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Synthesis and biological evaluation of radiolabeled curcumins and their ruthenium-arene complexes
The document details research on the synthesis and biological evaluation of radiolabeled curcumins and their ruthenium-arene complexes for applications in Alzheimer's disease and cancer treatment. It outlines the chemical processes involved in creating the 123I-labeled curcumin and the characterization of ruthenium complexes, while emphasizing their reduced effectiveness compared to natural curcumin. Future studies are suggested to further investigate the biodistribution and bioaccumulation of these compounds in vivo.
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Synthesis and biological evaluation of radiolabeled curcumins and their ruthenium-arene complexes
- 1. UNIVERSITY OF CAMERINO SCHOOLOF PHARMACY MASTER’S DEGREE PHARMACEUTICAL CHEMISTRY AND TECHNOLOGY SYNTHESIS AND BIOLOGICAL EVALUATION OF RADIOLABELED CURCUMINS AND THEIR RUTHENIUMARENE COMPLEXES STUDENT: LUCA PALMIERI TUTOR: PROF. CLAUDIO PETTINARI DR. DOMENICO MARTINI
- 2. Curcumin Yellow-gold pigment Obtained throughextraction usually from Curcuma-Longa plant Used as a spice and food colorant Chemically Polyphenols family Hydrophobic compound
- 3. Curcumin Molecular targets andbiological activity Anti-inflammatory (pancreatitis, arthritis, IB D and gastritis) Well-known contraindications (GERD, stomach upset, slow blood clotting) Antioxidant Antiproliferative Tumoricidal
- 4. Curcumin and its rolein Alzheimer Disease (AD) Neurofibrillary tangles Cognitive deterioration Amyloid-β aggregation Progressive memory loss Senile plaques Behavioral disorders
- 5. Curcumin Structure-Activity relationship R2 studies Thearomatic end groups Linker length require one or more polar hydrogen bonding Compounds with an approximate substitutions for an Å are better linker length of 8-16 optimal Aβ aggregation inhibition inhibitors R3 studies R1 studies Compounds Linker flexibility lacking a 2° phenyl group have than Compounds with more a less one or inhibitory activity two sp3-hybridized carbons don’t properly react with Aβ plaques (Reinke et al., Chem. Biol. Drug Des., 2007)
- 6. Curcumin and radioisotopes whatif we could use it for imaging ? Half-life 13.22 hours Within 6h and 4 weeks 123I Energy emitted Suitable energy rays emitter • Pure gamma for medical use • Positrons emitter
- 7. Aim of thework Synthesis of Curcumin as a tin or borate precursor for the 123I labeling of Curcumin and the binding of the compound with β-amyloid plaques in Alzheimer disease (AD) through in-vivo tests.
- 8. Synthesis of the123I-Curcumin HCl n-Butylamine 1) 2) 2) 3) 2) 3) 4) 4) 3) 5) 5) 6) 6) Pd(dppf)Cl2 + bis(neopentylglicolato)diboron B2O3 + Precursor + B2O stirred in ethyl 2,4 pentanedionestirred3in ethyl acetate at 80 °C dissolved 80 °C for 30’. Iodo-vanillin + (n-BuO) B left to stir at in acetate atin potassium3acetate, flushed80 °C for argon and added with first solution 30’, then added to the dry DMSO. Solution Vanillin + (n-BuO)3B piperidinethe mixture and left to stir for 15’ Mixture added with added to and stirred at left to stir of Ligand 1 and continue to stir at Addiction at 80 °C 80°C for more 30’ for further 30’ Addictionmore almost at 50 at 100further130’. 80 °C for of with HCl 4h Acidification n-Butylamine °C for °C for h Acidification withunder reduced pressure Solvent removed HCl at 50 °C for more and Extraction with ethyl acetate and water 30’ Extraction with with Na SO and water and anhydrification ethyl acetate 2 4 anhydrification with Na2SO4 Recrystallization with ethanol Purification through flash chromatography and recrystallization with ethanol + Pd(dppf)Cl2 bis(neopentylglicolato)diboron KHF2
- 9. 1) 2) 2) 3) 3) Na123I Ligand 3in methanol KHF2 ++ BF3K-Curcumin + Chloramine-T stirred at 60 °C Hand-agitation for 30’. Addiction of sodium thiosulfite through Wash with hexane and filtration Isolation gooch of product via silica Sep-Pak® C18 cartridge Na123I Na123I 123I-Curcumin
- 10. Synthesis of the123I-Curcumin HCl n-Butylamine 1) 2) 3) 4) 5) 6) B2O3 + Precursor stirred in ethyl acetate at 80 °C Bromo-vanillin + (n-BuO)3B left to stir at 80 °C for 30’, then added to the first solution Mixture added with piperidine and stirred at 80°C for more 30’ Acidification with HCl at 50 °C for further 30’. Extraction with ethyl acetate and water and anhydrification with Na2SO4 Recrystallization with ethanol + Pd(Ph3P)4 Me3Sn-SnMe3
- 11. 1) 2) 3) 4) 5) 6) Hexamethylditin + Ligand2 + 1,4-dioxane Na123I + Me3Sn-Curcumin+ HCl stirred at 60 stirred at °C for 30’.100 °C for about 1h Removal initiated adding H2O and stirring Reaction of the solvent under 2reduced pressure for 10’ Purification NaHSO3 Addiction ofby column chromatography Extraction using ethyl acetate and passage through an anhydrous Na2SO4 plug Removal of the solvent with a gentle N2 flow Purification by HPLC using a semipreparative column Na123I Na123I 123I-Curcumin Starting product: Yield: 20% 75%
- 12.
- 13. In-vivo test Ventral viewof co-registered SPECT/CT images of 123I-Curcumin Mouse 1 Mouse 2 Mouse 3 Mouse 4 15 min post injection 30 min post injection 60 min post injection (no CT shown) 120 min post injection (no CT shown) The tracer was cleared within 15 min by the liver showing hepatobilliary clearance from the circulation and no sign of accumulation in deposit sites.
- 14. Metal complexes andcoordination with curcumin Platinum-based complexes • • • • • Side effects in normal tissues Nephrotoxicity Neurotoxicity Ototoxicity Nausea and vomiting Acquired resistance during therapy Ruthenium-based complexes Ruthenium has: Lower toxicity Higher selectivity
- 15. Aim of thework The role of a complex between the iodo-curcumin and the Ruthenium pcymene dimer will be researched as a possible antioxidant and antitumoral compound. Evaluating his chemical synthesis, characterization, and in-vitro studies.
- 16. Synthesis of theRu-complex 1 Temp. Time st attempt 1MeOH RT 24 h 2nd attempt 50 °C RT 4h 24 h 3rd attempt RT Other conditions 3d KOH 4th attempt 40-50 °C 5h reflux 5th attempt 40-50 °C 24 h 6th attempt 40-50 °C 2d reflux + KOH reflux RT 3d
- 17. Purification of theRu-complex 1
- 18. Synthesis of theRu-complex 2 KOH MeOH Temp. Time 1st attempt RT 24 h 2nd attempt 50 °C 4h RT 24 h RT 3d 3rd attempt Other conditions 4th attempt 40-50 °C 5h reflux 5th attempt 40-50 °C 24 h reflux + KOH 6th attempt 40-50 °C 2d reflux RT 7th attempt 3d RT 24 h + AgCF3SO3
- 19. Bio-evaluation of Ru-complex1 MTT cytotoxic assay (in-vitro test) 72 h incubation 120 Abs 540 nm 100 80 60 40 20 MDA-MB 0 HCT116 Concentration The compound wasn’t significantly active, especially compared with the cytotoxic activity of the sole curcumin which is cytotoxic just at concentrations of 10 µg/mL.
- 20. Bio-evaluation of Ru-complex1 Antioxidant activity assay (in-vitro test) DPPH method DPPH ABTS ABTS method Based upon the discoloration of DPPH radical in presence of an antioxidant compound, and measuring it spectrophotometrically IC50 IC50 M M Ru-complex 1 373.3( 9.5) 22.5( 1.2) Based upon the discoloration of the ABTS radical in presence of an antioxidant compound, and measuring it spectrophotometrically Curcumin 32.6 (±5) 5.1( 0.2) 15.4( 1.4) 69.0( 0.5) Trolox IC50 = The concentration of compound that affords a 50% reduction in the assay The complex showed an important decrease of activity, compared to the natural curcumin.
- 21. Conclusions • Five curcumin-likeligands were synthesized and chemically characterized • Two of these ligands reacted with a radioisotope to give a new radio-ligand • Unfortunately, the radio-ligand showed no sign of bio-accumulation in β-amyloid deposit sites in mice • A new Ru-complex was synthesized, chemically characterized, and tested in-vitro for its antioxidant and cytotoxic activities • The complex showed to possess a decreased cytotoxic and antioxidant effects compared to curcumin Future perspectives It should be interesting to synthesize a complex containing radiolabeled curcumin and test it, not just in-vitro but also, in-vivo in order to follow its biodistribution and bioaccumulation.
- 22.