WO2014175841A1 - Palladium complexes of curcumin and its analogues and methods of preparation of the same - Google Patents

Palladium complexes of curcumin and its analogues and methods of preparation of the same Download PDF

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WO2014175841A1
WO2014175841A1 PCT/SK2014/050004 SK2014050004W WO2014175841A1 WO 2014175841 A1 WO2014175841 A1 WO 2014175841A1 SK 2014050004 W SK2014050004 W SK 2014050004W WO 2014175841 A1 WO2014175841 A1 WO 2014175841A1
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curcumin
analogues
general formula
palladium
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French (fr)
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Natalia MIKLASOVA
Roman MIKLAS
Ferdinand DEVINSKY
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Univerzita Komenskeho V Bratislave
Centrum Vedecko-Technickych Informacii Sr (Cvti Sr)
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    • 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 System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/006—Palladium compounds
    • C07F15/0066—Palladium compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to palladium(II) complexes of curcumin and its analogues, as well as the process for preparing the same. These compounds are able to inhibit the growth of certain types of human cancer cells.
  • Curcumin as well as its analogues (which are present mostly in the enol form, depending on the solvent (Stankovic I., 61st IFCFA, Chemical and Technical Assessment, 2004, 1- 7)), as a ligand is able to form complexes with metals, mainly iron, copper, zinc, but also palladium (e.g. Kuhlwein, F.; Polborn K.; Beck W., Zeitschrift fuer Anorganische und dealt Chemie, 623(8), 1997, 1211- 1219; Krishnankuttz K., Venugopalan P., Synth. React. Inorg. Met.-Org. Chem., 28(8), 1998, 1313-1325; Sundaryono, A.
  • metals mainly iron, copper, zinc, but also palladium
  • WO 2008/076965 Al discloses the palladium(II) complex tris(dibenzylideneacetone)dipalladium [Pd 2 (DBA) 3 ], however, this complex does not contain curcumin and the process for preparing the complexes of curcumin and its analogues with metal is not disclosed.
  • US 2010261923 Al discloses zinc-curcumin complexes, John V. D. et al. in Antitumor activity of synthetic curcuminoid analogues (l,7-diaryl-l,6-heptadiene-3,5-dione) and their copper complexes, Appl. Organomet. Chem. Vol. 20, pp.
  • the present invention provides palladium(II) complexes of curcumin and its analogues of general formula: OCOCH 3
  • Ri and R 2 are each independently hydrogen, hydroxy, methoxy or ethoxy.
  • the present invention also provides the process for preparing the palladium(II) complexes by reacting [( ?,R)-N,N,N',N'-tetramethylcyclohexane-l,2-diamine)Pd(OAc)2] (hereinafter referred to as "[(tmcyda)Pd(OAc) 2 ]”) or [ 1 ,4-dimethylpiperazine)Pd(OAc) 2 ] (hereinafter referred to as "[(dmpip)Pd(OAc) 2 ]”) of general formula:
  • the chlorinated solvent is preferably chloroform or dichloromethane .
  • the reaction can be carried out in the presence of 15 to 40 ⁇ aqueous base solution selected from the group comprising NaOH, KOH and LiOH, preferably 30 ⁇ of 1M aqueous NaOH, as well as in anhydrous methanol, preferably isopropyl alcohol, at the temperature of 20 to 50 °C for 20 to 50 hours or in anhydrous chloroform at the temperature of 20 to 60 °C for 20 to 140 hours.
  • aqueous base solution selected from the group comprising NaOH, KOH and LiOH, preferably 30 ⁇ of 1M aqueous NaOH, as well as in anhydrous methanol, preferably isopropyl alcohol, at the temperature of 20 to 50 °C for 20 to 50 hours or in anhydrous chloroform at the temperature of 20 to 60 °C for 20 to 140 hours.
  • the curcumin or its analogue (0.05 mmol - 0.30 mmol) is dissolved in 5 - 20 ml of dry alcohol (CI - C4) or chlorinated solvent (chloroform, dichloromethane).
  • the solution of palladium(II) complex (0.05 mmol - 0.20 mmol) in 5 - 20 ml of dry alcohol (CI - C4) or chlorinated solvent (chloroform, dichloromethane) with or without 30 ⁇ of IM aqueous base solution (NaOH, KOH, LiOH) is added to this solution.
  • the reaction mixture is stirred for 12 - 140 hours at the temperature between 15 and 50 °C and then filtered.
  • the solvent is removed under the reduced pressure and the residue is purified by chromatography (Si0 2 , CHC1 3 : MeOH).
  • the procedure was the same as in Example 1, except that anhydrous isopropyl alcohol was used instead of anhydrous methanol.
  • Example 4a Process for preparing Complex 2b, wherein - OC3 ⁇ 4, R? - OCH
  • the structures of complexes of curcumin and its analogues with palladium la - 4b represent novel compounds. They were tested on human prostate cancer cells. It was confirmed that the complexation with palladium increased the anti-tumor activity of curcumin.
  • the palladium(II) complexes of curcumin are able to inhibit the growth of certain types of human cancer cells: ovarian carcinoma, colorectal carcinoma, melanoma, cervical carcinoma, liver carcinoma, prostate carcinoma and breast carcinoma (Table 1). Table 1. Examples of antineoplastic activity of compounds of the invention
  • the compounds exhibit activity also against cancer cells with developed resistance to standard metal based drugs (A2780cis cells of ovarian carcinoma resistant to Cis-platin, HT-29 and Colo320 cell lines resistant to Oxalilplatin), see Table 2.

Abstract

The invention relates to palladium(II) complexes of curcumin and its analogues of general formula (Formula (A)) wherein R1 and R2 are each independently hydrogen, hydroxy, methoxy or ethoxy, as well as the process for preparing the same by reacting the complex compounds [(tmcyda)Pd(OAc)2 ] or [(dmpip)Pd(OAc)2] of general formula ((Formula (B) with curcumin or its analogues of general formula (Formula (B)) wherein R1 and R2 are the same as defined above, in an alcohol having 1 to 4 carbon atoms, or in chlorinated solvents, selected from the group comprising chloroform and dichloromethane, for 12 to 140 hours at the temperature of 15 to 50 °C.

Description

PALLADIUM COMPLEXES OF CURCUMIN AND ITS ANALOGUES AND METHODS OF PREPARATION OF THE SAME
TECHNICAL FIELD
This invention relates to palladium(II) complexes of curcumin and its analogues, as well as the process for preparing the same. These compounds are able to inhibit the growth of certain types of human cancer cells.
BACKGROUND OF THE INVENTION
Curcumin, as well as its analogues (which are present mostly in the enol form, depending on the solvent (Stankovic I., 61st IFCFA, Chemical and Technical Assessment, 2004, 1- 7)), as a ligand is able to form complexes with metals, mainly iron, copper, zinc, but also palladium (e.g. Kuhlwein, F.; Polborn K.; Beck W., Zeitschrift fuer Anorganische und Allgemeine Chemie, 623(8), 1997, 1211- 1219; Krishnankuttz K., Venugopalan P., Synth. React. Inorg. Met.-Org. Chem., 28(8), 1998, 1313-1325; Sundaryono, A. Nourmamode, C. Gardrat, A. Fritsch , A. Castellan, Journal of Molecular Structure, 649, 2003, 177-190; Ghedini M.; Pucci D.; Crispini A.; Bellusci A.; La Deda M.; Aiello I.; Pugliese T. Inorg. Chem. Commun. 10(2), 2007, 243-246; de Fatima A.; Modolo L.V.; Neres A.T.M.; Ferreira C.V.; de Souza A.C.S., Current Bioactive Compounds, 4(3), 2008, 189- 199; Pucci D.; Bloise R.; Bellusci A.; Bernardini S.; Ghedini M.; Valentini A.; Crispini A., Molecular Crystals and Liquid Crystals, 481, 2008, 14-25; Baum L.; Ng A., J. Alzhaimer Dis. 6, 2004, 367-377). Some research teams have focused on the preparation of palladium(II) complexes with bidentate ligands [(bipy)Pd(pCurc)][CF3S03], wherein bipy = 2,2' - bipyridine (Valentini A.; Conforti F.; Crispini A.; De Martino A.; Condello R.; Stellitano C; Rotilio G.; Ghedini M.; Federici G.; Bernardini S.; Pucci D., J. Med. Chem. 52(2), 2009, 484-491) and [LPd(curc)], or [(L)Pd(curc22)], wherein L = hexadecyl 2- phenylchinoline-4-carboxylate (Pucci D.; Bloise R.; Bellusci A.; Bernardini S.; Ghedini M.; Pirillo S.; Valentini A.; Crispini A., J. Inorg. Biochem. 101(7), 2007, 1013- 1022). Valentini et al. in Synthesis, oxidant properties and antitumor effect of a heteroleptic palladium(II) complex of curcumin on human prostate cancer cells, J. Med. Chem. Vol. 52, pp. 484-491, 2009, as well as Pucci D. et al. in Curcumin and cyclop alladated complexes: a recipe for bifunctional biomaterials, vol. 101, pp. 1013- 1022, 2007 disclose the preparation of long-chain ligands (dinonylbipyridine and hexadecylphenylchinoline), wherein alcohol (exclusively methanol) is used as a solvent.
WO 2008/076965 Al discloses the palladium(II) complex tris(dibenzylideneacetone)dipalladium [Pd2(DBA)3], however, this complex does not contain curcumin and the process for preparing the complexes of curcumin and its analogues with metal is not disclosed. US 2010261923 Al discloses zinc-curcumin complexes, John V. D. et al. in Antitumor activity of synthetic curcuminoid analogues (l,7-diaryl-l,6-heptadiene-3,5-dione) and their copper complexes, Appl. Organomet. Chem. Vol. 20, pp. 477-482, 2006 discloses copper complexes with curcuminoids: of 1,7- bis(4-hydroxyphenyl)-l,6-heptadiene-3,5-dione, l,7-di(2-furyl)-l,6-heptadiene-3,5-dione, l,7-di(2-naphtyl)-l,6-heptadiene-3,5-dione, l,7-bis(2-chlorophenyl)-l,6-heptadiene-3,5- dione) types, which are complexes without palladium, with unsaturations in side chains attached to curcumin.
Rodrigues M. A. et al in Palladium complex containing curcumin as a ligand, Am. J. Chem. Vol. 2, pp. 157-159, 2012 disclose palladium(II) complexes with two curcuminoids as ligands, and WO 2012/076696 Al discloses the complexes of curcuminoids with carbonyls of metals selected from Co, Fe, Mn, Ru, Rh, Ni, Mo, V, Cr, but not complexes with palladium. In all cases the metal carbonyl binds to unsaturated systems containing triple, double, and aromatic bonds as side substituents.
It is an object of the present invention to provide and prepare new complexes of curcumin and its analogues having new structures, which are able to inhibit the growth of human cancer cells.
SUMMARY OF THE INVENTION
The present invention provides palladium(II) complexes of curcumin and its analogues of general formula: OCOCH3
Figure imgf000005_0001
wherein Ri and R2 are each independently hydrogen, hydroxy, methoxy or ethoxy.
The present invention also provides the process for preparing the palladium(II) complexes by reacting [( ?,R)-N,N,N',N'-tetramethylcyclohexane-l,2-diamine)Pd(OAc)2] (hereinafter referred to as "[(tmcyda)Pd(OAc)2]") or [ 1 ,4-dimethylpiperazine)Pd(OAc)2] (hereinafter referred to as "[(dmpip)Pd(OAc)2]") of general formula:
Figure imgf000005_0002
with curcumin or analogues of curcumin of general formula:
Figure imgf000005_0003
form in alcohols having 1 to 4 carbon atoms, or in chlorinated solvents, for 12 to 140 hours at the temperature of 15 to 50°C. The chlorinated solvent is preferably chloroform or dichloromethane .
Preferably, the reaction can be carried out in the presence of 15 to 40 μΐ aqueous base solution selected from the group comprising NaOH, KOH and LiOH, preferably 30 μΐ of 1M aqueous NaOH, as well as in anhydrous methanol, preferably isopropyl alcohol, at the temperature of 20 to 50 °C for 20 to 50 hours or in anhydrous chloroform at the temperature of 20 to 60 °C for 20 to 140 hours.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
General process for preparing the complexes of curcumin and its analogues with palladium:
The curcumin or its analogue (0.05 mmol - 0.30 mmol) is dissolved in 5 - 20 ml of dry alcohol (CI - C4) or chlorinated solvent (chloroform, dichloromethane). The solution of palladium(II) complex (0.05 mmol - 0.20 mmol) in 5 - 20 ml of dry alcohol (CI - C4) or chlorinated solvent (chloroform, dichloromethane) with or without 30 μΐ of IM aqueous base solution (NaOH, KOH, LiOH) is added to this solution. The reaction mixture is stirred for 12 - 140 hours at the temperature between 15 and 50 °C and then filtered. The solvent is removed under the reduced pressure and the residue is purified by chromatography (Si02, CHC13 : MeOH).
Example 1: Process for preparing Complex la, wherein R = OCH , R? = OH
An equimolar amount of [(tmcyda)Pd(OAc)2] solution in 5 ml of anhydrous methanol and 30 μΐ of IM aqueous NaOH was added to curcumin solution (0.15 mmol) in 15 ml of anhydrous methanol. The reaction mixture was stirred for 24 hours at 23 °C.
A dark violet powder was obtained, yield = 55 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1.25 (q, 2H) 1.50 (q, 2H) 1.80 (m, 2H) 2.19 (m, 2H) 2.83 (s, 6H) 2.85 (s, 6H) 3.23 (q, 2H) 3.90 (s, 6H) 5.85 (s, 1H) 6.69(d, 2H) 6.81 (d, 2H) 7.10 (d, 2H) 7.21 (s, 2H) 7.44 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 25.3 (2 C) 25.5 (2 C) 43.6 (2 C) 56.5 (4 C) 73.2 (1 C) 111.6 (2 C) 116.6 (2 C) 123.2 (2 C) 123.3 (2 C) 124.1 (2 C) 128.6 (2 C) 142.0 (2 C) 149.5 (2 C) 150.5 (2 C) 180.0 (2 C)
IR CKB vnax icm"1) 3431, 2941, 1619, 1592, 1501, 1393, 1285, 1162, 1124, 997, 845, 632, 594
Example la: Process for preparing Complex la, wherein Ri = OCH , R? = OH The procedure was the same as in Example 1, except that anhydrous isopropyl alcohol was used instead of anhydrous methanol.
A dark violet powder was obtained, yield = 48 %.
^-NMR (CD3OD, 300 MHz) δ (ppm) 1.25 (q, 2H) 1.50 (q, 2H) 1.80 (m, 2H) 2.19 (m, 2H) 2.83 (s, 6H) 2.85 (s, 6H) 3.23 (q, 2H) 3.90 (s, 6H) 5.85 (s, 1H) 6.69(d, 2H) 6.81 (d, 2H) 7.10 (d, 2H) 7.21 (s, 2H) 7.44 (d,2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 25.3 (2 C) 25.5 (2 C) 43.6 (2 C) 56.5 (4 C) 73.2 (1 C) 111.6 (2 C) 116.6 (2 C) 123.2 (2 C) 123.3 (2 C) 124.1 (2 C) 128.6 (2 C) 142.0 (2 C) 149.5 (2 C) 150.5 (2 C) 180.0 (2 C)
^ (KB vn^cm-1) 3431, 2941, 1619, 1592, 1501, 1393, 1285, 1162, 1124, 997, 845, 632, 594
Example 2: Process for preparing Complex lb, wherein R_^ = OCH3, R? = OH
An equimolar amount of [(dmpip)Pd(OAc)2] solution in 5 ml of anhydrous methanol was added to curcumin solution (0.30 mmol) in 15 ml of anhydrous methanol. The reaction mixture was stirred for 48 hours at 20 °C.
A dark red powder was obtained, yield = 47 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 2.63 (s, 6H) 2.75 (d, 4H) 3.88 (d, 4H) 3.90 (s, 6H)
5.85 (s, 1H) 6.67 (d, 2H) 6.80 (d, 2H) 7.07 (d, 2H) 7.19 (s, 2H) 7.46 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 49.2 (2C) 59.0 (4C) 62.1 (1C) 114.0 (2C) 119.1
(2C) 125.4 (2C) 126.6 (4C) 131.2 (2C) 144.8 (2C) 152.0 (2C) 153.0 (2C) 182.4 (2C)
IR (KBr) Vmax icm"1) 3436, 2930, 1724, 1582, 1502, 1397, 1284, 1225, 1155, 1115, 997,
964, 825, 796, 590
Example 2a: Process for preparing Complex lb, wherein R^ = OCH , R? = OH
The procedure was the same as in Example 2, except that butanol was used instead of anhydrous methanol.
A dark red powder was obtained, yield = 35 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 2.63 (s, 6H) 2.75 (d, 4H) 3.88 (d, 4H) 3.90 (s, 6H) 5.85 (s, 1H) 6.67 (d, 2H) 6.80 (d, 2H) 7.07 (d, 2H) 7.19 (s, 2H) 7.46 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 49.2 (2C) 59.0 (4C) 62.1QC) 114.0 (2C) 119.1 (2C) 125.4 (2C) 126.6 (4C) 131.2 (2C) 144.8 (2C) 152.0 (2C) 153.0 (2C) 182.4 (2C) IR (KBr) v^ icm"1) 3436, 2930, 1724, 1582, 1502, 1397, 1284, 1225, 1155, 1115, 997, 964, 825, 796, 590
Example 3: Process for preparing Complex 2a, wherein = OCH3, R? = OCH
An equimolar amount of [(tmcyda)Pd(OAc)2] solution in 5 ml of anhydrous chloroform and 30 μΐ of 1M aqueous NaOH were added to a curcumin analogue solution (0.12 mmol) in 10 ml of anhydrous chloroform. The reaction mixture was stirred for 48 hours at 25 °C. A yellow powder was obtained, yield = 59 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1.29-1.39 (m, 2H) 1.48-1.59 (m, 2H) 1.81 (m, 2H) 1.89 (s, 3H) 2.20 (m, 2H) 2.85 (s, 6H) 2.87 (s, 6H) 3.25 (m, 2H) 3.87 (s, 6H) 3.89 (s, 6H) 5.89 (s, 1H) 6.75(d, 2H) 6.98 (d, 2H) 7.21 (d, 2H) 7.25 (s, 2H) 7.47 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 25.89 (1C) 26 77 (2C) 27.36 (2C) 45.49 (4C) 58.25 (2C) 58.35 (2C) 70.90 (2C) 75.05 (2C) 113.28 (2C) 114.51 (2C) 125.83 (2C) 125.95 (2C) 131.49 (2C) 131.70 (2C) 143.49 (2 C) 152.67 (2C) 181.88 (2C)
IR (KBr) Vmax icm"1) 3436, 2931, 2860, 1728, 1620, 1597, 1508, 1465, 1400, 1268, 1139, 1025, 997, 845, 697, 585.
Example 3a: Process for preparing Complex 2a, wherein Rj^ = OCH3, R? = OCH
The procedure was the same as in Example 3, except that dichloromethane was used instead of anhydrous chloroform.
A yellow powder was obtained, yield = 55 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1.29-1.39 (m, 2H) 1.48-1.59 (m, 2H) 1.81 (m, 2H) 1.89 (s, 3H) 2.20 (m, 2H) 2.85 (s, 6H) 2.87 (s, 6H) 3.25 (m, 2H) 3.87 (s, 6H) 3.89 (s, 6H) 5.89 (s, 1H) 6.75(d, 2H) 6.98 (d, 2H) 7.21 (d, 2H) 7.25 (s, 2H) 7.47 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 25.89 (1C) 26.77 (2C) 27.36 (2C) 45.49 (4C) 58.25 (2C) 58.35 (2C) 70.90 (2C) 75.05 (2C) 113.28 (2C) 114.51 (2C) 125.83 (2C) 125.95 (2C) 131.49 (2C) 131.70 (2C) 143.49 (2 C) 152.67 (2C) 181.88 (2C)
IR (KBr) Vmax icm"1) 3436, 2931, 2860, 1728, 1620, 1597, 1508, 1465, 1400, 1268, 1139, 1025, 997, 845, 697, 585.
Example 4: Process for preparing Complex 2b, wherein Ri = OCH3, R? = OCH3 An equimolar amount of [(dmpip)Pd(OAc)2] solution in 5 ml of anhydrous methanol was added to a curcumin analogue solution (0.20 mmol) in 10 ml of anhydrous methanol. The reaction mixture was stirred for 44 hours at 20 °C.
A yellow powder was obtained, yield = 28 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1.90 (s, 3H) 2.64 (s, 6H) 2.75 (d, 4H) 3.86 (s, 6H) 3.88 (s, 6H) 3.90 (d, 4H) 5.89 (s, 1H) 6.72 (d, 2H) 6.96 (d, 2H) 7.16 (dd, 2H) 7.21 (s, 2H) 7.49 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 24.98 (1C) 46.72 (2C) 56.45 (2C) 56.56 (2C) 59.62 (4C) 106.11 (1C) 111.40 (2C) 112.71 (2C) 123.92 (2C) 124.00 (2C) 129.77 (2C) 141.93 (2C) 150.87 (2C) 152.69 (2C) 179.94 (2C)
IR (KBr) Vmax icm"1) 2929, 1618, 1597, 1580, 1503, 1451, 1393, 1257, 1136, 1021, 997, 996, 834, 797, 697.
Example 4a: Process for preparing Complex 2b, wherein - OC¾, R? - OCH
The procedure was the same as in Example 2, except that ethyl alcohol was used instead of anhydrous methanol.
A yellow powder was obtained, yield = 25 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1.90 (s, 3H) 2.64 (s, 6H) 2 75 (d, 4H) 3.86 (s, 6H) 3.88 (s, 6H) 3.90 (d, 4H) 5.89 (s, 1H) 6.72 (d, 2H) 6.96 (d, 2H) 7.16 (dd, 2H) 7.21 (s, 2H) 7.49 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 24.98 (1C) 46.72 (2C) 56.45 (2C) 56.56 (2C) 59.62 (4C) 106.11 (1C) 111.40 (2C) 112.71 (2C) 123.92 (2C) 124.00 (2C) 129.77 (2C) 141.93 (2C) 150.87 (2C) 152.69 (2C) 179.94 (2C)
IR (KBr) Vmax icm"1) 2929, 1618, 1597, 1580, 1503, 1451, 1393, 1257, 1136, 1021, 997, 996, 834, 797, 697.
Example 5: Process for preparing Complex 3a. wherein R = H. R? = OC¾
An equimolar amount of [(tmcyda)Pd(OAc)2] solution in 5 ml of anhydrous chloroform was added to a curcumin analogue solution (0.25 mmol) in 5 ml of anhydrous chloroform. The reaction mixture was stirred for 100 hours at 22 °C and then for 40 hours at 50 °C. A dark red powder was obtained, yield = 25 %. XH-NMR (CD3CI3, 300 MHz) δ (ppm) 1.31-1.43 (m, 2H) 1.56-1.64 (m, 2H) 1.81 (s, 3H) 2.02 (d, 2H) 2.17 (m, 2H) 2.89 (s, 6H) 2.90 (s, 6H) 3.45 (m, 2H) 3.85 (s, 6H) 5.63 (s, 1H) 6.50 (d, 2H) 6.91 (d, 4H) 7.33 (d, 2H) 7.48 (d, 4H)
13C-NMR (CD3CI3, 75 MHz) δ (ppm) 24.30 (2C) 24.33 (1C) 43.77 (2C) 49.98 (2C) 55.43 (2C) 72.02 (4C) 77.22 (2 C) 104.80 (1C) 114.44 (4C) 122.75 (2C) 127.61 (2C) 129.71 (4C) 139.91 (2C) 161.31 (2C) 178.19 (2C)
ffi. (KBr) Vmax icm"1) 3432, 2932, 1631, 1602, 1573, 1511, 1463, 1421, 1396, 1300, 1253, 1171, 1099, 998, 829, 724, 633, 556.
Example 6: Process for preparing Complex 3b, wherein R_^ = H, RT = OCH3
An equimolar amount of [(dmpip)Pd(OAc)2] solution in 5 ml of anhydrous methanol was added to a curcumin analogue solution (0.20 mmol) in 5 ml of anhydrous methanol. The reaction mixture was stirred for 44 hours at 22 °C.
A yellow powder was obtained, yield = 33 %.
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1.89 (s, 3H) 2.62 (s, 6H) 2.74 (d, 4H) 3.82 (s, 6H)
3.88 (d, 4H) 5.85 (s, 1H) 6.69 (d, 2H) 6.94 (d, 4H) 7.49 (d, 2H) 7.55 (d, 4H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 24.19 (1C) 46.68 (2C) 55.92 (2C) 59.62 (4C) 106.05
(1C) 115.52 (4C) 123.62 (2C) 129.28 (2C) 130.89 (4C) 141.67 (2C) 162.96 (2C) 179.95
(2C)
IR (KBr) Vmax icm"1) 2930, 1617, 1602, 1573, 1493, 1422, 1387, 1311, 1250, 1160, 1111, 992, 826, 795, 698.
Example 7: Process for preparing Complex 4a, wherein R = OCH CH , R? = OH
An equimolar amount of [(tmcyda)Pd(OAc)2] solution in 5 ml of anhydrous chloroform was added to a curcumin analogue solution (0.17 mmol) in 5 ml of anhydrous chloroform. The reaction mixture was stirred for 24 hours at 22 °C.
A dark brown powder was obtained, yield = 46 %.
1H-NMR (CD3OD, 300 MHz) δ (ppm) 1.25 (t, 2H), 1.44 (t, 5H), 1.80 (d, 2H), 1.89 (s, 3H), 2.18 (d, 2H), 2.84 (d, 12H), 3.20 (d, 2H), 4.14 (q, 4H), 5.83 (s, 1H), 6.65 (d, 2H), 6.81 (d, 2H), 7.10 (d, 2H), 7.19 (s, 2H), 7.42 (d, 2H) 13C-NMR (CD3OD, 75 MHz) δ (ppm) 15.14 (2C), 24.12 (1C), 25.29 (2C), 25.56 (2C),
43.64 (2C), 49.14 (2C), 65.70 (2C), 73.23 (2C), 105.59 (1C), 113.76 (2C), 116.76 (2C), 123.18 (2C), 124.09 (2C), 128.53 (2C), 142.02 (2C), 146.66 (2C), 150.90 (2C), 180.0 (3C) IR (KBr) Vmax Ccm"1) 3427, 2977, 2938, 1618, 1586, 1506, 1391, 1285, 1167, 1124, 1041, 999, 845, 632, 602
Example 8: Process for preparing Complex 4b, wherein = OCH?CH^, R? = OH
An equimolar amount of [(dmpip)Pd(OAc)2] solution in 5 ml of anhydrous chloroform was added to a curcumin analogue solution (0.17 mmol) in 5 ml of anhydrous chloroform. The reaction mixture was stirred for 22 hours at 22 °C.
A brown powder was obtained, yield = 50 .
XH-NMR (CD3OD, 300 MHz) δ (ppm) 1 44 (t, 6H), 1 91 (s, 3H), 2.62 (s, 6H), 2.74 (d, 4H), 3.88 (d, 4H), 4.13 (q, 4H), 5.84 (s, 1H), 6.64 (d, 2H), 6.81 (d, 2H), 7.07 (d, 2H), 7.17 (s, 2H), 7.44 (d, 2H)
13C-NMR (CD3OD, 75 MHz) δ (ppm) 15.28 (2C), 23.35 (1C), 46.80 (2C), 49.52 (2C),
59.65 (2C), 65.75 (2C), 86.45 (1C), 113.16 (1C), 116.88 (2C), 123.20 (1C), 124.15 (2C), 128.70 (2C), 142.34 (2C), 148.68 (2C), 148.71 (2C), 150.79 (1C), 179.88 (3C)
IR (KBr) Vmax icm"1) 3427, 2979, 1619, 1590, 1507, 1396, 1283, 1166, 1125, 1041, 999, 969, 824, 795, 603.
The structures of complexes of curcumin and its analogues with palladium la - 4b represent novel compounds. They were tested on human prostate cancer cells. It was confirmed that the complexation with palladium increased the anti-tumor activity of curcumin. The palladium(II) complexes of curcumin are able to inhibit the growth of certain types of human cancer cells: ovarian carcinoma, colorectal carcinoma, melanoma, cervical carcinoma, liver carcinoma, prostate carcinoma and breast carcinoma (Table 1). Table 1. Examples of antineoplastic activity of compounds of the invention
Figure imgf000012_0001
The compounds exhibit activity also against cancer cells with developed resistance to standard metal based drugs (A2780cis cells of ovarian carcinoma resistant to Cis-platin, HT-29 and Colo320 cell lines resistant to Oxalilplatin), see Table 2.
Table 2. Examples of antineoplastic activity of compounds of the invention
Figure imgf000012_0002
As can be seen in Tables above, these complexes exhibit both the antiradical and antitumor activity, which demonstrates their cytotoxicity and inhibitory effect on certain cancer cell lines.

Claims

Claims
1. The palladium(II) complexes of curcumin and its analogues of general formula
Figure imgf000013_0001
wherein Ri and R2 are each independently hydrogen, hydroxy, methoxy or ethoxy.
2. The process for preparing palladium(II) complex compounds of general formula according to claim 1, characterized in that the complex compounds [(R,R)-N,N,N',N'- tetramethylcyclohexane-l,2-diamine)-Pd(OAc)2] or [1,4-dimethylpiperazine)- Pd(OAc)2] of general formula
Figure imgf000013_0002
are reacting with curcumin or its analogues of general formula
Figure imgf000013_0003
oxo form wherein Ri and R2 are the same as defined in claim 1, in an alcohol having 1 to 4 carbon atoms, or in chlorinated solvents, selected from the group comprising chloroform and dichloromethane, for 12 to 140 hours at the temperature of 15 to 50 °C.
3. The process according to claim 2, characterized in that the reaction is carried out in an alcohol having 3 to 4 carbon atoms.
4. The process according to claim 2, characterized in that the reaction is carried out in the presence of 15 to 40 μΐ of aqueous base solution selected from the group comprising NaOH, KOH and LiOH.
5. The process according to claim 2, characterized in that the reaction is carried out in anhydrous methanol at the temperature of 20 to 50 °C for 20 to 50 hours.
6. The process according to claim 2, characterized in that the reaction is carried out in anhydrous isopropyl alcohol at the temperature of 20 to 50 °C for 20 to 50 hours.
7. The process according to claim 2, characterized in that the reaction is carried out in anhydrous chloroform at temperature of 20 to 60 °C for 20 to 140 hours.
8. The process according to claim 2 and 3, characterized in that the reaction is carried out in the presence of 30 μΐ of 1M aqueous NaOH.
Abstract
Title of the invention: Palladium complexes of curcumin and its analogues and method of preparation the same
The invention relates to palladium(II) complexes of curcumin and its analogues of general formula
Figure imgf000015_0001
wherein Ri and R2 are each independently hydrogen, hydroxy, methoxy or ethoxy, as well as the process for preparing the same by reacting the complex compounds [(tmcyda)Pd(OAc)2] or [(dmpip)Pd(OAc)2] of general formula
Figure imgf000015_0002
with curcumin or its analogues of general formula
Figure imgf000015_0003
oxo form wherein Ri and R2 are the same as defined above, in an alcohol having 1 to 4 carbon atoms, or in chlorinated solvents, selected from the group comprising chloroform and dichloromethane, for 12 to 140 hours at the temperature of 15 to 50 °C.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010956A (en) * 2022-06-09 2022-09-06 浙江科技学院 Poly-tannic acid nanotube material capable of selectively enriching Pd, application of poly-tannic acid nanotube material in purifying and recovering Pd in waste colloidal palladium and preparation method of poly-tannic acid nanotube material

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116925015A (en) * 2023-06-16 2023-10-24 黑龙江中医药大学 Active substance for inhibiting premature ovarian failure and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008076965A1 (en) 2006-12-18 2008-06-26 Jack Arbiser Novel palladium complexes inhibit n-myristoyltransferase activity in vitro and cancer growth in vivo
US20100261923A1 (en) 2007-12-14 2010-10-14 Sun Yat-Sen University Preparative method and application of zn(ii)-curcumin complex and zn(ii)-curcumin solid dispersions
WO2012076696A1 (en) 2010-12-09 2012-06-14 Universite Pierre Et Marie Curie (Paris 6) New metal carbonyl complexes of curcumin derivatives, their synthesis and their uses in therapeutic application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008076965A1 (en) 2006-12-18 2008-06-26 Jack Arbiser Novel palladium complexes inhibit n-myristoyltransferase activity in vitro and cancer growth in vivo
US20100261923A1 (en) 2007-12-14 2010-10-14 Sun Yat-Sen University Preparative method and application of zn(ii)-curcumin complex and zn(ii)-curcumin solid dispersions
WO2012076696A1 (en) 2010-12-09 2012-06-14 Universite Pierre Et Marie Curie (Paris 6) New metal carbonyl complexes of curcumin derivatives, their synthesis and their uses in therapeutic application

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
ALESSANDRA VALENTINI ET AL: "Synthesis, Oxidant Properties, and Antitumoral Effects of a Heteroleptic Palladium(II) Complex of Curcumin on Human Prostate Cancer Cells", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 2, 22 January 2009 (2009-01-22), pages 484 - 491, XP055016380, ISSN: 0022-2623, DOI: 10.1021/jm801276a *
BAUM L.; NG A., J. ALZHAIMER DIS., vol. 6, 2004, pages 367 - 377
FATIMA A.; MODOLO L.V.; NERES A.T.M.; FERREIRA C.V.; DE SOUZA A.C.S., CURRENT BIOACTIVE COMPOUNDS, vol. 4, no. 3, 2008, pages 189 - 199
GHEDINI M.; PUCCI D.; CRISPINI A.; BELLUSCI A.; LA DEDA M.; AIELLO 1.; PUGLIESE T., INORG. CHEM. COMMUN., vol. 10, no. 2, 2007, pages 243 - 246
JOHN V. D. ET AL.: "Antitumor activity of synthetic curcuminoid analogues (1,7-diaryl-1,6-heptadiene-3,5-dione) and their copper complexes", APPL. ORGANOMET. CHEM., vol. 20, 2006, pages 477 - 482, XP008109056, DOI: doi:10.1002/aoc.1089
KRISHNANKUTTY K ET AL: "Metal Chelates of Curcuminoids", SYNTHESIS AND REACTIVITY IN INORGANIC AND METALLORGANICCHEMISTRY, MARCEL DEKKER INC. NEW YORK, US, vol. 28, no. 8, 1998, pages 1313 - 1325, XP009147937, ISSN: 0094-5714 *
KRISHNANKUTTZ K.; VENUGOPALAN P., SYNTH. REACT. INORG. MET.-ORG. CHEM., vol. 28, no. 8, 1998, pages 1313 - 1325
KUHLWEIN, F.; POLBORN K.; BECK W., ZEITSCHRIFT FUER ANORGANISCHE UND ALLGEMEINE CHEMIE, vol. 623, no. 8, 1997, pages 1211 - 1219
PUCCI D. ET AL., CURCUMIN AND CYCLOPALLADATED COMPLEXES: A RECIPE FOR BIFUNCTIONAL BIOMATERIALS, vol. 101, 2007, pages 1013 - 1022
PUCCI D.; BLOISE R.; BELLUSCI A.; BERNARDINI S.; GHEDINI M.; PIRILLO S.; VALENTINI A; CRISPINI A., J. INORG. BIOCHEM., vol. 101, no. 7, 2007, pages 1013 - 1022
PUCCI D.; BLOISE R.; BELLUSCI A; BERNARDINI S.; GHEDINI M.; VALENTINI A; CRISPINI A., MOLECULAR CRYSTALS AND LIQUID CRYSTALS, vol. 481, 2008, pages 14 - 25
RODRIGUES M. A. ET AL.: "Palladium complex containing curcumin as a ligand", AM. J. CHEM., vol. 2, 2012, pages 157 - 159
STANKOVIC I., 61ST JFCFA, CHEMICAL AND TECHNICAL ASSESSMENT, 2004, pages 1 - 7
SUNDARYONO, A.; NOURMAMODE, C.; GARDRAT, A.; FRITSCH , A. CASTELLAN, JOURNAL OF MOLECULAR STRUCTURE, vol. 649, 2003, pages 177 - 190
VALENTINI A.; CONFORTI F.; CRISPINI A.; DE MARTINO A.; CONDELLO R.; STELLITANO C.; ROTILIO G.; GHEDINI M.; FEDERICI G.; BERNARDINI, J. MED. CHEM., vol. 52, no. 2, 2009, pages 484 - 491
VALENTINI ET AL.: "Synthesis, oxidant properties and antitumor effect of a heteroleptic palladium(II) complex of curcumin on human prostate cancer cells", J. MED. CHEM., vol. 52, 2009, pages 484 - 491

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010956A (en) * 2022-06-09 2022-09-06 浙江科技学院 Poly-tannic acid nanotube material capable of selectively enriching Pd, application of poly-tannic acid nanotube material in purifying and recovering Pd in waste colloidal palladium and preparation method of poly-tannic acid nanotube material

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