WO1998035972A1 - Complejo de platino con actividad antineoplasica - Google Patents
Complejo de platino con actividad antineoplasica Download PDFInfo
- Publication number
- WO1998035972A1 WO1998035972A1 PCT/ES1998/000027 ES9800027W WO9835972A1 WO 1998035972 A1 WO1998035972 A1 WO 1998035972A1 ES 9800027 W ES9800027 W ES 9800027W WO 9835972 A1 WO9835972 A1 WO 9835972A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- platinum
- platinum complex
- complex
- dna
- mercaptopyrimidine
- Prior art date
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 45
- 230000000118 anti-neoplastic effect Effects 0.000 title abstract description 8
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 208000002495 Uterine Neoplasms Diseases 0.000 claims abstract description 5
- 208000032839 leukemia Diseases 0.000 claims abstract description 5
- 206010046766 uterine cancer Diseases 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 4
- -1 anion 2-mercaptopyrimidinate Chemical class 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 7
- 229910020427 K2PtCl4 Inorganic materials 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 abstract 1
- 108020004414 DNA Proteins 0.000 description 31
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 19
- 229960004316 cisplatin Drugs 0.000 description 19
- 239000012634 fragment Substances 0.000 description 14
- 239000013612 plasmid Substances 0.000 description 11
- 238000005056 compaction Methods 0.000 description 9
- 230000003993 interaction Effects 0.000 description 8
- 230000002776 aggregation Effects 0.000 description 7
- 238000004220 aggregation Methods 0.000 description 7
- 238000011534 incubation Methods 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229940034982 antineoplastic agent Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WTCRPVQWYABJEI-UHFFFAOYSA-N [Pt+] Chemical compound [Pt+] WTCRPVQWYABJEI-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000004630 atomic force microscopy Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- BSJGASKRWFKGMV-UHFFFAOYSA-L ammonia dichloroplatinum(2+) Chemical compound N.N.Cl[Pt+2]Cl BSJGASKRWFKGMV-UHFFFAOYSA-L 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000000978 circular dichroism spectroscopy Methods 0.000 description 1
- 238000001142 circular dichroism spectrum Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Definitions
- This invention relates to a new complex of Pt (III), its pharmaceutical compositions, its use for the preparation of antineoplastic drugs, and a method of preparing said complex.
- antineoplastic agents used in cancer therapy are some platinum compounds.
- Cisplatin and carboplatin which are both Pt (II) compounds, represent the first and second generation of platinum antineoplastic drugs, respectively.
- Pt (IV) compounds that have been used in therapy, such as iproplatin and tetraplatin. But all these antineoplastic platinum agents have important adverse effects. Thus, providing new and / or better platinum antineoplastic agents is a problem that is not yet adequately resolved.
- This invention provides a new symmetric complex of Pt (III), (Pt-Pt) -dichlorotetrakisf ⁇ - (2 (lH) -pyrimidinothionate-Nl: S2)] di-platinum of formula (I),
- S-N represents the anion 2-mercaptopirimidinate, that is:
- the platinum complex (I) is a brown solid prepared here for the first time.
- Goodgame and cois. (Inora. Chiro. Acta 1986, vol. 120, pp. 91-101) have published the preparation, as an orange solid, of a constitutional isomer of (I), namely the non-symmetrical complex of Pt (III) that Chemical Abstracts Service has called (Pt-Pt) - dichlorotetrakis [ ⁇ - (2 (1H) -pyrimidinothionate-Nl: S2)] di-platinum and signed with the CAS registration number [106548-19-0], of formula ( II), in which SN represents the same 2-mercaptopyrimidinate anion as in (I). But a therapeutic activity for said compound (II) has never been mentioned or suggested.
- the 195 Pt-NMR spectrum of the platinum complex (I) shows a single signal at -1179 ppm (referred to K 2 PtCl ⁇ ), which corresponds to an oxidation state Pt (III) and represents an intermediate displacement between those of Pt (II) and those of Pt (IV) for a similar environment.
- the presence of a single signal for Pt (III) in the platinum complex (I) indicates that the two platinum atoms have a symmetrical environment, of the PtClN2S 2 type.
- the crystalline structure indicates that there are two types of environments for Pt: PtClN 3 S and PtClNS 3 .
- Example 1 Another embodiment of this invention, illustrated in Example 1, is a method of preparing the platinum complex (I) comprising mixing an aqueous solution of dipotassium tetrachloroplatinate (K 2 PtCl 4 ) with an aqueous suspension of 2-mercaptopyrimidine, at a temperature between ambient and 50 ° C, preferably at about 40 ° C.
- the molar ratio between dipotassium tetrachloroplatinate and 2-mercaptopyrimidine is about 1: 2.
- Another embodiment of this invention is a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of the platinum complex (I), in combination with pharmaceutically acceptable excipients for oral or parenteral administration.
- This invention also relates to a method of treating a mammalian suffering from cancer, which comprises administering to said mammal an effective amount of the platinum complex (I), in combination with pharmaceutically acceptable excipients.
- another embodiment of this invention is the use of the platinum complex (I) for the preparation of a medicament for the treatment of cancer in mammals.
- cancer It is selected from the group consisting of human leukemia and human uterine cancer.
- compositions of the platinum complex (I) can be formulated in the form of solid preparations such as tablets, pills, granules, capsules, powders or the like; or in the form of liquid preparations such as solutions, suspensions, emulsions or the like. They are preferred excipients or carriers for oral administration of (I), sucrose, starch, lactose, crystalline cellulose, kaolin, talc, calcium carbonate, magnesium carbonate and the like.
- a pharmaceutical composition of (I) is used in parenteral administration, it is preferably formulated as a suppository, injection, intravenous drip infusion, or the like.
- the compound (I) is preferably dissolved or suspended in distilled water or in an aqueous solution of sodium chloride.
- the compound (I) is preferably dissolved in a suitable fluid, such as physiological saline.
- a suitable fluid such as physiological saline.
- cocoa butter, glycergelatin, macrogol or laurin is preferably used as a base.
- Example 2 illustrates the interaction of the platinum (I) complex with DNA using various techniques, and justifies its surprisingly high antineoplastic activity.
- the platinum complex (I) due to the presence of two weak sites on the opposite sides of the complex (the two Pt-Cl bonds), causes the double helix to unwind and destabilizes the secondary structure of the DNA, at room temperature.
- Other experiments indicate that the platinum complex (I) bond induces an interaction between different DNA molecules.
- Experiments of circular dichroism and UV spectroscopy prove that the platinum complex (I) induces a certain decrease in the DNA denaturation temperature.
- An Atomic Forces Microscopy study of the interaction of the platinum complex (I) with a linear DNA fragment indicates the formation of a cluster that has an area larger than a fragment alone, thus indicating that The complex produces the aggregation of several DNA fragments.
- the antineoplastic activity of the platinum complex (I) is illustrated in Example 3 by in vitro assays with two tumor cell lines: the human uterine cancer HeLa cells and the human leukemia HL-60 cells.
- the platinum complex (I) is more active than cisplatin in both lines.
- the drastic effects of (I) on the DNA are probably related to the structure of the complex, but it cannot be ruled out that the oxidation state III plays a role in the cytotoxicity mechanism.
- An additional advantage of the use of the complex (I) in therapeutics lies in its relatively low toxicity.
- Figure 1 is a photomicrograph of plasmid PBR322 alone.
- Figure 2 is a photomicrograph of plasmid PBR322 after 24 h of incubation with cisplatin, illustrating DNA compaction.
- Figure 3 is a photomicrograph of the plasmid
- Figure 4 is a photograph of atomic force microscopy (Atomic Forces Microscopy) of hliM, a linear DNA fragment.
- Figure 5 corresponds to the hliM fragment after 24 h of incubation with cisplatin, illustrating the compaction of the DNA molecules.
- Figure 6 corresponds to the hliM fragment after 24 h of incubation with the platinum complex (I), illustrating the compaction and aggregation of the DNA molecules
- Figure 7 is a graphic illustration of the variation in the percentage of survival (S,%) of the HL-60 tumor cells with the dose (C, ⁇ M) of the cisplatin (Cispt) and the platinum complex (I).
- Figure 8 is a graphic illustration of the variation in the percentage of survival (S,%) of HeLa tumor cells with the dose (C, ⁇ M) of cisplatin (Cispt) and platinum complex (I). The variation (practically zero) has also been included with the dose of 2-mercaptopyrimidine (Spym).
- the brown solid obtained was characterized as the platinum complex (I), by the following spectroscopic data: FT-IR, v (cm ⁇ ): 1605S, 1575S, 1542m, 1248m, 1175m, 1026W, 1024W, 752s, 484m, 440w , 432w, 296w, 225w. ⁇ ⁇ -NMR, d 6 -DMSO, ⁇ (ppm): 9.24d, 8.68s, 7.36t. 13 C-NMR, d 6 -DMS0, ⁇ (ppm): 180.69, 158.63, 157.36, 117.76. 195 Pt-NMR, d 6 -DMSO, ⁇ (ppm): -1179 (single peak).
- Figures 1, 2 and 3 show photomicrographs obtained with Philips EM 200 and Philips EM 301 electronic transmission microscopes at 80,000 V, the first working at 25,800 and 54,900 increases and the second at 16,000, 20,000 and 26,000 increases.
- Figure 1 corresponds to plasmid PBR322 alone;
- Figure 2 corresponds to the plasmid incubated with cisplatin, at a 0.50 molar ratio, for 24 h;
- Figure 3 corresponds to the plasmid incubated with (I), at a 0.50 molar ratio, for 24 h.
- the plasmid was only in a closed circular shape, with different degrees of curl; a small percentage of linear form was also observed (Figure 1).
- Cisplatin caused a compaction in the plasmid, as previously described ( Figure 2).
- the platinum complex (I) not only caused a compaction, but also a lateral aggregation with other plasmid molecules ( Figure 3).
- Compaction with (I) was more intense than with cisplatin, under the same experimental conditions. This indicated that (I) induces some kind of interaction between different plasmid molecules, probably due to platinum bonding with two different molecules.
- Figures 4, 5 and 6 show the images obtained by atomic force microscopy (using an Extended Extended Nanoscope III, Digital Instruments, Santa Barbara, CA, working in TMAFM mode at about 100 nN).
- Figure 4 corresponds to hliM, a linear fragment of DNA;
- Figure 5 corresponds to the same DNA incubated 24 h with cisplatin;
- Figure 6 corresponds to the same DNA incubated 24 hours with the platinum complex (I).
- the concentration in DNA was the same in all samples.
- the cisplatin seemed to compact and distort. In the magnification corresponding to 400 nm, several points were observed where the fragment was double. The measurement of the length of this fragment in the microscope revealed such modification. The area measurement also showed that there was no aggregation between the different linear DNA fragments.
- the type of cisplatin binding to DNA is reflected, mainly to two internal N sites. However, after incubation of the DNA with (I), aggregation and compaction phenomena were observed.
- the cluster formed had an area greater than that of a single fragment, indicating that the presence of the complex had caused the aggregation of several DNA fragments.
- the linkage of (I) induces the interaction between different DNA molecules. Probably (I) is linked through two lateral sites, after the Pt-Cl bond has been hydrolyzed. It was found that the observed effect was not due to the ligand itself.
- EXAMPLE 3 Antineoplastic activity of the platinum complex (I) The tests were performed on two tumor cell lines: HeLa cells of human uterine cancer, and HL-60 human leukemia cells. The tests were conducted with cisplatin as a reference, with the 2-mercaptopyrimidine ligand (Spym), and with the platinum complex (I) prepared in Example 1.
- Figures 7 and 8 show the survival percentage, S (%), versus dose (C, ⁇ M), for the HL-60 and HeLa tumor lines, respectively.
- the corresponding LC 50 parameters were the following: For the HL-60 tumor line, 35.0 ⁇ M with cisplatin and 3.5 ⁇ M with (I); for the HeLa tumor line, 37.0 ⁇ M with cisplatin and 3.5 ⁇ M with (I). The values of (I) were better than those of cisplatin, in the case of the HL-60 tumor line. The difference between cisplatin and (I) was still greater in the case of the HeLA tumor line. 2-Mercaptopyrimidine (Spym) alone did not cause cell death.
- aqueous suspension of the platinum complex (I) is loaded in vials, under aseptic conditions. Each vial contained 50 mg of (I). The vials were dried, sterilized and sealed. When used as an injection, 10 mL of physiological saline was added to each vial to prepare the injection.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU58644/98A AU5864498A (en) | 1997-02-13 | 1998-02-10 | Platinum complex with antineoplasic activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ESP9700403 | 1997-02-13 | ||
ES9700403 | 1997-02-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998035972A1 true WO1998035972A1 (es) | 1998-08-20 |
Family
ID=8298399
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/ES1998/000027 WO1998035972A1 (es) | 1997-02-13 | 1998-02-10 | Complejo de platino con actividad antineoplasica |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU5864498A (es) |
WO (1) | WO1998035972A1 (es) |
-
1998
- 1998-02-10 AU AU58644/98A patent/AU5864498A/en not_active Abandoned
- 1998-02-10 WO PCT/ES1998/000027 patent/WO1998035972A1/es active Application Filing
Non-Patent Citations (3)
Title |
---|
D. GOODGAME ET AL.: "Synthesis and X-Ray structural studies of some dinuclear Platinum (III) complexes of pyrimidine-2-thione and 2-thiouracil", INORGANIC CHIMICA ACTA,, vol. 120, no. 1, 1986, pages 91 - 101 * |
G. CERVANTES ET AL.: "Antitumor activity of a Pt (III) derivative of 2-mercaptopyrimidine", METAL-BASED DRUGS,, vol. 4, no. 1, 1997, pages 9 - 18 * |
T. UEMURA ET AL.: "ESR of Pt (III) in anticancer platinum pyrimidine green", CHEMICAL PHYSICS LETTERS,, vol. 142, no. 5, 1987, pages 423 - 425 * |
Also Published As
Publication number | Publication date |
---|---|
AU5864498A (en) | 1998-09-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Galanski et al. | Recent developments in the field of tumor-inhibiting metal complexes | |
KR100484504B1 (ko) | 쿠커비투릴 유도체를 주인 분자로서 포함하고 있는 내포화합물 및 이를 포함한 약제학적 조성물 | |
PT943331E (pt) | Formulacoes que contem oxaliplatina | |
US20070207993A1 (en) | Molybdenum carbonyl complexes for treating rheumatoid arthritis and other inflammatory diseases | |
CN105753922A (zh) | 用于肿瘤治疗四价铂糖基配合物及其制备方法 | |
WO2007073226A1 (en) | Method for treating a mammal by administration of a compound having the ability to release co | |
FI116058B (fi) | Kolme ydintä käsittävät kationiset platinakompleksit, joilla on kasvaimenvastainen vaikutus, sekä niitä sisältävät farmaseuttiset koostumukset | |
US6340770B1 (en) | Platinum (IV) complex used as anti-cancer agent and preparing method thereof | |
PT701440E (pt) | Complexos tri(platinicos) | |
WO2005090372A2 (en) | Platinum carboxylate anticancer compounds | |
WO1998035972A1 (es) | Complejo de platino con actividad antineoplasica | |
EP0793667B1 (en) | Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them | |
ES2284061T3 (es) | Procedimiento para la produccion de sales y derivados de trans- o cis-diamoniodiclorodihidroxoplatino (iv) y su uso para la produccion de principios activos farmaceuticos. | |
ES2198580T3 (es) | Nuevas sales de compuestos anionicos de ru (iii), utilizados como agentes antimetastasicos y antineoplasticos. | |
US7268245B2 (en) | Multinuclear platinum compounds | |
ES2272755T3 (es) | Agente antitumoral organometalico. | |
US8703756B2 (en) | Synthetic procedure and cancer treatment with cisplatin derivatives | |
ES2206230T3 (es) | Complejos dimericos de rutenio adecuados como agentes antineoplasticos y antimetastasicos. | |
ES2246150B1 (es) | Compuestos trans de platino (ii) de formula trans-(ptcl2(oxima)(amina)), con actividad antitumoral. | |
ES2200967T3 (es) | Complejos de rutenio (ii) con gran actividad antitumoral y antimetastasica. | |
JP2005511497A (ja) | 光反応性化合物および組成物 | |
ES2401553T3 (es) | Complejo de platino con actividad antitumoral | |
ES2214137B1 (es) | Compuestos trans de platino (ii) de formula trans- (ptcl2 (amina) ( dimetilamina)), con actividad antitumoral. | |
KR101560263B1 (ko) | 신규 4핵 아렌-루테늄 화합물 및 이를 유효성분으로 함유하는 암질환의 치료 또는 예방용 약학조성물 | |
ES2321785B1 (es) | Tionato complejos de platino(ii) de estequiometria (pt(r)(r')(l)(l'))n con actividad antitumoral. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 1998535381 Format of ref document f/p: F |
|
122 | Ep: pct application non-entry in european phase |