ES2651114B2 - Carbosilane dendrimers with polyphenolic groups and their uses - Google Patents

Abstract

Derbrímeros carbosilanos with polyphenolic groups and their uses. In the present invention dendrimers of carbosilane nature are described which contain polyphenolic groups in their structures. # Furthermore, the invention relates to its method of obtaining and its uses as antioxidant agents (radical scavengers) and antitumor agents for use in the cosmetic industry and pharmaceutical industry.

Description

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DESCRIPTION

CARBOSILAN DENDRÍMEROS WITH POLYPHENOLIC GROUPS AND ITS USES

The present invention relates to dendritic macromolecules containing a skeleton of a carbosilane nature and having in its structure polyphenolic groups (GPF). The compounds of the invention are potent antioxidant agents and free radical scavengers and are thus useful for application in the following sectors of activity: cosmetic industry and pharmaceutical industry.

STATE OF THE PREVIOUS TECHNIQUE

Oxidative stress is a cellular phenomenon produced by the imbalance between prooxidant and antioxidant species. This term is the basis of Denham Harman's theory, postulated in 1956.1 that blames the causes of aging on reactive oxygen species (ROS) produced in the mitochondria.

ROS are oxygenated free radicals that occur mostly in the mitochondria because 98% of the Ü2 that reaches the cells is directed to this organelle. In it, through the electronic transfer chain, oxygen is reduced with four electrons and protons to water. However, in certain cases an incomplete reduction can occur that results in the formation of superoxide radical (0.2 *), hydrogen peroxide (H2O2) and hydroxyl radical (OH *) .2 These compounds are excessively reactive, producing mutations in biological macromolecules.

The damage produced by these compounds arises at different levels, mainly in DNA, lipids and proteins. As for the DNA, the modifications that these species produce, lead to problems in the expression of many proteins, among which the enzymatic complexes I and IV of the electronic transfer chain that cause a considerable decrease in ATP.3 stand out.3 The lack of energy, in turn, triggers a biological response that increases the amount of ROS produced.

In addition, not only ROS are produced due to metabolic activity. External and environmental factors such as pollution, tobacco and exposure to ionizing radiation are risk factors that increase the concentration of free radicals due to cellular damage caused, above all, at the genomic level.

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The accumulation of these dysfunctions caused by oxidative stress has been linked, in recent years, to diseases such as cancer, atherosclerosis, Parkinson's or Alzheimer's disease.4 * 6

As a defense against the action of these compounds, the cell has developed several mechanisms capable of eliminating excess ROS and one of them is the generation of antioxidant species. One way to classify these antioxidant agents is, depending on the way they act, by dividing into enzymatic and non-enzymatic. Among the former, superoxide dismutase, catalase and glutathione peroxidase stand out, which together reduce the superoxide radical to water. Non-enzymatic systems comprise a very large number of organic compounds capable of reacting directly with ROS by stabilizing the radicals and reducing their activity. Within non-enzymatic systems, one of the most important families are polyphenolic derivatives, which are generated in the secondary metabolism of plants, and can be found actively in foods such as fruits (red grapes, raspberries, blueberries, strawberries. ..) and vegetables (broccoli, tomato, peppers, spinach ...). In addition, they are also very present in tea, cocoa and olive oil.7 8

In recent years, polyphenols have gained great interest for their beneficial properties for health, for their important antioxidant capacity in their action to combat oxidative stress produced by free radicals, which improves the performance and protection of cells. Thus, they have been attributed beneficial effects in the prevention of both functional and structural alterations and against the development of various diseases (cancer, cardiovascular diseases and neurodegenerative diseases) associated with an increase in the processes of cellular oxidation. 9 * 12

Polyphenols are chemical compounds that have at least one aromatic ring to which one or more hydroxyl groups are attached. There are thousands of polyphenols classified in families and subfamilies such as catechins, tannins, flavonoids, anthocyanins, stilbenes, lignans.

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In addition to their incredible antioxidant abilities, polyphenols display great potential as anti-inflammatory agents by inhibiting the NF-Kappa-B factor, as antiglycans, reducing the harmful effect of sugars on proteins, and as a longevity enhancer.13 However, the The main drawback of using polyphenols is their short half-life and low bioavailability.14 It is therefore necessary to develop controlled release systems of bioactive molecules that act as transporters throughout the body, providing them with greater stability against degradation, and facilitating its diffusion through biological barriers and, therefore, access to target cells. Within this type of systems, dendritic polymers are a new class of macromolecules that have well-defined properties that make them very interesting materials for applications in nanomedicine and nanotechnology.15'18 Among them are dendrimers of monodisperse structure and whose synthesis It allows a high control of its structure. 19‘21

Due to their properties, dendrimers can be applied in different fields of science such as nanoscale catalysis, chemical sensors, unimolecular micelles, imitation of the function of enzymes, encapsulation of molecules, molecular recognition, diagnostic agents and also as vehicles for the transport of genes and drugs, electrochemistry or cosmetics, among others. Excellent reviews that include all these applications are published in the literature.21'27 Dendrimers are ideal systems to increase the solubility and increase the lifetime of various drugs or bioactive molecules, as they pass through certain tissues, improving transit across biological barriers. 28,29

Recently, dendrimers have been described that have polyphenoic groups (GPF) in their structure, which are capable of giving characteristic properties to the dendritic molecule by functionalizing its surface, so that they can act as potent antioxidants and free radical scavengers and of this In this way they are useful for their application in the sectors of activity both in the cosmetic industry and in the pharmaceutical industry.

However, there are not many dendritic systems that contain terminal polyphenoic groups described in the literature to date.30'32 Among the different dendritic skeletons described in the literature, those of carbosilane nature have turned out to be

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very interesting due to its applications in biomedicine as transport agents of nucleic material and / or drugs, as antibacterial, anticancer or antiviral agents among others.33'37

Dendrimers of carbosilane nature with polyphenolic groups in their structure of the present invention represent an interesting alternative for use in the pharmaceutical and / or cosmetic industry.

DESCRIPTION OF THE INVENTION

The present invention gives rise to dendrimers of carbosilane structure, that is, they contain silicon-carbon bonds in their structure and functionalized on their periphery with phenolic groups (monohydroxy, dihydroxy or polyhydroxy). Dendrimer means those three-dimensional macromolecules of arborescent construction, spherical in nature, highly branched, synthesized from a polyfunctional nucleus. These compounds significantly improve the properties such as antioxidants, free radical scavengers, and anticancer agents of the phenolic compounds alone. The invention provides a method for obtaining it and its uses in different sectors of activity.

The compounds of the invention are useful in the cosmetic and pharmaceutical industry. In the cosmetic industry they can be used for the treatment of the skin as components of anti-aging creams, sun creams or as beauty products for hair. And in the pharmaceutical industry, these compounds may be used as new drugs or formulations containing them, for the prevention and treatment of neurodegenerative, tumor, cardiovascular diseases as well as being used as anti-inflammatory, antimicrobial or antiviral.

One aspect of the present invention relates to a carbosilane dendrimer with polyphenolic groups on the surface (hereinafter compound of the invention). By "carbosilane dendrimer" refers to a spherical branched macromolecule, where the dendrimer's growth nucleus is polyfunctional, the growth units, branches or branches have carbosilane skeleton and the outer layer, surface or periphery of the dendrimer incorporates functional groups. This surface or periphery would be the one corresponding to the extremities of the branches.

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• By "polyfunctional core" (Nu) in the present invention is meant a polyvalent element or compound covalently linked with at least two branches, that is, at least it must be divalent. In a preferred embodiment, the core is tetravalent and more preferably, the core is a silicon atom. However, the core can be any polyfunctional derivative from which it is possible to grow a dendrimer of a carbosilane nature, from those known to a person skilled in the art, such as and without limitation, a polyphenolic core, or an amino core or polyamine

• “External layer” means an external layer consisting of units equal to or different from the group of general formula I

X

Yes ---- KRO— ■ T — W] m

(^ 2) 3-111

(I)

"T = N = CH; NH-CH2; NHCO

where

* R R *

image 1

where:

- R, is an alkyl chain, or the following group Ri = - (CH2) z-S- (CH2) and- where "z" represents an integer ranging from 2 to 5; preferably "z" is 2 or 3; "Y" represents an integer that varies from 1 to 10; preferably between 1 and 5.

- R2 is a (C1-C4) alkyl group, preferably R2 is a methyl group;

- m is an integer that varies between 1 and 3, preferably m is 1;

- W is the polyphenolic terminal group, where at least one R * group is a hydroxyl group (-OH) and the rest of R * groups present in the molecule can be the same or different and are independently selected from hydroxyl (-OH ), hydrogen (H), (C1-C4) alkyl or methoxide (-OMe). Preferably R *, are hydroxyls. Preferably the polyphenolic groups will be derivatives of vanillin, gallic acid and ferulic acid.

- T is an imino group (-N = CH-); amino (-NH-CH2-), ammonium (- + NH2-CH2-) or amido (- NHCO-).

The term "alkyl" refers in the present invention to aliphatic, linear or branched chains, having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propi!

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i-propyl, n-butyl, tert-butyl or sec-butyl, preferably has 1 to 3 carbon atoms.

The carbosilane dendrimer of the present invention can also be cationic, when the nitrogen atoms of the outer layers are quaternized.

Therefore, the present invention not only includes the compounds themselves, but any of their salts. Preferably the halogen salts, which can be selected from chloride, bromide, iodide salts; or triflate. Preferably the salts are chloride.

In a preferred embodiment, the dendrimer of the invention may be first, second or third generation. The term "generation" (Gn) refers to the number of iterative branches that are necessary for the preparation of the dendrimer.

However, the dendrimer can also be zero generation, as depicted in formula II:

I

I

Nu -) - S¡— (R-i) —T — W Me

where

T N = CH: NH-CH2; NHCO,

Me: CH3

(■ i)

where: Nu represents a polyfunctional core as defined above, Ri is defined in formula I and is preferably a propyl group, p is an integer that varies between 2 and 6, preferably p is 4 when the core is silicon : Me is a methyl group (CH3), W is the polyphenolic terminal group described above and T is defined in formula I. By way of example, if the core is silicon the dendrimer of formula (II) can be of formula ( lia):

Yes-

I

Yes— (R,) - T-W

I

(lia)

where; W, R1, p and T are defined above.

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In another preferred embodiment, the dendrimer is at least first generation and can be represented by the following general formula (III):

image2

(III)

where: Nu represents a polyfunctional nucleus as defined above; Ra, Ri and R2, are the same or different, and represent a (C1-C6) alkyl group; m is an integer that varies between 1 and 3 preferably m is 2; W is the polyphenolic terminal group described above and T is defined in formula I. If the core is silicon the dendrimer of formula (III) can be of formula (Illa):

image3

(Illa)

where: W, R1, R2, Ra m, p and T, are defined above.

In another preferred embodiment, the dendrimer is at least second generation and can be represented by the following formula (IV):

Nu-f-Rb — Mr

image4

image5

(IV)

where: Nu represents a polyfunctional nucleus as defined above; Ra, Rt>, Ri, R2 and R3, are the same or different, and represent a (C1-C6) alkyl group; m and n are the same or different and are an integer that varies between 1 and 3; preferably m and / or n is 2; W is the polyphenolic terminal group defined above and T is defined in formula I. If the core is silicon the dendrimer of formula (IV) can be of formula (IVa):

image6

(IVa)

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where: W, Ra, Rb, Ri, R2 and R3, m, n, p and T, are defined above.

In another preferred embodiment, the dendrimer is at least third generation and can be represented by the following formula (V):

image7

(V)

where: Nu represents a polyfunctional nucleus as defined above; Ra, Rb, Rc, Ri. R2, R3 and R4 are the same or different, and represent an alkyl group (CrCe); m, n and q are the same or different and is an integer that varies between 1 and 3; preferably it is m, n and / or q is 2; W is the polyphenolic terminal group defined above and T is defined in formula I. If the core is silicon the dendrimer of formula (V) can be of formula (Va):

image8

(Goes)

where: W, Ra, Rb, Rc, R1, R2, R3, R4, m, n, q, p and T, are defined above.

In these dendrimers of formula (II), (Ha), (III), (Illa), (IV), (IVa) or (V), (Va), the radicals R1, Ra, Rb, or Rc may be the same or different, and preferably represent a (C2-C4) alkyl group, more preferably they are a propyl group. In another preferred embodiment, the radicals R2, R3 or R4 are independent of each other, and represent a (C1-C4) alkyl group, more preferably they are a methyl group.

Synthesis of spherical dendrimers with terminal polyphenolic groups.

The synthesis of spherical dendrimers is carried out by two synthetic routes depending on the nature of the polyphenol chosen to funclonalize the dendrimeric surface.

In general, the dendrimers described in this section can be represented as Gn- (F) x, where:

n indicates the number of generation G.

F, indicates the nature of the functional groups located on the periphery of the dendrimer.

x denotes the number of terminal units present in the dendrimer.

Synthetic Route 1:

Reduction amination reaction between the polyphenolic precursor with an aldehyde group 10 in the structure and a precursor dendrimer having terminal amino-NH2 groups.

In a preferred embodiment of the process of the invention, the reaction is carried out in the presence of an organic solvent, preferably THF, in two steps:

1. Condensation reaction between the polyphenolic precursor and the spherical dendrimer of heading in the presence of a dehydrating agent, preferably MgSC> 4 (scheme 1).

2. Reduction of the imino bond formed in the previous step with a reducing agent, preferably LÍAIH4, in the presence of an organic solvent, preferably THF and at 0 ° C (scheme 1).

N '"Gc

n = 0 => m = 4

n = l => m = 8 n = 0 => m = 4 (1) n = 0 => m = 4 (3)

20 n = 1 => m = 8 (2) n = l => m = 8 (4)

-scheme 1-

image9

image10

Compounds of an ionic nature are obtained by quaternization of the amino groups present in the structures with a solution of hydrogen chloride in THF 25 (scheme 2).

image11

HCI (2M Et; Q), 0 ° C THF

n = 0 => m = 4 (3)

n = l => m = 8 (4)

n = 0 => m = 4 (5)

n = l => m = 8 (6)

image12

-scheme 2-

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Synthetic Route 2:

Formation of an amido bond between a precursor dendrimer with amino terminal groups and a polyphenolic derivative with an acid group as a substituent. The reaction is carried out in a microwave.

In a preferred embodiment of the process of the invention, the reaction is carried out with gallic acid and in the presence of an organic solvent, preferably THF, and the coupling agent hexafluorophosphate 2- (1-H-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium (HBTU). The reaction is carried out in a microwave at 75 ° C and 40W. The reaction time depends on the dendrimer generation to be synthesized. In a preferred embodiment of the invention the reaction time for a first generation dendrimer is 30 min.

image13

n = 0 => m = 4

n = 1 -> m = 8

HTBU

THF (dry),

MW, 75 ° C

n = 0 => m = 4

n = l => m = 8

image14

image15

-schema 3-

DESCRIPTION OF THE FIGURES

Figure 1. Structures of dendrimers GO- [Si (CH2) 3N = Ph (OMe) (OH)] 4 (1), G1- [Si (CH2) 3NHPh (OMe) (OH)] 8 (2) and G1 - [Si (CH2) 3NH2 + Ph (OMe) (OH) Cl] 8 (5)

EXAMPLES:

The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.

Synthesis of GO- [Si (CH2) 3N = Ph (OMe) (OH)] 4 (1)

On 0.264 g of G0- [NH2] 4 (0.40 mmol) in dry THF, activated MgS04 was first added, then added 0.268 g of vanillin (1.76 mmol). It was left under constant stirring for one day, at room temperature and inert atmosphere. It was later filtered to remove MgS04 and taken to dryness. Product 1, figure 1, was obtained as an orange-yellow oil (175 mg; Rdto = 86.9%).

1 H-NMR (CDCI3): 8.11 (s, 4H, N = CH); 7.40 (s, 4H, (CH30) Cipso-CArH); 7.05 (s, 4H, (HO) Cipso-CArH-CArW); 6.90 (s, 4H, (HO) Cipso-CArW); 3.85 (s, 12H, Cipso-OCW3); 3.53

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(t, 8H, CW2-N = CH); 1.64 (m, 8H, CH2CW2CH2N); 1.25 (m, 8H, SiCH2Ctf2CH2S¡); 0.49 (t, 24H, SiCH2CH2Ctf2SiCW2CH2); -0.07 (s, 24H, Si (CW3) 2); (Cpso-0H) is not observed. 13C-NMR (MeOD): 161.0 (N = CH); 147.5 (Cipso-OH + C / pso-OCH3); 124.6 (HCAr-CArH-C¡pso-CH = N); 114.1 {(HO) Cipso-HCAr-CArH); 107.3 (HCAr-Cipso-OCH3); 60.1 (CH2- N = CH); 53.2 (Cipso-OCH3) 23.4 (SiCH2CH2CH2N); 18.1 (S¡CH2CH2CH2SiCH2CH2); 16.9 (S¡CH2CH2CH2SiCH2CH2); 15.5 (S¡CH2CH2CH2S¡CH2CH2); 10.7

(S¡CH2CH2CH2SiCH2CH2); -3.1 (Si (CH3) 2); {Cipso-CH = N) is not observed.

Elemental analysis (CgíHioíNíOeSIs): Theoretical:% C: 64.17; % H: 8.75; % N: 4.68. Experimental:% C: 63.57; % H: 8.53; % N: 4.46.

Masses: [M + H] + = 1197.69 urn; [M + 2H] + 2/2 = 599.34 urn.

Synthesis of G1- [S¡ {CH2) 3N = Ph (OMe) (OH)] 8 (2)

Compound 2 has been prepared following a procedure analogous to that described for the synthesis of compound 1, starting with G1- [NH2] 8 (0.230 g; 0.14 mmol), vanillin (0.170 g; 1.12 mmol) and MgSO4. In this way, compound 2 is obtained as an orange oil (183 mg; Rdto = 91.1%).

1 H-NMR (CDCIa): 8.11 (s, 8H, N = CW); 7.40 (s, 8H, (CH30) Cipso-CArW); 7.05 (s, 8H, (HO) Cipso-CArH-CArW); 6.88 (s, 8H, (HO) Cipso-CArH); 3.82 (s, 24H, Cipso-OCH3); 3.53 (t. 16H, CHrN = CH); 1.64 (m, 16H, CH2CW2CH2N); 1.26 (m, 16H, SiCH2CH2CH2Si); 0.49 (t, 48H, SÍCW2CH2CW2SÍCH2CH2); -0.08 (s, 48H, Si (C «3) 2); (Cipso-OW) is not observed. 13C-NMR (CDCI3): 160.8 (N = CH); 127.5 (Cypso-CH = N); 123.9 ((HO) Cipso-HCAr-CArH); 114.4 (HCAr-CArH-Cipso-CH = N); 108.7 (HCAr-Clpso-OCH3); 64.9 (CH2-N = CH); 56.1 {Cipso-OCH3); 25.5 (SiCH2CH2CH2N); 20.0 (SiCH2CH2CH2SiCH2CH2); 18.8 ((CH3) Si (CH2CH2CH2Si-) 3; 18.4 ((CH3) (CH2CH2CH2Si) Yes (CH2CH2CH2Si-); 17.7 ((CH3) 2SiCH2CH2CH2SiCH2CH2); 13.0 (SiCH2CH2CH2Si (CH3)); -3.3 (CH3) (-3.3 (CH3)); 2); -5 ((CH2CH2CH2) 3Si (CH3)). (Cipso-OH), (Cipso-OCH3) and ((CH3) 2SiCH2CH2CH2N) are not observed. Elemental analysis (CwH ^ NgOieShs): Theoretical:% C: 63.85;% H: 9.08;% N: 4.14 Experimental:% C: 62.33;% H: 8.95;% N: 4.80.

Synthesis of GO- [Si (CH2) 3NHPh (OMe) (OH)] 4 (3)

A 200 mg solution of the 0 (1) generation dendrimer (1.64 x 10-4 mol in 50 measures THF is kept under stirring in a water / ice bath and 0.30 mL of a commercial solution of 2.4 M LiAIH4 in THF is added. (7.15 x 10.4 mol) drop by drop After half

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hour, the bath is removed and the mixture is kept at room temperature until the reaction time is complete. Once finished, the solvent is removed by evaporation in a vacuum line, 30 mL of dichloromethane is added, the flask is placed on ice, and the same amount of water is added to carry out the hydrolysis. The organic phase is extracted three times with 30 mL of water, dried with anhydrous MgSO4 and then the solvent is evaporated in the rotary evaporator. Thus, compound 3 is obtained as an orange solid (175 mg; Rdto = 86.9%).

1H-NMR (CDCh): or = -0.12 (s, 24H, Si (CH3) 2), 0.49 (m, 24H, S¡CW2CH2CW2S¡ CH2CH2), 1.23 (m, 8H, SiCH2CH2CH2Si), 1.47 (m, 8H , CH2CM2CH2NH), 2.59 (t, 8H, CH2CW2NH), 3.69 (s. 8H, NHCW2Ph), 3.78 (s, 12H, ArOCH3), 6.75 (wide s, 8H, CArW), 6.87 (s, 4H, CArtf). 13C-NMR (CDCb): 5 = -3.5 (Si (CH3) 2), 12.7 (SiCH2CH2CH2Si CH2CH2), 17.4 (SiCH2CH2CH2SiCH2CH2), 18.5 (SiCH2CH2CH2SiCH2CH2), 20.0 (SiCH2CH2CH2CH2 CH2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2CH2H2 (CH2CH2H2) ), 53.0 (NHCH2Ph), 55.6 (CAr-OCH3),

111.6 (CArH), 114.8 (CAfH), 121.4 (CArH), 129.1 (GpSoCH2NH), 145.7 {Cip $ 0OH), 147.3 (CpsoOCHa). Mass spectrometry: [M + H] + = 1205.74 urn. Elemental analysis (C64Hii2N408S5): C, 63.74; H, 9.36; N, 4.65; Exp .: C, 63.02; H, 9.17; N, 4.48.

Synthesis of G1- [Si (CH2) 3NHPh (OMe) (OH)] 8 (4)

Compound 4, figure 1, has been prepared following a procedure analogous to that described for the synthesis of dendrimer 3, starting from 200 mg of precursor 2 (7.38 x 10.5 mol) and 0.27 mL of 2.4 M LiAlhU in THE (6.50 x 10'4 mol). In this way, compound 4 is obtained as an orange oil (168 mg; Rdto = 83.5%). one

1H-NMR (CDCb): 5 = -0.12 (s, 48H, Si (CW3) 2), 0.04 (s, 24H, CH2Si (CH3) CH2), 0.49 (m, 48H, SiC «2CH2CW2S¡CW2CH2), 1.25 (m, 16H, SiCH2CH2CH2Si), 1.47 (m, 16H,

CH2CH2CH2NH), 2.59 (t, 16H, CH2CH2NH), 3.66 (s, 16H, NHCW2Ph), 3.69 (s, 24H, ArOCH3), 4.76 (s, 8H, CArOH), 6.70 (wide s, 16H, CArW), 6.82 (s, 8H, Ca, H), 13C-NMR (CDCb): 6 = -5.0 ((CH2CH2CH2) 3S¡ (CH3)), -3.4 (Si (CH3) 2), 12.8 (SiCH2CH2CH2Si (CH3)),

17.6 ((CH3) 2SiCH2CH2CH2SiCH2CH2), 18.4 ((CH3) (CH2CH2CH2 Yes) Yes (CH2CH2CH2Si-), 18.8 ((CH3) Yes (CH2CH2CH2Si-) 3, 20.0 (SiCH2CH2CH2SiCH2CH2), 23.9 (SiCHH2) 53.6 (NHCH2Ph), 55.6 (CArOCH3) 111.3 (CArH), 114.9 (CArH), 121.0 (CArH), 131.0 (C, pS0CH2NH), 145.4 (C, PsoOH), 147.3 (C ^ oOCHs).

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masses: [M + 2H] 2 * = 1362.85 urn. Elemental analysis (Ci44H26oNaOi6S¡i3): C, 63.47; H, 9.62; IM, 4.11; Exp .: C, 62.66; H, 8.79; N. 3.7

Synthesis of GO- [Si (CH2) 3NH2 + Ph (OMe) (OH) C | -] 4 (5)

To a solution of 100 mg of compound 3 (8.29 x 10.5 mol) in 10 mL of dichloromethane are added 0.18 mL of a solution of 2M HCI in Et20 (3.55 x 10.4 mol) keeping the flask in a bath of ice. In this way an oily orange precipitate appears. The supernatant is removed and the solvent is removed by evaporation in a rotary evaporator. As a result, compound 5 is obtained as an orange solid (110 mg; Rdto = 98.1%).

1H-NMR (CD3OD): or = 0.04 (s, 24H, Si (CW3) 2), 0.65 (m, 24H, SiCW2CH2CH2Si CW2CH2), 1.41 (m, 8H, SiCH2C «2CH2S¡), 1.76 (m, 8H, CH2CW2CH2NH), 3.01 (t, 8H, CH2CH2NH), 3.91 (s, 12H, ArOCH3), 4.14 (s, 8H, NHCW2Ph), 6.86 (d, 1H, CArH), 6.99 (d, 1H, CArW), 7.21 ( s, 1H, CArW). 13C-NMR (CD3OD): or = -3.3 (Si (CH3) 2), 13.2 (SiCH2CH2CH2Si CH2CH2), 18.5 (SÍCH2CH2CH2SÍCH2CH2), 19.8 (SiCH2CH2CH2SiCH2CH2), 20.8 (SiCH2CH2CH2CH2CH2H2 CH2CH2) CH2CH2) , 52.2 (NHCH2Ph),

56.6 (CArOCH3), 114.5 (CArH), 116.5 (CArH), 123.5 (CArH), 124.2 (C, pSoCH2NH), 148.8 (C / psoOH), 149.3 (C / pspOCH3). Elemental analysis (C64H116CI4N4O8SÍ5): C, 56.86; H, 8.65; N, 4.14; Exp .: C, 56.42; H, 8.62; N, 3.89.

Synthesis of G1- [Si (CH2) 3NH2 + Ph (OMe) {OH) C | -] 8 (6)

Compound 6, figure 1, has been prepared following a procedure similar to that described for 5. starting from 100 mg of dendrimer 4 (3.67 x 10.5 mol) and 0.16 mL of 2M HCI in Et20 (3.23 x 10-4 mol) . In this way compound 6 is obtained as an orange solid (108 mg; Rdto = 97.6%).

TH-NMR (CD3OD): 5 = 0.00 (s, 48H, Si (CH3) 2), 0.05 (s, 24H, CH2Si (CW3) CH2), 0.65 (m, 48H, SiCH2CH2CW2SiCW2CH2), 1.43 (m, 16H, SiCH2CW2CH2S¡). 1.77 (m, 16H, CH2CW2CH2NH), 3.01 (t, 16H, CH2CW2NH), 3.92 (s, 24H, ArOCtt3), 4.14 (s, 16H, NHCtf2Ph), 4.76 (s, 8H, CArOH), 6.88 (wide s, 16H, CArH), 7.00 (wide s, 8H, CArW), 7.23 (wide s, 8H, CArH). 13C-NMR (CD3OD): or = -4.7 ((CH2CH2CH2) 3Si (CH3)), -3.0 (Si (CH3) 2), 13.3 (SiCH2CH2CH2Si (CH3)), 19.7 ((CH3) 2SiCH2CH2CH2SiCH2CH2), 19.9 (( CH3) (CH2CH2CH2 Yes) Yes (CH2CH2CH2Si-), 20.0 ((CH3) Yes (CH2CH2CH2Si-) 3l 20.9

(S1CH2CH2CH2SÍCH2CH2), 21.9 (SiChhChbCHíNH), 51.2 (CH2NHCH2), 53.3 (NHCH2Ph),

56.6 (CArOCH3), 114.6 (C „rH), 116.5 (C4rH), 123.5 (C ^ rH), 124.2 (C, pS0CH2NH), 148.8 (C / psoOH), 149.2 (C / PS0OCH3). Elemental analysis (C144H268CI8N8O16SÍ13): C, 57.34; H, 8.96; N, 3.71; Exp .: C, 56.79; H, 8.98; N, 3.44.

ANTIOXIDANT AND ANTITUMORAL CAPACITY OF THE DENDRÍMEROS OF THE INVENTION

Antioxidant capacity tests

As examples of the antioxidant capacity of some compounds of the present invention, the determination methods used and the results obtained for some of the compounds are detailed.

1. ABTS test

15 Discoloration test with the cationic radical ABTS **: it is based on the quantification of the decolorization of the ABTS radical **, due to the interaction with hydrogen or electron donor species.38-39 The cationic radical ABTS ** is a chromophore that absorbs at a wavelength of 734 nm and is generated by an oxidation reaction of ABTS (2,2'-azino-bis- (3-ethyl benzothiazolin-6-sulfonate) with 20 potassium persulfate. Measurements were made at a wavelength of 734 nm. The evaluation used 10 pL of a 3 mM solution of the compound to be measured and 990 pL of the solution of the ABTS radical ** At 30 min of reaction at room temperature and in the dark, the change in absorbance with respect to the reagent reference was read, at a wavelength of 734 nm. The reagent reference consisted of a solution of ABTS radical with the solvent of the sample. the reaction time, the absorbance of the solutions and inhibition percentages are calculated using the equation:

n /, L-L- ■ »^^^ mu, estra ~ ^^^ white *

% lnhibicion = —----------——----------- x 100

• 4í> SconfroI -4 ®Sgianco 2

2. DPPH test.

A-a-diphenyl-fl-picrilhydrazyl radical cation (DPPH-) decolorization test: to measure the free radical scavenging capacity, the degree of

discoloration caused by the antioxidant agent to a DPPH methanolic solution using the Brand-Williams method, with some modifications.40

For this test, a duplicate control is prepared by adding 50pL of the 0.1 mM solution of the DPPH radical and 50pL of MeOH. Samples are prepared just like the control

but substituting the 50pL of MeOH for 1.66pL of the solution of the compounds (3mM) and 48.33pL of MeOH so that the antioxidant is at a concentration of 50pM the same as the radical. Once the compounds have been added to the radical, the mixtures are kept 30 minutes in the dark at room temperature.

10

After the reaction time has elapsed, the absorbance of the solutions at 517.00 nm is measured and the percentages of inhibition are calculated using the equation:

n,, - * ^ bscontrol ^ b ^ sample.

% Inhibition = ----------—------------------- x 100

Table 1. Results of antioxidant activity of compounds 1-6

 Compound

 Amount of phenolic groups per molecule ANTIOXIDANT PROPERTIES radical scavenging (%) [OH] = 50 pM

 DPPH ABTS

 one

 4 31.9 71.2

 2

 8 34 84.6

 3

 4 58 96.6

 4

 8 50.5 88.4

 5

 4 13.1 87.9

 6

 8 20.5 60.3

 Vanillin

 1 0 58

The results obtained by both methods show that polyphenolic derivatives (1-6) have a higher antioxidant activity than free vanillin, since a lower molar concentration of phenolic groups results in greater inhibitions. Among them, the compounds that have the amino bond and the ammonium group, prepared in this work, turn out to have more activity than those with imino bond, susceptible to hydrolysis. It should also be noted that, in compounds 1-6, an increase in antioxidant capacity is observed as generation increases.

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Antitumor activity assays

Antitumor activity assays were carried out on the human PC3 cell lines, which correspond to prostate cancer, and the Hela line, which corresponds to cervical cancer. The technique used to determine cytotoxicity was an MMT test. The results obtained show that vanillin alone does not show antitumor activity in any of the two lines tested, while when it is present in dendritic structures, the cytotoxlcity shown is quite high (Table 2). In both cell lines, it is observed that the first generation dendrimer is the one with the highest antitumor capacity.

Table 2. Results of antitumor activity of compounds 3-6

 Compound

 Number of phenolic groups per molecule IC50a pg / rnL ± SD

 HeLa Pc3

 3

 4 3.3 ± 0.4 3.91 ± 0.27

 4

 8 5.6 ± 1.5 0.88 ± 0.20

 5

 4 3.54 ± 0.03 2.35 ± 0.82

 6

 8 3.8 ± 0.4 2.39 ± 0.53

 Vanillin

 1 +100 +100

INDUSTRIAL APPLICATION

The uses of these compounds are based on their antioxidant properties and therefore may have application in the pharmaceutical and / or cosmetic industry.

In the field of biomedlcin, the compounds of the invention will act as antioxidant agents, since they can protect products that are particularly sensitive to oxidation. In addition, they can be used as therapeutic agents "per se".

In the sense used, the term "therapeutically effective amount" refers to the amount of the composition calculated to produce the desired effect and, in general, will be determined, among other causes, by the characteristics of the composition, age, state and background of the patient, the severity of the disease, and the route and frequency of administration.

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Another aspect of the present invention relates to the potential use of these compounds as antioxidant agents for the preparation of compositions with cosmetic applications such as skin care or makeup products, in masks of eyelashes, eyebrows, anti-aging creams, shadows of eyes, blushes, eyeliner; or as constituents of lotions, creams and cleansing milks.

When the cosmetic composition according to the invention is used for the protection of hair, it can be presented in the form of shampoos, lotions, gels or compositions for rinsing, to be applied before or after! shampoo, before or after a coloration or discoloration, or before, during or after permanent or de-curing treatment. It can also be presented in the form of lotions or gels for styling or treating, lotions or gels for stretching or curling, hair lacquers, permanent or straightening compositions, or coloring compositions or hair discoloration.

When the composition of the invention can be used as a makeup product for eyelashes, eyebrows or skin, it would be presented, for example, in the form of epidermis treatment creams, background makeup, lipsticks, eye shadow for eyelids, blushes, eyeliners (also called "eye-llners") or masks.

When the composition of the invention is a pharmaceutical composition, it can be a solid or liquid composition, useful for oral, parenteral or rectal administration or for topical treatment.

The solid pharmaceutical compositions useful for oral administration may be powders, capsules, tablets, film-coated tablets or microcapsules; and may contain excipient (s). Liquid pharmaceutical compositions for oral administration are solutions, suspensions or emulsions (milk or cream). Pharmaceutical compositions for parenteral administration are generally sterile solutions of the active agents.

The compounds of the invention can be used alone or in combination with one or more compounds of the invention, or in combination with one or more other drugs.

(or in any combination thereof). In general, the formulation will be associated with the presence of one or more pharmacologically acceptable excipients. The term "excipient" is used in the present invention to describe any ingredient other than the compound (s) of the invention. The choice of excipient will depend largely on factors such as means of administration, effect of the excipient on solubility and the nature of the dosage form.

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Claims (15)

5 10 fifteen twenty 25 30 1. Dendritic carbosilane compound comprising: - A polyfunctional nucleus (Nu). The nucleus may be any polyfunctional derivative from which it is possible to grow a dendrimer of carbosilane nature, such as a tetrafunctional nucleus such as a silicon atom, but also and without limitation, a trifunctional polyphenolic nucleus such as 1,3,5 trihydroxybenzene or difunctional as hydroquinone. It can also be an amino or polyamine nucleus. - An outer layer, consisting, totally or partially, of equal or different units of the group of formula (I): S¡ - [{R,) - t — W] m (R2) 3-m d) 'T = N = CH: NH-CH2; nhco where " • R R * image 1 where: - R1 is an alkyl chain, or the following group Ri = - (CH2) z-S- (CH2) and ~ where "z" represents an integer ranging from 2 to 5; preferably "z" is 2 or 3; "Y" represents an integer that varies from 1 to 10; preferably "y" varies between 1 and 5; - R2 is a (C1-C4) alkyl group, preferably R2 is a methyl group: - m is an integer and varies between 1 and 3, preferably m is 1; - W is the polyphenolic terminal group, where at least one R * group is a hydroxyl group (-OH) and the rest of R * groups present in the molecule can be the same or different and are independently selected from among hydroxyl (OH) hydrogen (H), (C1-C4) alkyl or methoxide (-OMe). Preferably R *, are hydroxyls. Preferably the polyphenolic groups will be derivatives of vanillin, gallic acid and ferulic acid; - T is an imino group (-N = CH-W); amino (-NH-CH2-W), ammonium (- + NH2-CH2-W) or amido (-NHCO-W). 2. Dendrimer according to claim 1, wherein the polyphenolic derivative W is vanillin or a derivative of gallic acid or a derivative of ferulic acid without ruling out others. Dendrimer according to claims 1 to 2, wherein p is 1. Dendrimer according to claims 1 to 2, wherein R2 is methyl. Dendrimer according to any one of claims 1 to 2, wherein R1 is a propyl group. Dendrimer according to any one of claims 1 to 2, wherein Ri = - (CH2) z-S- (CH2) and "z" = 2 and "y" = 2. Carbrosilane dendron, formula VI, comprising an outer layer of formula VIII and a focal point of formula Vil. - The focal point (formula Vil) comprises the units W and T, which are defined in Figure I, (claim 1) and the group - (CH2) i; where: i is an integer that varies from 1 to 10, preferably i varies from 1 to 5 and more preferably i is 4. - The outer layer of the dendron consists, totally or partially, of equal or different units of the group of formula (VIII): where: R6 is a (C1-C4) alkyl group, preferably R6 is a methyl group; m is an integer and varies between 1 and 3, preferably m is 2; and R5 is the following group - (CH2) z-S- (CH2) and -R7; "Z" represents an integer that varies from 2 to 5; preferably "z" is 2 or 3; and "y" represents an integer that varies from 1 to 10; preferably "y" varies between 1 and 5. Compound according to claim 7, wherein R7 is a group -N (CH3) 2 or an ammonium group - + N (CH3) 3- W — T— (CH2), - Si - (- R5 (VI) image2 where: Compound according to claim 7, wherein R7 is a -C02H or -C02Me group or any of its salts. 5 10 fifteen twenty 25 30 35 10. Compound according to claim 7, R7 is a -SO3H or -OSO3H group or any of its salts. 11. Dendron according to the preceding claims, 7-10, wherein the polyphenolic derivative W is vanillin, a derivative of gallic acid or a derivative of ferulic acid, without ruling out others. 12. Dendron according to any of claims 7 to 11, wherein in R5, Rs = - (CH2) z-S- (CH2) rR7. "Z" = 2, and "y" = 2. 13. Compound of formula (IX): Et3 — Si - [(R,) -— T-W] () X) wherein: Et is an ethyl group and R1, T and W are described in any of claims 1 to 12. 14. Method for obtaining dendrimers according to any of claims 1 to 13, comprising: the reductive amination reaction between the polyphenolic precursor with an aldehyde group in the structure and a precursor dendrimer having terminal NH2 amino groups. 15. Method for obtaining dendrimers according to any one of claims 1 to 13, comprising: the formation of an amide bond between a precursor dendrimer with amino terminal groups and a polyphenolic derivative with an acid group as a substituent. 16. Composition comprising at least one compound of formula I, VI or IX described in any of claims 1-15. 17. Composition according to claim 16, wherein said composition is food, nutraceutical, cosmetic or pharmaceutical. 18. Composition according to claim 16 further comprising a pharmaceutically acceptable carrier. 19. Composition according to claim 16, wherein it further comprises another active ingredient.

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 Composition according to any of the preceding claims 16-19, wherein said composition is in a form suitable for topical, oral or parenteral administration.

 5 21.

 Use of the dendritic macromolecules according to any of claims 1 to 15, as an antioxidant and radical scavenging agent in a cosmetic formulation, whether for capillary, dermatological use, for nails, eyelashes and eye shadow.

 10 22.

 Use the dendritic macromolecules according to any of claims 1 to 15, as a drug for the treatment of cancer.

 2. 3.

 Use the dendritic macromolecules according to any of claims 1 to 15, as a drug for the treatment of neurodegenerative diseases.

 15 24.

 Use the dendritic macromolecules according to any of claims 1 to 15, as a drug for the treatment of infectious diseases, viral or bacterial in nature.

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