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    • 专利摘要:
    The present invention relates to carbosilane metallodendrimers containing coordinated metal complexes to Schiff base ligands. In addition, the invention describes the process for obtaining it and its uses as antitumor agents as well as antibacterials against Gram (+) and Gram (-) bacteria for use in the pharmaceutical industry. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2735282A1
    申请号:ES201800146
    申请日:2018-06-15
    公开日:2019-12-17
    发明作者:De La Mata F Javier Mata；Ramirez Rafael Gomez；Lopez Paula Ortega；Gallego Sandra Garcia；Del Olmo Natalia Sanz；Rubio Alicia Triguero；Diaz Marta Maroto
    申请人:Universidad de Alcala de Henares UAH；
    IPC主号:
    专利说明:

    [0001]
    [0002] m e t a l o d e n d r ím e r o s d e n a t u r a l e z a c a r b o s il a n o c o n t e n ie n d o
    [0003]
    [0004] The present invention relates to dendritic macromolecules containing a skeleton of a carbosilane nature and having in its structure coordinated metal complexes to Schiff base ligands. The compounds of the invention are potent antitumor and antibacterial agents, and are useful for application in medicine.
    [0005]
    [0006] STATE OF THE PREVIOUS TECHNIQUE
    [0007] Schiff bases are functional groups of general formula R2C = NR '(where R' ^ H) that have been used in a wide variety of applications as metal ion coordinating ligands, thanks to the possibility of easily modulating their design.1 In this sense, the imine groups can participate in the formation of chelate-like complexes thanks to the presence of a nitrogen atom, or a functional group, such as -OH or -SH, near the group -C = N
    [0008]
    [0009] At the therapeutic level, Schiff's bases and the metal complexes derived from them have demonstrated a wide variety of biological activities including antibacterial, antifungal, antiviral, antimalarial, anti-inflammatory, antioxidant, pesticide, cytotoxic, enzyme inhibitor and anti-cancer.1 One of the more representative examples is the mononuclear compound [Cu (Pyimpy) (CI) 2], also known as Cu-P1, a metal complex capable of inhibiting the growth of breast cancer in rats.2
    [0010]
    [0011] The therapeutic strategy of using polynuclear complexes against diseases such as cancer or bacterial infections allows to enhance their activity by binding to different biomolecular targets through more than one metal nucleus. However, in some cases the treatment response rate is very low, both in mononuclear and polynuclear metal systems, due to i) its limited solubility, i) the appearance of intrinsic or acquired resistance to treatment or iii) a non-specific distribution that affects both cancer and normal cells. The use of nanotechnology proposes new solutions for these obstacles through nanoscopic-sized platforms that facilitate the transport of drugs and provide additional properties such as increased solubility, selectivity, multi-valence or controlled release.3 These nanosystems include micelles, metal nanoparticles , liposomes, carbon nanotubes and dendritic systems, among others. In particular, dendrimers are highly branched structures of polymeric type with monodispersed and globular structure, whose controlled synthesis allows establishing a unique structure-reactivity relationship between nanoscopic systems.4 The functionalization of dendritic systems with imine type ligands on the surface is considered A useful and versatile strategy for anchoring metal ions. Various metallodendrimers with Schiff base ligands have been described, with promising results. Among them, the systems with polypropyleneimine (DAB), 5 polyamidoamine (PAMAM) 6 and phosphorhydrazone type skeletons stand out.7
    [0012]
    [0013] In the field of biomedicine, carbosilane-type dendritic systems have proven very versatile with promising applications as transport agents for nucleic material and / or drugs, such as antibacterial, anticancer or antiviral agents, among others.8 '9> 10 11 ■ 12 Likewise, metallodendrimers derived from them have shown novel therapeutic applications. 13 14 '15
    [0014]
    [0015] The carbosilane metallodendrimers with mine groups in their structure of the present invention represent an interesting alternative for use in the pharmaceutical industry.
    [0016]
    [0017] DESCRIPTION OF THE INVENTION
    [0018] The present invention collects dendrimers of carbosilane structure, whose skeleton is composed of silicon-carbon and carbon-carbon bonds, functionalized in their terminal groups with Schiff base ligands that coordinate metal complexes. Schiff's base (or azomethine) is defined as a functional group that contains a carbon-nitrogen double bond, where the nitrogen atom is attached to an aryl or alkyl group that stabilizes the mine. Dendrimer is defined as a macromolecule of polymeric type with monodispersed, highly branched nature and spherical topology. The family of dendritic polymers significantly increases the properties antibacterial and antitumor of isolated metal complexes. The invention provides a method for obtaining it and its uses in the medical area.
    [0019]
    [0020] The compounds described in the invention are useful in the pharmaceutical industry, and can be used as new drugs or formulations containing them, for the treatment of tumor diseases and as antimicrobial drugs.
    [0021]
    [0022] One aspect of the present invention relates to a carbosilane dendrimer with Schiff base type terminal groups and coordinated metal complexes (referred to as "the compound of the invention" hereinafter). By "carbosilane dendrimer" refers to a polymeric macromolecule type spherical-branched, 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 corresponding to the extremities of the ramifications.
    [0023] • 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
    [0024] • By "outer layer" means a terminal layer consisting of units equal to or different from the group of general formula I:
    [0025]
    [0026]
    [0027]
    [0028]
    [0029] where:
    [0030] - Ri is an alkyl chain, preferably of 2 or 3 CPL groups;
    [0031] - R2 is a (C1-C4) alkyl group, preferably R2 = CPL;
    [0032] - m is an integer that varies between 1 and 3, preferably m = 1;
    [0033] - T is the Schiff base-type terminal ligand where the aromatic ring may have ortho or para substituents . Preferably Y is N, CH or C-OH; and Z is CH or N, The terminal ligand has to coordinate metal complexes, where preferably M is ruthenium (II) or copper (II). The metal ion coordination sphere may contain additional X ligands, the same or different, with x being an integer ranging from 1 to 4. Preferably, X is Cl, 0 N 02, H20, r ^ -CsHs, 1,3, 5-triaza-7-phosphoadamantane (PTA), CH3CN.
    [0034]
    [0035] 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-propyl, i-propyl, n-butyl, tert-butyl or sec-butyl, preferably chains of 1 to 3 carbon atoms.
    [0036]
    [0037] In a preferred embodiment, the metallodendrimer of the invention may be first, second or third generation. The term "generation" (Gn) refers to the number of iterative steps that are necessary for the preparation of the dendrimer, where n is an integer, preferably 1-3.
    [0038]
    [0039] In another preferred embodiment, the metallodendrimer is at least first generation and can be represented by the following general formula (II):
    [0040]
    [0041]
    [0042]
    [0043]
    [0044] where: Nu represents a polyfunctional nucleus as defined above; Ra, R1 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; p is an integer that varies between 2 and 6, preferably p is 4 when the core is silicon; and T is defined in formula I. If the core is silicon the dendrimer of formula (II) can be of formula (lia):
    [0045]
    [0046]
    [0047]
    [0048]
    [0049] where: R1, R2, Ra m and T, are defined above.
    [0050] In another preferred embodiment, the dendrimer is at least second generation and can be represented by the following formula (III):
    [0051]
    [0052]
    [0053]
    [0054]
    [0055] where: Nu represents a polyfunctional nucleus as defined above; Ra, Rb, Ri, R2 and R3, are the same or different, and represent an alkyl group (C i-C s); m and q are the same or different and are an integer that varies between 1 and 3; preferably m and / or q is 2; T is the Schiff base terminal group defined above which is defined in formula I. If the core is silicon the dendrimer of formula (III) can be of formula (Illa):
    [0056]
    [0057]
    [0058]
    [0059]
    [0060] where: Ra, Rb, R1, R2 and R3, m, q and T, are defined above.
    [0061]
    [0062] In another preferred embodiment, the dendrimer is at least third generation and can be represented by the following formula (IV):
    [0063]
    [0064]
    [0065]
    [0066]
    [0067] where: Nu represents a polyfunctional nucleus as defined above; Ra, Rb, Re, R1. R2, R3 and R4 are the same or different, and represent a (C1-C6) alkyl group; m, q, syp are the same or different and is an integer that varies between 1 and 3; preferably m, q, s / op is 2; and T is defined in formula I. If the core is silicon the dendrimer of formula (IV) can be of formula (IVa):
    [0068]
    [0069]
    [0070] where: Ra, Rbl Re, Ri, R2, R3, R4, m, q, s, p and T, are defined above.
    [0071]
    [0072] In these dendrimers of formula (II), (lia), (III), (Illa), (IV) or (IVa), the radicals R1, Ra, Rb or Rc may be the same or different, and preferably represent an alkyl chain (C2-C4), more preferably they are a propyl type chain. 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.
    [0073]
    [0074] Synthesis of spherical metallodendrimers with terminal iminopyridine groups. The synthesis of spherical metallodendrimers is made from the precursors iminopyridine Gi- [NCPh (oN)] 4 (I), G2- [NCPh (oN)] 8 (II) and G3- [NCPh (oN)] i6 (III ) previously described13 with a metal salt of interest by coordination reactions. Depending on the metal precursor used, subsequent ligand exchange and contraction reactions may be necessary.
    [0075]
    [0076] In a preferred synthesis of the process of the invention, the reaction between the dendritic precursor and the metal salt of Cu (ll), preferably Cu (N03) 2, is carried out in the presence of an organic solvent, preferably DMF, in a single step at room temperature (scheme 1).
    [0077]
    [0078]
    [0079]
    [0080] Scheme 1
    [0081]
    [0082] In another preferred synthesis of the process of the invention, the reaction between the dendritic precursor and the metal salt of Ru (ll), preferably [(r | 5 C5H5) Ru (CH3CN) 3] PF6, is carried out in the presence of an organic solvent, preferably dry dichloromethane, in three steps (scheme 2).
    [0083]
    [0084] F. Coordination reaction of the metal salt to the dendritic precursor in an organic solvent, preferably dry dichloromethane, for 30 minutes.
    [0085] 2. Ligand exchange reaction, preferably PTA, in an organic solvent such as dry dichloromethane, at room temperature and for 12 h.
    [0086] 3. Counter-exchange reaction, preferably chloride, by an ion exchange resin.
    [0087]
    [0088]
    [0089] n = 3, m = 16 (12)
    [0090]
    [0091] Scheme 2
    [0092]
    [0093] DESCRIPTION OF THE FIGURES
    [0094] Figure 1. Examples of copper carbosilane metallodendrimer structures with nitrate ligands.
    [0095]
    [0096] Figure 2. Examples of ruthenium carbosilane metallodendimer structures with rf-CsHs and PTA ligands.
    [0097]
    [0098] EXAMPLES
    [0099] The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
    [0100]
    [0101] Synthesis of Gi- [NCPh (o-N) Cu (ON02) 2-H20] 4 (1)
    [0102] Dendritic precursor Gi- [NCPh (oN)] 4 I (69.2 mg, 0.068 mmol) dissolved in DMF is added slowly over a solution of Cu (N03) 23H20 (65.7 mg, 0.27 mmol) in DMF The reaction progresses with stirring at room temperature for 24 h. Compound 1 is isolated by evaporation of the solvent in vacuo as a green solid (102.5 mg, 82%). CwH iooC ^ N ibOíbS ís (1840.1 g / mol). AE (%): cale. C, 36.55; H, 5.48; N, 12.18. exp. C, 36.15; H, 5.17; N, 12.34. IR, v (C = N): 1646.39 cnr1.
    [0103]
    [0104] Synthesis of G2- [NCPh (o-N) Cu (ON02) 2 H20] 8 (2)
    [0105] The second generation metallodendrimer is prepared following the same procedure as for the first generation analog, using the following reagents: G2- [NCPh (oN)] 8 II (54.1 mg, 0.023 mmol) and Cu (N03) 2-3 H20 (44.5 mg, 0.18 mmol). Compound 2 is isolated by evaporation of the solvent in vacuo as a green solid (64.7 mg, 70%). C 128H236CU8N32O56YES13 (3992.9 g / mol). AE (%): cale. C, 38.50; H, 5.96; N, 11.23. exp. C, 38.91; H, 5.95; N, 11.97. IR, v (C = N): 1646.42 cn r1.
    [0106]
    [0107] Synthesis of Gi - {[NCPh (o-N) Ru (n5-C5Hs) (CH3CN)] PF6} 4 (4)
    [0108] Using inert atmosphere conditions, the dendritic precursor Gi- [NCPh (oN)] 4 I (78.4 mg, 0.077 mmol) is added at 0 ° C on a solution of the ruthenium salt [(q5-C5H5) Ru (CH3CN) 3] PFs (133.6 mg, 0.31 mmol) in dry CH2CI2. The reaction progresses at 0 ° C for 5 min, and is then left 30 min until reaching room temperature, with continuous stirring. Compound 4 is obtained as a reddish solid that was not isolated. Ca4Hi24F24Ni2P4Ru4SÍ5 (2426.5 g / mol). 1H-NMR (CD3CN): or -0.01 (s, 24H, - (CH3) 2SiG1); 0.57 (m, 24H, -SíCH2-); 1.36 (m, 8H, -SiCH2CH2CH2S¡); 1.70 (m, 8H, (-SiCH2CF / 2CH2N); 4.16 (m, 4H, -SiCH2CH2CH2N); 4.42 (m, 24H, -S¡CH2CH2CH2N and -C5 / - / 5); 7.44 (m, 4H, C hf ™)] 7.88 (m, 8H, CH ^ 0 ^); 8.53 (s, 4H, N = C H) 9.33 (m, 4H, CHpY (m)).
    [0109]
    [0110] Synthesis of G2 - {[NCPh {o-N) Ru (n5-C5H5) (CH3CN)] PF6} 8 (5)
    [0111] The second generation metallodendrimer is prepared following the same procedure as for the first generation analog, using the following reagents: G2- [NCPh (oN)] 8 II (81.3 mg, 0.034 mmol) and [(q5-C5H5) Ru ( CH3CN) 3] PF6 (119.6 mg, 0.27 mmol). Compound 5 is obtained as a reddish solid that was not isolated. Ci84H282F48N24P8Ru8Sii3 (5163.7 g / mol). 1H-NMR (CD3CN): 5-7.0 (s, 12H, -CH3SiG1); -OR. 01 (s, 48H, - (CH3) 2SiG2); 0.56 (m, 64H, -SiC H2 -) 1.35 (m, 24H, -SiCH2C tf2CH2Si-); 1.81 (m, 16H, (-SiCH2CH2CH2N); 4.17 -SiCH2CH2CH2N); 4.39 (m, 48H, -SiCH2CH2C / - / 2N and -C5H5); 7.44 (m, 8
    [0112] Synthesis of Gi - {[NCPh (o-N) Ru (n5-C6H5) <PTA)] PF6} 4 (7)
    [0113] On the reaction mixture prepared to obtain compound 4 (0.077 mmol), the 1,3,5-triaza-7-phosphoadamantane PTA ligand (48.4 mg, 0.308 mmol) is added. The reaction is stirred for 12 h and the solution is washed with water. After evaporation of the solvent, compound 7 is obtained as a reddish solid (122.4 mg, 55%). CiooHi6oF24N2oP8Ru4S¡5 (2890.9 g / mol). 1H-NMR ((CD3) 2CO): 5 0.05 (s, 24H, - (CH3) 2SiG1); 0.68 (m, 24H, -SiCH2-); 1.45 (m, 8H, -SiCH2CP2CH2Si); 2.07 (m, 8H, (-SiCH2CH2CH2N); 3.82 (s, 24H, -NCW2NPTA); 4.35 (m, 32H, -SiCH2CH2CH2N and -NCH2PPTA); 4.90 (s, 20H, -C5P5); 7.44 (m, 4H, C h f ^ y, 8.01 (m, 4H, CHptfm>); 8.16 (m, 4H, C tfM and, 8.76 (s, 4H, -N = CH); 9.30 (m, 4H, C hf ^). 13C { 1H} -RMN ((CD3) 2CO): 5 -2.9 (- (CH3) 2SiG1); 13.1 (-S¡CH2CH2CH2N); 18.5-20.9 (-SiCH2CH2CH2Si); 27.8 (-SiCH2CH2CH2N); 53.0 (-NCH2NPTA); 72.3 (-SiCH2CH2CH2N); 73.5 (-NCH2Ppta); 77.2 (C **); 125.7-156.9 (-C5Hs); 162.6 (-N = CH). 31P-NMR ((CD3) 2CO): 5 -38.3 (s , -CHjP ™); -144.1 (sp, PFS) ESI: [M + 4] + = 577.68 urn.
    [0114]
    [0115] Synthesis of G2. {[NCPh (o-N) Ru (n5-C5H5) (PTA)] PF6} 8 (8)
    [0116] The second generation metallodendrimer is prepared following the same procedure as for the first generation analog, using the following reagents: reaction mixture of compound 5 (0.034 mmol) and PTA (43.2 mg, 0.275 mmol). Compound 8 is isolated as a reddish solid (107.7 mg, 52%). C2i6H354F48N4oPi6Ru8Sii3 (6092.6 g / mol). 1H-NMR ((CD3) 2CO): 5-7.0 (s, 12H, - (CH3) SiG1); -0.01 (s, 48H, - (CP3) 2SiG2); 0.56 (m, 64H, -SiC H2 -) 1.35 (m, 24H, -SiCH2CH2CH2S¡); 1.81 (m, 16H, -SiCH2CP2CH2N); 3.80 (m, 48H, -NCH2NPTA); 4.39 (m, 64H, -S¡CH2CH2CH2N and -NCH2PPTA); 4.89 (s, 40H, -C5Hs); 7.44 (m, 8H, Ar); 7.88 (m, 16H, Ar); 8.17 (m, 8H, Ar); 8.53 (s, 8H, -N = C H) 9.33 (m, 8H, Ar). 13C {1H} -RMN ((CD3) 2CO): 5 -4.2 (- (CH3) 2SiG2); -2.5 (- (CH3) SiG1); 13.3 (-SiCH2CH2CH2N); 18.6-20.9 (-SiCH2CH2CH2Si); 27.9 (-SiCH2CH2CH2N); 52.7 (-NCH2NPTA); 72.5 (-SiCH2CH2CH2N); 73.5 (-NCH2Ppta); 77.3 {C *) 125.7-156.9 (CAr); 162.6 (-N = CH). 31P-NMR ((CD3) 2CO): or -38.1 (s, -CHzP * 3 ™); -144.4 (sp, PF6).
    [0117]
    [0118] Synthesis of Gi - {[NCPh (o-N) Ru (n5-CsH5) {PTA)] CI} 4 (10)
    [0119] The metallodendrimer 7 (122.4 mg) is dissolved in an Acetone / H20 mixture and the counterion change is performed, adding the Amberlite IRA-402 ion exchange resin to the solution. Compound 10 is isolated as a reddish solid after evaporating the solvent (122.7 mg, 65%). C ^ o H ie oC LN ^ R ^ S is (2452.9 g / mol). 1 H-NMR ((CD3) 2CO): 6 0.10 (s, 24H, - (CW3) 2SiG1); 0.67 (m, 24H, -SiC H2 -) 1.46 (m, 8H, -SiCH2CW2CH2S¡); 1.96 (m, 8H, -SiCH2CH2CH2N); 3.77 (s, 24H, -NCH2NPTA); 4.42 (m, 32H, -S¡CH2CH2CH2N and -NCH2PPTA); 4.87 (s, 20H, -C5H5); 7.46 (m, 4H, Ar); 7.98 (m, 4H, Ar); 8.12 (m, 4H, Ar); 8.66 (s, 4H, -N = C H) 9.22 (m, 4H, Ar). 31P-NMR ((CD3) 2CO): 5-36.4 (s, -CH2Ppta). AE (%). Cale .: C, 48.97; H, 6.57; N, 11.42. Exp .: C, 48.92; H, 6.99; N, 9.98. ESI: [M + 4] + = 577.68 urn.
    [0120]
    [0121] Synthesis of G 2 - {[NCPh (oN) Ru (n5-C5H 5 ) (PTA)] CI } 8 (11)
    [0122] The second generation metallodendrimer is prepared following the same procedure as for the first generation analog, using the following reagents: compound 8 (107.7 mg) and Amberlite IRA-402. Compound 11 is isolated as a reddish solid after evaporating the solvent (106.4 mg, 60%). C ^ eH ^ CIsNUaPeRusSiis (5216.48 g / mol). 1H-NMR ((CD3) 2CO): or -0.01 (s, 12H, - (CH3) SiG1); 0.11 (s, 48H, - (CH3) 2SiG2); 0.67 (m, 64H, -SiCH2-); 1.44 (m, 24H, -SiCH2CH2CH2Si); 1.97 (m, 16H, -S¡CH2CH2CH2N); 3.78 (m, 48H, -NCH2NPTA); 4.45 (m, 64H, -SiCH2CH2CH2N and -NCH2Ppta); 4.86 (s, 40H, -CSH5); 7.43 (m, 8H, Ar); 7.99 (m, 16H, Ar); 8.15 (m, 8H, Ar); 8.69 (s, 8H, -N = C H) 9.22 (m, 8H, Ar). 31P-NMR ((CD3) 2CO): 5 -36.2 (s, -CH 2 ^ ™). AE (%). Cale .: C, 49.73; H, 6.84; N, 10.74. Exp .: C, 49.69; H, 6.99; N, 9.34.
    [0123]
    [0124] ANTITUMORAL AND ANTIBACTERIAL CAPACITY OF THE METALODENDRIMEROS OF THE INVENTION
    [0125] As examples of the antitumor and antibacterial capacity presented by some compounds of the present invention, the determination methods employed and the results obtained for selected compounds are detailed.
    [0126]
    [0127] 1. In vitro antitumor capacity by MTT assay
    [0128] Antitumor activity assays were carried out in various tumor and healthy cell lines. The selected tumor lines were PC3, corresponding to advanced prostate cancer; MCF7 and HCC1806, of breast cancer; HT29, of colon cancer; and HeLa, from cervical cancer. The 142BR line of fibroblasts was used as a non-tumor reference. The technique used to determine cell viability was an MTT assay. Each of the compounds has been measured at least three times independently in order to obtain reproducible results.
    [0129] Cells were seeded in 96-well plates at a concentration of 1.1 x 105 cells / m !. After 24 h, the compounds were added at different concentrations in the range 0-100 pM. After 24 h of treatment, 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazole (MTT) bromide in PBS, at a concentration of 0.1 mg / ml, was added in the dark. After 1.5 h, the medium was removed from the wells, dissolving the crystals formed in DIVISE with gentle agitation. The cell viability was determined in the Multiskan FC spectrophotometer, by absorbance measurements of the soluble formazan salt generated by living cells at 570 nm by subtracting the "background" measured at 620 nm. The relative cell viability (%) with respect to the control (untreated cells) is calculated based on the formula: [A] test / [Á] control x 100. Each test is performed in triplicate.
    [0130]
    [0131] Table 1. Results of in vitro antitumor activity of selected metallodendrimers in tumor cell lines (HeLa, MCF7, PC3, HCC1806 and HT29) and healthy (142BR).
    [0132]
    [0133]
    [0134]
    [0135]
    [0136] The MTT test results show significantly lower IC50 values for tumor lines treated with first and second generation metallodendrimers, compared to the cell line used as a control. In addition, in some cases the first generation systems are more effective than their older generation analogs, probably due to the necessary hydrophobic-hydrophilicity balance or their greater ability to interact with the cell membrane due to their structure.
    [0137] 2. Antibacterial capacity through evaluation of CMI and CMB
    [0138] The antibacterial activity of selected compounds has been evaluated in Staphylococcus aureus (Gram +) and Escherichla coli (Gram-) by calculating the MIC (minimum inhibitory concentration) and CMB (minimum bactericidal concentration). The CMI indicates the minimum amount of an agent that can inhibit the growth of a microorganism (bacteriostatic effect), while the CMB refers to the minimum amount of an agent that can kill a microorganism (bactericidal effect).
    [0139]
    [0140] CMI determination test (ISO 20776-1). The test was carried out in triplicate for each desired compound concentration. The microplates are incubated at 37 ° C using an ELX808ÍU ultra-microplate reader (Bio-Tek Instruments).
    [0141]
    [0142] CMB determination test. The CMB was calculated by inoculating 5 pL of the samples used to calculate the MIC in a Petri dish with Muller-Hinton agar. After 24 h of incubation at 37 ° C, the CMB was determined by selecting the minimum concentration where no growth was detected.
    [0143]
    [0144] Table 2. Bacteriostatic and bactericidal effects of the selected metallodendrimers.
    [0145]
    [0146]
    [0147]
    [0148]
    [0149] The results (Table 2) show the potent bacteriostatic and bactericidal activity of metallodendrimers, especially those of first generation, compared to the precursor metal salt Cu (N03) 2 used as a control. This activity is reproducible in both types of bacteria.
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    权利要求:
    Claims (16)
    [1]
    1. Carbonosilane metallodendrimer comprising:
    - A polyfunctional nucleus (Nu). The core can be any polyfunctional derivative from which it is possible to grow a carbosilane dendrimer.
    - An outer layer consisting of the same or different units of the group of formula (I):
    f S i - (R - T) m
    (R2) 3-m where
    [2]
    2. Metallodendrimer according to claim 1 wherein -N u (polyfunctional nucleus) is a tetrafunctional nucleus such as a silicon atom, a trifunctional polyphenolic nucleus such as 1,3,5-trihidoxybenzene or difunctional such as hydroquinone or an amino or polyamino nucleus.
    [3]
    3. Metallodendrimer according to claim 1, wherein the T-terminal ligand is a coordination complex derived from 4-iminopyridine, 2-minopyridine and phenolamine.
    [4]
    4. Metallodendrimer according to claims 1 to 3, wherein m is 1.
    [5]
    5. Metallodendrimer according to claims 1 to 3, wherein R2 is methyl.
    [6]
    6. Metallodendrimer according to any one of claims 1 to 3, wherein R1 is a propyl group.
    [7]
    7. Metallodendrimer according to any one of claims 1 to 3, wherein M = Cu (ll), Ru (ll).
    [8]
    Method for obtaining the metallodendrimers according to any one of claims 1 to 7, comprising: the coordination reaction of a Cu (ll) salt in the dendritic precursor with terminal Schiff base groups, where the Cu (ll) sai it is preferably Cu (N03) 2.
    [9]
    9. Method of obtaining the metallodendrimers according to any one of claims 1 to 7 comprising: the coordination reaction of a metal salt of Ru (ll) to the dendritic precursor with terminal Schiff base groups, where the ruthenium salt is preferably [ (q5-C5H5) Ru (CH3CN) 3] PF6; the ligand exchange reaction, where the preferably coordinated ligand is 1,3,5-triaza-7-phosphoadamantane (PTA); and the counterion exchange reaction, where the anion that is preferably introduced is chloride.
    [10]
    10. Composition comprising at least one compound of formula I, described in any of claims 1-9.
    [11]
    11. Composition according to claim 10, wherein said composition is pharmaceutical.
    [12]
    12. Composition according to claim 10 further comprising a pharmaceutically acceptable carrier.
    [13]
    13. Composition according to claim 10, further comprising another active ingredient.
    [14]
    14. Composition according to any of the preceding claims 10 to 13, wherein said composition is in a form suitable for topical, oral or parenteral administration.
    [15]
    15. Use the dendritic macromolecules according to any of claims 1
    to 14, for the preparation of a drug in the treatment of cancer.
    [16]
    16. Use the dendritic macromolecules according to any of claims 1 to 14, for the preparation of a medicament in the treatment of infectious diseases, of bacterial nature.
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    公开号 | 公开日
    ES2735282B2|2020-04-17|
    WO2019239001A1|2019-12-19|
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