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ChemSpider 2D Image | Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2) | C12H20N2O8Pt

Dicycloplatin.png

Dicycloplatin

Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2)

  • Molecular FormulaC12H20N2O8Pt
  • Average mass515.380 Da
  • 287402-09-9

Has antineoplastic activity; a supramolecular complex of 1,1-cyclobutane dicarboxylic acid and cis-diammine(1,1-cyclobutane dicarboxylate)platinum (II).

1,1-Cyclobutanedicarboxylic acid, ammonium platinum(2+) salt (2:2:1) [ACD/Index Name]
Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2)
287402-09-9 [RN]
DICYCLOPLATIN
UNII:0KC57I4UNB

Dicycloplatin is a chemotherapy medication used to treat a number of cancers which includes the Non-small-cell lung carcinoma and prostate cancer.[1]

Some side effects which are observed from the treatment by dicycloplatin are nauseavomitingthrombocytopenianeutropeniaanemiafatigueloss of appetiteliver enzyme elevation and alopecia. The drugs is a form of Platinum-based antineoplastic and it works by causing the mitochondrial dysfunction which leads to the cell death.[2]

Dicycloplatin was developed in China and it was used for phase I human trial clinical in 2006. The drug was approved for chemotherapy by the Chinese FDA in 2012.[3]

Image result for DICYCLOPLATIN SYNTHESIS

Medical uses

Dicycloplatin can inhibit the proliferation of tumor cells via the induction of apoptosis . It is used to treat a number types of cancer which are Non-small-cell lung carcinoma and prostate cancer.[4]

Side effects

Similar to cisplatin and carboplatin, dicycloplatin also contains some side effects, which are nauseavomitingthrombocytopenianeutropeniaanemiafatigueanorexia, liver enzyme elevation, and alopecia. However, with doses up to 350 mg/m(2), there is no significant toxicity; these effects are observed only at higher doses. Furthermore, the nephrotoxicity of dicycloplatin is reported to be less than that of cisplatin, and its myelosuppressive potency is similar to that of carboplatin.[5]

Chemical structure

Dicycloplatin consists of carboplatin and cyclobutane-1,1-dicarboxylic acid (CBDC) linked by the hydrogen bond. In the structure of dicycloplatin, there are two types of bond: O-H…O is the bond between the hydroxyl group of CBDC with carboxyl oxygen atom. It creates the one-dimensional polymer chain of carboplatin and CBDC. The second one is N-H…O which links between the ammoniagroup of carboplatin and oxygen of CBDC. It forms the two-dimensional polymer chain of carboplatin and CBDC. In aqueous solution, the 2D-hydrogen bonded polymeric structure of dicycloplatin is destroyed. Firstly, the bond between ammonia group of carboplatin and oxygen of CBDC breaks, thus inducing the formation of one-dimensional dicycloplatin. After that, the strong hydrogen bond breaks and creates an intermediate state of dicycloplatin. Finally, the rearrangement of different orientation of carboplatin and CBDC leads to the formation of intramolecular hydrogen bond and a supramolecule of dicycloplatin with two O-H…O and N-H…O is created.[6]

Mechanism of action

Similar to carboplatin, dicycloplatin inhibits the proliferation of cancer cells by inducing cell apoptosis. When treated with dicycloplatin, some changes in the properties of Hep G2 cells are observed: the declination of Mitochondria Membrane Potential, the release of cytochrome c from mitocondria to cytosol, the activation of caspase-9caspase-3 and the decrease of Bcl-2.[4] Those phenomena indicate the role of mitochondrial in the apoptosis by intrisic way.[7] Furthermore, the increase in caspase-8 activation is also observed. This can stimulate the apoptosis by activating downstream caspase-3 [8] or by cleaving Bid.[9] As a result, the cleavage of Bid (tBid) transfers to the mitochondria and induce mitochondrial dysfunction which promotes the release of cytochrome c from mitochondria to cytosol.[10] From the dicycloplatin-treated Hep G2 cell, an excessive amount of reactive oxygen species was detected,[4] which plays an important role in the release of cytochrome c. In the mitochondria, the release of hemoprotein happens through 2-step process: Firstly, the dissociation of cytochrome c from its binding to cardiolipin happens. Due to the reactive oxygen species, the cardiolipin is oxidized, thus reducing the cytochrome c binding and increase the concentration of free cytochrome c [11]

PATENT

WO2018171371

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018171371

Since the FDA approved cisplatin as an anticancer drug in 1978, the mortality rate of testicular cancer patients has been reduced from 100% to less than 10%. For patients with early detection, the cure rate can reach 100%, making cisplatin An outstanding representative of anticancer drugs. In 1986, the FDA approved the second-generation platinum anticancer drug carboplatin. Its anticancer spectrum is similar to that of cisplatin, but it has good water solubility and light toxicity. In 2002, the FDA approved the third-generation platinum anticancer drug oxaliplatin to enter clinical treatment of colorectal cancer. Its anticancer spectrum is different from cisplatin, and it does not produce cross-resistance with cisplatin.
In addition to the above three products, four products, including Nida Platinum, Shuplatin, Lobaplatin and Miplatin, have been listed in different countries and are the first in other countries.
In CN1311183A, Yang Xuqing et al. designed and prepared a new class of platinum antitumor drugs, diammonium platinum dichloride (II) derivatives, based on the abnormal changes in the spatial configuration of cancer cells DNA and RNA. A typical representative drug is bicycloplatinum. Bicycloplatinum in English is called Dicycloplatin, which is called bis(1,1-cyclobutanedicarboxylic acid) diammine platinum (II) (English name [Bis-(1,1-cyclobutane dicarboxylic acid)]diammine platinum(II) ), the structural formula is:
It is a supramolecular compound composed of carboplatin and 1,1-cyclobutanedicarboxylic acid through four hydrogen bonds. It is the first self-developed platinum antitumor drug in China with broad spectrum, low toxicity and high efficiency. It does not produce cross-resistance and good penetrability.
Bicycloplatinum is usually obtained by reacting carboplatin with 1,1-cyclobutanedicarboxylic acid. The prior art discloses various preparation methods, but both have the problems of complicated preparation process and low product purity.
CN1311183A As the earliest publication of bicycloplatin and its preparation method, it is disclosed that bicycloplatinum is prepared by the following method: carboplatin is dissolved in pure water at normal temperature, and then an equimolar amount of 1,1-cyclobutanedicarboxylic acid is added. After the reaction was completed, it was evaporated to dryness, washed with ethanol, and then recrystallized from distilled water. This method is cumbersome in operation due to the need for evaporation and recrystallization steps, and the yield of bicycloplatinum is low.
CN104693245A discloses a preparation method of bicyclo platinum, which is prepared by using carboplatin as a raw material in a ratio of 1:11 to 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1, and is protected from light at 0-60 ° C. After -9 days, the excess water is removed by concentration under reduced pressure or freeze-drying to obtain a bicyclic platinum product. Although according to reports, the HPLC purity of the product is more than 99%, it requires a long standing process, is inefficient, and greatly increases the risk of carboplatin decomposition, especially for the process of amplification; The heating and concentration in the final process makes the bicyclic platinum product exist in the higher temperature aqueous solution for a long time, and the product has a high risk of degradation, and the quality stability is inevitably affected. In fact, bicycloplatinum with the reported yield and purity was not obtained according to this method.
CN106132408A discloses a process for the preparation of another bicyclic platinum in which carboplatin is mixed with a corresponding ratio of 1,1-cyclobutanedicarboxylic acid and a solvent to form a suspension, and the precipitated solid formed is separated from the suspension. Although the report states that the obtained product does not contain XRPD detectable amount of carboplatin, the suspension method uses a small amount of solvent, so that the product formed during the reaction is also precipitated as a solid, which is mixed with the unreacted raw material solid. This prevents the reaction from proceeding and makes the purification of the product more difficult. Especially in the case where the product is coated with carboplatin, the carboplatin can hardly be removed by purification. Therefore, the suspension method has the disadvantages of difficulty in control, poor operability, and incapability of industrial scale-up production. In fact, bicycloplatinum with the reported yield and purity cannot be obtained according to this method as well.
1 is a nuclear magnetic resonance-hydrogen spectrum of the bicyclic platinum product of Example 1.
2 is a nuclear magnetic resonance-carbon spectrum of the bicyclic platinum product of Example 1.

Drawing

[ figure 1] 

[ figure 2] 
Preparation Example 1:
Take 20.0 g of cis-diiododiammine platinum (II), add 600 ml of purified water, stir well and heat to 80 ° C in water bath, then add 14.1 g of silver 1,1-cyclobutanedicarboxylate, after reacting for 30 minutes. The AgI slag was filtered off, and the filtrate was concentrated under reduced pressure to a residue of about 50 ml, cooled to room temperature, and the precipitated product was filtered. After recrystallization, the mixture was dried at 60 ° C to obtain 11.26 g of carboplatin, and the yield was 69.88%.
Example 1
32.0 g (222.2 mmol) of 1,1-cyclobutanedicarboxylic acid was taken, and 260 ml of water was added thereto, and the mixture was heated to 80 ° C in a water bath. Add 10.0 g (26.95 mmol) of carboplatin, stir for 40 minutes, cool at 10 ° C for 8 hours, filter the precipitated solid, wash the filter cake with appropriate amount of purified water, drain the washing water, and dry at 40 ° C under reduced pressure to obtain bicyclo platinum 9.32 g. The yield is 67.15% and the content is 99.78%. The obtained products were characterized by elemental analysis, negative ion electrospray mass spectrometry, nuclear magnetic resonance-hydrogen spectroscopy, nuclear magnetic resonance-carbon spectroscopy and X-ray diffraction. The content of bicycloplatin was measured by high performance liquid chromatography.
The test results are shown in Figure 1. The attribution of each peak is as follows:
The peak of chemical shift 1.7159-1.7793ppm is H a , the actual number of hydrogen nuclei is 2, and it is divided into 5 heavy peaks by 4 H b on both sides ; the peak of chemical shift 1.8281-1.8928ppm is H c , actual hydrogen the number of cores 2, a total of four sides by H D impact crack 5 doublet; 2.3965-2.4288ppm peak chemical shift of H B , the actual number of hydrogen nuclei to 4, were subjected to unilateral 2 H a of Effect split into three doublet; 2.7140-2.7457ppm peak chemical shift of H D , the actual number of hydrogen nuclei is 4, were subjected to unilateral 2 H Caffected divided into three split doublet; chemical shifts of the peaks 4.0497ppm is H E , the actual number of hydrogen nuclei 6 as broad singlet; due to D 2 exchange interaction of O, carboxy FIG active hydrogen protons H does not appear f peaks. 4. Nuclear Magnetic Resonance – Carbon Spectrum (D 2 O, 500MHz)
The test results are shown in Figure 2, where the peaks are as follows:
The peak of chemical shift 15.25ppm is C a ; the peak of chemical shift 15.39ppm is C h ; the peak of chemical shift 28.60ppm is C b ; the peak of chemical shift 31.02ppm is C g ; the peak of chemical shift 52.93ppm is C c ; The peak of chemical shift 56.19 ppm is C f ; the peak of chemical shift 176.11 ppm is C d ; the peak of chemical shift 181.85 ppm is C e .

PATENT

WO-2019161526

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019161526&tab=FULLTEXT&_cid=P20-K0667C-67730-1

One-pot method for preparing twin dicarboxylic acid diamine complex platinum (II) derivatives ( dicycloplatin ) comprising the separation of intermediate carboplatin or carboplatin analogue.

For the preparation of bicycloplatin, CN1311183A, as the earliest publication of bicycloplatin and its preparation method, discloses the preparation of bicycloplatinum by the following method: carboplatin is dissolved in pure water at normal temperature, and then an equimolar amount of 1,1-ring is added. Butane dicarboxylic acid was evaporated to dryness after completion of the reaction, washed with ethanol, and recrystallized from distilled water. The method needs to completely evaporate the solvent water, which increases the risk of degradation of the bicyclic platinum, and also introduces more impurities into the crude bicycloplatinum. Therefore, ethanol washing and recrystallization are required, and the operation is cumbersome, and the yield of the bicyclic platinum is low.

[0015]
CN104693245A discloses a preparation method of bicyclo platinum, which is prepared by using carboplatin as a raw material in a ratio of 1:11 to 1,1-cyclobutanedicarboxylic acid in a molar ratio of 1:1, and is protected from light at 0-60 ° C. After -9 days, the excess water is removed by concentration under reduced pressure or freeze-drying to obtain a bicyclic platinum product. Although according to reports, the HPLC purity of the product is more than 99%, it requires a long standing process, is inefficient, and greatly increases the risk of carboplatin decomposition, especially for the process of amplification; In the final process, the solvent water is completely evaporated to make the bicyclic platinum product exist in a relatively high temperature aqueous solution for a long time, and the product has a high risk of degradation, and the quality stability is inevitably affected. In fact, bicycloplatinum with the reported yield and purity was not obtained according to this method.

[0016]
CN106132408A also discloses a process for the preparation of another bicyclic platinum in which carboplatin is mixed with a corresponding ratio of 1,1-cyclobutanedicarboxylic acid and a solvent to form a suspension, and the precipitated solid formed is separated from the suspension. Although the report states that the obtained product does not contain XRPD detectable amount of carboplatin, the suspension method uses a small amount of solvent, so that the product formed during the reaction is also precipitated as a solid, which is mixed with the unreacted raw material solid. This prevents the reaction from proceeding and makes the purification of the product more difficult. Especially in the case where the product is coated with carboplatin, the carboplatin can hardly be removed by purification. Therefore, the suspension method has the disadvantages of difficulty in control, poor operability, and incapability of industrial scale-up production. In fact, bicycloplatinum with the reported yield and purity cannot be obtained according to this method as well.

Notes

  1. ^ D., Zhao; Y., Zhang; C., Xu; C., Dong; H., Lin; L., Zhang; C., Li; S., Ren; X., Wang; S., Yang; D., Han; X., Chen (February 2012). “Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding Study of Platinum Originating from Dicycloplatin, a Novel Antitumor Supramolecule, in Rats and Dogs by ICP-MS”. Biological Trace Element Research148 (2): 203–8. doi:10.1007/s12011-012-9364-2PMID 22367705.
  2. ^ G.Q., Li; X.G., Chen; X.P., Wu; J.D., Xie; Y.J., Liang; X.Q., Zhao; W.Q, Chen; L.W., Fu (November 2012). “Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis”PLOS ONE7 (11): e48994. Bibcode:2012PLoSO…748994Ldoi:10.1371/journal.pone.0048994PMC 3495782PMID 23152837.
  3. ^ J.J, Yu; X.Q, Yang; Q.H, Song; M. D., Mueller; S. C., Remick (2014). “Dicycloplatin, a Novel Platinum Analog in Chemotherapy: Synthesis of Chinese Pre-clinical and Clinical Profile and Emerging Mechanistic Studies”Anticancer Research34: 455–464.
  4. Jump up to:a b c Guang-quan, Li; Xing-gui, Chen; Xing-ping, Wu; Jing-dun, Xie; Yong-ju, Liang; Xiao-qin, Zhao; Wei-qiang, Chen; Li-wu, Fu (November 2012). “Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis”PLOS ONE7 (11): e48994. Bibcode:2012PLoSO…748994Ldoi:10.1371/journal.pone.0048994PMC 3495782PMID 23152837.
  5. ^ Li.S; Huang H; Liao H; Zhan J; Guo Y; Zou BY; Jiang WQ; Guan ZZ; Yang XQ (2015). “Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results”. International Journal of Clinical Pharmacology and Therapeutics51 (2): 96–105. doi:10.5414/CP201761PMID 23127487.
  6. ^ Y., Xu Qing; J., Xiang Lin; S., Q.; TANG, Ka Luo; Y., Zhen Yun; Z., Xiao Feng; T., You Qi (June 2010). “Structural studies of dicycloplatin, an antitumor supramolecule”. Science China Chemistry53 (6): 1346–1351. doi:10.1007/s11426-010-3184-z.
  7. ^ R., Kumar; P.E., Herbert; A.N., Warrens (September 2005). “An introduction to death receptors in apoptosis”. International Journal of Surgery3 (4): 268–77. doi:10.1016/j.ijsu.2005.05.002PMID 17462297.
  8. ^ Yang, BF; Xiao, C; Li, H; Yang, SJ (2007). “Resistance to Fas-mediated apoptosis in malignant tumours is rescued by KN-93 and cisplatin via downregulation of cFLIP expression and phosphorylation”. Clinical and Experimental Pharmacology and Physiology34 (12): 1245–51. doi:10.1111/j.1440-1681.2007.04711.xPMID 17973862.
  9. ^ Blomgran, R; Zheng, L; Stendahl, O (2007). “Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization”. Journal of Leukocyte Biology81 (5): 1213–23. doi:10.1189/jlb.0506359PMID 17264306.
  10. ^ Yin, XM (2006). “Bid, a BH3-only multi-functional molecule, is at the cross road of life and death”. Gene369: 7–19. doi:10.1016/j.gene.2005.10.038PMID 16446060.
  11. ^ Ott, M; Gogvadze, V; Orrenius, S; Zhivotovsky, B (May 2007). “Mitochondria, oxidative stress and cell death”. Apoptosis12 (5): 913–22. doi:10.1007/s10495-007-0756-2PMID 17453160.
Dicycloplatin
Dicycloplatin.png

Chemical structure of Dicycloplatin
Clinical data
Trade names Dicycloplatin
Synonyms Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2), 1,1-Cyclobutanedicarboxylic acid, compd. with (sp-4-2)-diammine(1,1-cyclobutanedi(carboxylato-kappaO)(2-))platinum (1:1)
Routes of
administration
Intravenous
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding < 88.7%
Elimination half-life 24.49 – 108.93 hours
Excretion Renal
Identifiers
CAS Number
ChemSpider
UNII
Chemical and physical data
Formula C12H20N2O8Pt
Molar mass 515.382 g/mol
3D model (JSmol)

/////////////Dicycloplatin

C1CC(C1)(C(=O)O)C(=O)O.C1CC(C1)(C(=O)[O-])C(=O)[O-].N.N.[Pt+2]

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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