthesized, in order to find compounds with increased chemical stability and, eventually, better anticancer activity against some human cancer cells [427]. Two of them (Table 3) met the requirements and were successively tested against melanoma cells, resulting in selectively toxic428].

New curcuminoids incorporating 4H-pyran heterocycles were prepared by one-pot condensation of curcumin with propanodinitrile and a substituted benzenecarbaldehyde (Scheme 48)[443]. The consequent modification of β-dicarbonyl moiety improved inhibition of the α-glucosidase, one of the enzymes responsible for carbohydrate hydrolyses and therefore for postprandial hyperglycemia. This feature, together with antioxidant activity, has possible beneficial consequences against diabetes mellitus, especially because no toxic effect was observed on the common human intestine microflora.

7.5. Reducing the Length of Unsaturated Chain

A curcumin analogue, 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)Penta-2,4-diene-1-one showed anti-inflammatory activity in mice(Table3)[429]. Similar com-pounds with the same skeleton were used to establish the importance of reactive oxygen species upregulation in the suppression of tumorigenesis[444]. According to the authors, these compounds are promising for the development of an anti-cancer drug with few side effects.

A similar but shorter compound, (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenyl prop-2-ene-1-one, was prepared to start from 2-hydroxyphenyl methyl ketone and benzoyl

chloride (Scheme 49). The resulting molecule showed selective cytotoxicity on breast cancer MCF-7 cells [445], human colon cancer cell lines [446] and human osteosarcoma cells[447].

7.6. Derioatioes with Only "Half" of the Curcumin Structure

A family of compounds, named by the authors retro-curcuminoids, was prepared to maintain only"half" of the curcumin structure (Scheme 50), because the β-dicarbonyl moiety was considered responsible for curcumin scarce stability [448]. The resulting compounds showed relevant cytotoxic activity against human cancer cell lines, but they did not injure healthy cells.

A synthetic amide analog showed anti-oxidative and anti-inflammatory properties. It was tested with good results on hepatic steatosis in mice with induced obesity [430](Table 3).

A library of curcumin-resveratrol hybrids was synthesized starting from the hydrazide derivative of substituted cinnamic acid and a series of substituted benzaldehydes [449]. The example illustrated in Scheme 51 refers to the most promising hybrid as an antitumor multi-target agent.

7.7. Photosensitizers

Curcumin might be an excellent photosensitizer, due to its good biocompatibility, but the practical use is strongly limited by its low stability and scarce solubility in water. A solution was searched preparing curcumin derivatives with cationic substituents [450](Figure 14).

All the derivatives showed high stability with pH and temperature. As to photodynamic properties, they were able to promote photodynamic inactivation of E.coli, with the Hexa-cationic species being the most effective, probably because of the high hydrophilicity.

A comparative study was performed on different curcumin derivatives synthesized ad hoc, with the aim to increase the tissue penetration, increasing the absorption maximum. Thus,1,11-diphenyl-1,3,8,10-undecatetraene-57-dione and 1,7-bis(4'-dimethylaminophenyl)-1,6-heptadienyl-3,5-dione presented promising characteristics in terms of generating reactive oxygen species and, therefore, of efficacy in photodynamic therapy [431]. 8. Conclusions

Natural phenols and their derivatives with biological activities constitute a fast-growing research topic, in view of their many presents and future applications. Their structural diversity offers many possibilities of chemical transformations, aimed at overcoming the drawbacks of natural phenols. However, apart from some guidelines that emerged from the huge number of publications, such as the need to meliorate stability and bioavailability of the bioactive compounds, the picture of structural requirements is not yet complete, in view of optimizing in vivo and in-field applications.