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Lopez-Hernandez, Javier E. ; Nayeem, Nazia ; Ceron-Carrasco, Jose P. , et al. Eur. J. Org. Chem.,2023,29(59):e202302045. DOI: 10.1002/chem.202302045 PubMed ID: 37507346
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Abstract: New heterometallic binuclear and trinuclear platinum(IV)-gold(I) compounds of the type [Pt(L)n Cl2 (OH){(OOC-4-C6 H4 -PPh2 )AuCl}x ] (L=NH3 , n=2; x=1, 2; L=diaminocyclohexane, DACH, n=1; x=2) are described. These compounds are cytotoxic and selective against a small panel of renal, bladder, ovarian, and breast cancer cell lines. We selected a trinuclear PtAu2 compound containing the PtIV core based on oxaliplatin, to further investigate its cell-death pathway, cell and organelle uptake and anticancer effects against the triple-negative breast cancer (TNBC) MDA-MB-231 cell line. This compound induces apoptosis and accumulates mainly in the nucleus and mitochondria. It also exerts remarkable antimigratory and antiangiogenic properties, and has a potent cytotoxic effect against TNBC 3D spheroids. Trinuclear compounds do not seem to display relevant interactions with calf thymus (CT) DNA and plasmid (pBR322) even in the presence of reducing agents, but inhibit pro-angiogenic enzyme thioredoxin reductase (TrxR) in TNBC cells.
Keywords: Chemotherapeutics ; TNBC ; gold ; heterometallic phosphanes ; platinum
Purchased from AmBeed: 61825-94-3 ; 6066-82-6
CAS No. : | 6066-82-6 | MDL No. : | MFCD00005516 |
Formula : | C4H5NO3 | Boiling Point : | - |
Linear Structure Formula : | C4H4(O)2N(OH) | InChI Key : | NQTADLQHYWFPDB-UHFFFAOYSA-N |
M.W : | 115.09 | Pubchem ID : | 80170 |
Synonyms : |
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Chemical Name : | 1-Hydroxypyrrolidine-2,5-dione |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P261-P280-P271-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dicyclohexyl-carbodiimide; In 1,4-dioxane; at 5 - 20℃; for 20h; | 2.2 ml (25 mmol) DCCD was added at 5C to a solution of 1.43 ml (25 mmol) acetic acid and 2.2 ml (0.25 mmol)N-hydroxysuccinimide in 50 ml dioxane. The reaction mixture was stirred at 20C for 20 h. The resulting precipitate wasfiltered off and washed with dry dioxane. The filtrates were combined and evaporated to yield 3.65 g (93%) of the productas white crystals. Rf 0.41 (C), Rf 0.75 (I); m.p. 103-105C. 1H NMR (DMSO-d6): 2.34 (3H, s, -CH3CO-), 2.80 (4H, m, -CH2CH2- OSu). |
With 1,2-dichloro-ethane; In dichloromethane; for 3h; | General procedure: To a stirred solution of appropriate acid 44a-f (1.96mmol) in CH2Cl2 (3mL) were added NHS (0.361g, 3.14mmol) and EDC (0.601g, 3.14mmol). After 3h, the mixture was diluted with CH2Cl2 (40mL). The organic layer was washed with brine (2×40mL), saturated aqueous NaHCO3 (40mL) and brine (2×40mL), dried over Na2SO4, filtered and concentrated to give NHS activated esters (80-100% yield) that were used immediately without further purification. | |
With dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃;Inert atmosphere; | The syntheses of GlcNAc and GlcNGc from glucosamine were based on the method described by Lapidot [31]. The procedure for the synthesis of GlcNAc was performed as follows: acetic acid (0.286 mL, 5 mmol) was added to a solution of N-hydroxysuccinimide (0.575 g, 5 mmol) in dry ethyl acetate (23 mL). A solution of dicyclohexylcarbodiimide (1.03 g, 5 mmol) in ethyl acetate (2 mL)was then added. The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. Then, the precipitate of the reaction mixture was removed by centrifugation at 13,400 g for 10 min. The supernatant contained an NHS-ester of acetic acid was dried by rotary evaporation under reduced pressure and re-dissolved in dry 17 mL of methanol. D-Glucosamine hydrochloride(0.862 g, 4 mmol) and triethylamine (0.56 mL) were then added and dissolved by placing the sample ina heated sonication bath (50 C for 1 h). The reaction mixture was then stirred at room temperature for 16 h. The sample was again dried using rotary evaporation and washed three times with ethyl acetate(1 mL) to remove the unreacted starting material. After vacuum drying of the sample using centrifugal evaporation, the product was dissolved in 8 mL of 10% methanol in water (v/v). The supernatant was collected and concentrated using a rotary evaporator under reduced pressure. For the synthesisof GlcNGc, glycolic acid (0.3 mL, 5 mmol) was used instead of acetic acid. As judged by TLC analysis, the conversion of D-glucosamine to the reaction products 4a or 4b reached approximately 70%. These amidated reaction products were then used directly as starting material for the enzymatic sialylation reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; triethylamine; In ethanol; ethyl acetate; isopropyl alcohol; | EXAMPLE 12 1.27 g (0.011 mol) of N-hydroxysuccinimide were initially introduced into 10 ml of ethyl acetate, a solution of 3.22 g (0.012 mol) of diphenyl chlorophosphate in 10 ml of ethyl acetate was added and then a solution of 2.53 g (0.025 mol) of triethylamine in 10 ml of ethyl acetate was added dropwise in the course of 10 minutes, the temperature rising to 41° C. A thick, white suspension resulted, which was treated with a solution of 0.6 g (0.01 mol) of acetic acid in 10 ml of ethyl acetate and heated at 45°-55° C. for 16 hours. After ending of the reaction, the solid was filtered off and washed with 2*3 ml of ethyl acetate. The combined filtrates were evaporated in vacuo and the semicrystalline residue which remained was washed by stirring with 20 ml of ethanol for 30 minutes. The white solid thus obtained was filtered off, washed with 2*3 ml of ethanol, sucked dry and then washed by stirring with 10 ml of isopropanol. After filtering off, washing with 2*2 ml of isopropanol and drying in vacuo, 1.1 g (70percent) of white acetic acid succinimidyl ester were obtained. M.p.: 130°-134° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Into a 100- mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of <strong>[23351-91-9]5-bromoisophthalic acid</strong> (3 g, 11 76 mmol, 1 00 equiv, 96percent) in THF (20 mL) followed by NHS (3 g, 2609 mmol, 220 equiv) at 0-50C To this was added a solution of DCC (5 6 g, 27 18 mmol, 2 20 equiv) m THF (20 mL) dropwise with stirring at 0-50C The resulting solution was stirred overnight at room temperature The solids were filtered out and the filtrate was concentrated under vacuum The crude product was re-crystalhzed from DCM/ethanol in the ratio of 1 10 This resulted m 4 g (75percent) of the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
323 mg | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h;Inert atmosphere; | EXAMPLE 4 SYNTHESIS OF PROBE COMPOUND, DYn-Naph [0147] The DYn-Naph compound (FIG. 5) may be synthesized by the following method (FIG. 6A, Scheme 2). To a dry round bottom flask flushed with nitrogen was added 6-amino-2-napthoic acid (200 mg, 1.07 mmol), NHS (135.18 mg, 1.17 mmol), and dry DMF (2 mL). The reaction mixture was cooled in an ice-bath. EDC-HC1 (224.71 mg, 1.17 mmol) was added and the reaction mixture was allowed to react at 0 °C for 30 min, then the reaction was brought up to room temperature and allowed to mix for an additional 3 hrs. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated for the next step. To a dry round bottom flask flushed with nitrogen was added the NHS-ester of Intermediate Compound (1) (323 mg, 1.13 mmol), which was suspended in dry DMF (4 mL). 4-pentyneamine (292.5 mg, 3.52 mmol) and DIPEA (613 uL, 3.52 mmol) were subsequently added and the reaction mixture was allowed to mix at 75 °C overnight under nitrogen. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated. Flash column chromatography was used for purification (1 : 1 EtOAc:Hexanes, 10percent MeOH in EtOAc spiked with 1percent TEA) to yield 188.2 mg of Intermediate Compound (2) (70percent yield). To a dry round bottom flask flushed with nitrogen was added 3-methoxy-5-oxocyclohex-3-9-enecarboxylic acid (115.39 mg, 0.678 mmol), EDC-HC1 (194.48 mg, 1.02 mmol), and DMAP (99.4 mg, .813 mmol). The flask was sealed under nitrogen. Intermediate Compound (2) (188.2 mg, 0.746 mmol) was resuspended in dry DMF (2 mL) and added to the reaction mixture followed by the addition of TEA (95 mu, 0.678 mmol). The reaction mixture was brought up to 85 °C and allowed to mix overnight under nitrogen. The reaction was quenched with the addition of water and extracted with EtOAc. The organic phases were combined and dried over MgS04, filtered, and concentrated. Flash column chromatography was used for purification (1 : 1 Hexanes:EtOAc, 7:3 EtOAc:Hexanes, 5percent MeOH in EtOAc) to yield 138.1.6 mg of product (46percent yield). In a round bottom flask, Intermediate Compound (3) (138.1 mg, 0.34 mmol) was suspended in a 1 : 1 Acetonitrile:Water solution (5 mL). 10percent> CAN (18.8 mg, 0.034 mmol) was added and the reaction mixture was refluxed at 95 °C for 3 hrs., resulting in the synthesis of DYn-Naph (FIG. 5). The reaction was then cooled and concentrated and directly purified by HPLC. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h;Inert atmosphere; | To a dry round bottom flask flushed with nitrogen was added 6-amino-2-napthoic acid (200 mg, 1.07 mmol), NHS (135.18 mg, 1.17 mmol), and dry DMF (2 mL). The reaction mixture was cooled in an ice-bath. EDC-HCl (224.71 mg, 1.17 mmol) was added and the reaction mixture was allowed to react at 0 °C for 30 min, then the reaction was brought up to rt and allowed to mix for an additional 3 hrs. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated for the next step without further purification. To a dry round bottom flask flushed with nitrogen was added the NHS-ester (323 mg, 1.13 mmol) which was suspended in dry DMF (4 mL). 4-pentyneamine (292.5 mg, 3.52 mmol) and DIPEA (613 uL, 3.52 mmol) were subsequently added and the reaction mixture was allowed to mix at 75 °C overnight under nitrogen. The reaction was quenched with the addition of saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. Flash column chromatography was used for purification (1:1 EtOAc:Hexanes, 10percent MeOH in EtOAc spiked with 1percent TEA) to yield 188.2 mg of (5) (70percent yield over 2 steps) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 24h; | 5-Bromo-N-(1-propyl-1H-benzo[d]imidazol-2-yl)isophthalamide 13. A mixture of <strong>[23351-91-9]5-bromoisophthalic acid</strong> (100 mg, 4.1 mumol), N-propylaminobenzamidazole (72 mg, 4.1 mumol), N-hydroxysuccinimide (56 mg, 4.9 mumol), DMAP (5 mg, 0.4 mumol) and EDC (234 mg, 1.2 mmol) were dissolved in methylene chloride (5 mL), treated with Hunig's base (53 mg, 4.1 mumol) and stirred for 1 d to give 12. The reaction mixture was then treated with 9/1 MeOH/NH4OH (5 mL) and stirred for 2 h. The mixture was concentrated to a solid, dissolved in DMSO, added to a column and chromatographed (50 g isco C18, 0 to 100percent MeOH with 0.2percent formic acid) to give 13 (71 mg, 43percent) as a white powder. LC/MS gave a single peak with m/z=401.1 [M+1]+ and 823.1 [2M+Na]+. 1H-NMR (dmso-d6) delta 12.77 (br s, 1H), 8.65 (br s, 1H), 8.45 (br s, 1H), 8.22 (br s, 1H), 8.17 (br s, 1H), 7.54-7.60 (m, 3H), 7.28 (t, J=8 Hz, 1H), 7.24 (t, J=8 Hz, 1H), 4.27 (t, J=7 Hz, 2H), 1.85 (h, J=7 Hz, 2H), 0.92 (t, J=7 Hz, 3H). |