Development of Stable Amino-Pyrimidine-Curcumin Analogs: Synthesis, Equilibria in Solution, and Potential Anti-Proliferative Activity.

With the clear need for better cancer treatment, naturally occurring molecules represent a powerful inspiration. Recently, curcumin has attracted attention for its pleiotropic anticancer activity in vitro, especially against colorectal and prostate cancer cells. Unfortunately, these encouraging results were disappointing in vivo due to curcumin's low stability and poor bioavailability. To overcome these issues, herein, the synthesis of eight new pyrimidine-curcumin derivatives is reported. The compounds were fully characterized (1H/13C NMR (Nuclear Magnetic Resonance), LC-MS (Liquid Chromatography-Mass Spectrometri), UV-Vis spectroscopy), particularly their acid/base behavior; overall protonation constants were estimated, and species distribution, as a function of pH, was predicted, suggesting that all the compounds are in their neutral form at pH 7.4. All the compounds were extremely stable in simulated physiological media (phosphate-buffered saline and simulated plasma). The compounds were tested in vitro (48 h incubation treatment) to assess their effect on cell viability in prostate cancer (LNCaP and PC3) and colorectal cancer (HT29 and HCT116) cell lines. Two compounds showed the same anti-proliferative activity as curcumin against HCT116 cells and improved cytotoxicity against PC3 cells.

Radiolabeled Chalcone Derivatives as Potential Radiotracers for ß-Amyloid Plaques Imaging.

Natural products often provide a pool of pharmacologically relevant precursors for the development of various drug-related molecules. In this review, the research performed on some radiolabeled chalcone derivatives characterized by the presence of the α-ß unsaturated carbonyl functional group as potential radiotracers for the imaging of ß-amyloids plaques will be summarized. Chalcones' structural modifications and chemical approaches which allow their radiolabeling with the most common SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) radionuclides will be described, as well as the state of the art regarding their in vitro binding affinity and in vivo biodistribution and pharmacokinetics in preclinical studies. Moreover, an explanation of the rationale behind their potential utilization as probes for Alzheimer's disease in nuclear medicine applications will be provided.

Applications of Radiolabelled Curcumin and Its Derivatives in Medicinal Chemistry.

Curcumin is a natural occurring molecule that has aroused much interest among researchers over the years due to its pleiotropic set of biological properties. In the nuclear medicine field, radiolabelled curcumin and curcumin derivatives have been studied as potential radiotracers for the early diagnosis of Alzheimer's disease and cancer. In the present review, the synthetic pathways, labelling methods and the preclinical investigations involving these radioactive compounds are treated. The studies entailed chemical modifications for enhancing curcumin stability, as well as its functionalisation for the labelling with several radiohalogens or metal radionuclides (fluorine-18, technetium-99m, gallium-68, etc.). Although some drawbacks have yet to be addressed, and none of the radiolabelled curcuminoids have so far achieved clinical application, the studies performed hitherto provide useful insights and lay the foundation for further developments.

Bridging pyrimidine hemicurcumin and Cisplatin: Synthesis, coordination chemistry, and in vitro activity assessment of a novel Pt(II) complex.

In the upcoming decades, the incidence and mortality rates of cancer are expected to rise globally, with colorectal and prostate cancers among the most prevalent types. Despite advancements in molecular targeted therapy, platinum-based chemotherapies remain the cornerstone of treatment, especially for colorectal and prostate cancer, with oxaliplatin and cisplatin being extremely effective due to their DNA-targeting capabilities. In our pursuit of new platinum-based chemotherapeutics that are potentially less toxic and more effective, we have explored the combination of the Pt-binding groups of the diaminocyclohexane ring used in oxaliplatin, with the stable amino-pyrimidine hemicurcumin moiety. This new derivative exhibit improved stability in physiological conditions and increased solubility in aqueous media, demonstrating promising effects on cell proliferation of both colorectal and prostate cells. We report herein the complete synthesis and chemical characterization in solution of the new derivative [(1R,2R)-N1-(3-(4-((E)-2-(2-Amino-6-methylpyrimidin-4-yl)vinyl)-2-methoxyphenoxy) propyl) cyclohexane-1,2-diamine] (MPYD). Our analysis includes an examination of its acid-base equilibria, speciation and stability in physiological conditions. The synthesis and in situ formation of Pt(II) complexes were investigated by nuclear magnetic resonance spectroscopy, while density functional theory calculations were employed to elucidate the chemical structure in solution. Results on the biological activity were obtained through cell viability assays on different colorectal and prostate cell lines (HCT116, HT29, PC3 and LNCaP).

Curcumin-Based ß-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs.

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the ß-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the ß-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the ß-keto-enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 ß-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto-enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto-enol form. A complete 1H/13C NMR and UV-Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

Effect of olive ripening degree on the oxidative stability and organoleptic properties of cv. Nostrana di Brisighella extra virgin olive oil.

The evaluation of the influence of olive ripening degree on the stability of extra virgin olive oils by the determination of the oxidative stability index, the DPPH(*) radical test, and the quali-quantitative analysis of phenolic compounds, as well as the study of the variation of their sensory profiles, plays a key role in the assessment of the overall olive oil quality. Olives of the cv. Nostrana di Brisighella grown in the north-central Italian region of Emilia-Romagna were picked at four different stages of ripeness and immediately processed in an experimental mill. The polar extracts of oil samples were submitted to spectrophotometric analysis of total phenols and o-diphenols and to liquid chromatographic determination of their quali-quantitative profile (HPLC-DAD/MSD). To attain a complete description of oil samples, fatty acid composition, ultraviolet indices (K(232), K(270), and deltaK), free acidity degree, and peroxide value were also determined according to the European Union methods stated in Regulation 2568/91 (1, Off. J. Eur. Communities 1991, L248, 1-82). Sensory quantitative descriptive analysis (QDA) and triangular tests were performed to establish the influence of olive ripening degree on the resulting oil's organoleptic properties. The evolution of the analytical parameters studied shows that the ripeness stage of Nostrana di Brisighella olives that yields the best oil corresponds to a Jaén index value between 2.5 and 3.5. Oils produced from olives harvested within this time frame present a superior sensory profile accompanied by the highest possible chemical and nutritional properties.