Potent Anti-Cancer Properties of Phthalimide-Based Curcumin Derivatives on Prostate Tumor Cells

Metastatic castration-resistant prostate cancer is commonly treated with chemotherapy, whose effect is less than satisfactory. This raised the need for novel agents for the treatment of prostate cancer. In the present study, five phthalimide-based curcumin derivatives were synthesized and completely characterized to assess improved stability, pharmacodynamics, and radical scavenging ability. To investigate the potential application in anti-cancer therapy, the anti-proliferative activity of the synthesized molecules was determined on aggressive prostate tumor cells. We demonstrated that the K3F21 derivative has increased potency compared to curcumin, in terms of GI50, anti-proliferative and anti-migrating activities. K3F21 inhibits anchorage-dependent and -independent growth of prostate cancer cells by altering the expression of key genes controlling cell proliferation, such as Cylins D1, B1 and B2, and apoptosis, among which Puma, Noxa, and Bcl-2 family members. Finally, the anti-cancer activity of K3F21 was demonstrated by the analysis of cancer-associated PI3K/AKT, ERK, and p38 signaling pathways

Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (68Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68Ga-DOTA-C21 exhibits decent stability (57 \ub1 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 \ub1 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68Ga-DOTA-C21 is 3.57 \ub1 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 \ub1 0.2. High amount of activity (12.73 \ub1 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 \ub1 3.3% ID/g), lungs (8.42 \ub1 0.8% ID/g), liver (5.81 \ub1 0.5% ID/g) and heart (4.70 \ub1 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer

Synthesis, characterization and metal coordination of a potential β-lactamase inhibitor: 5-Methyl-2-phenoxymethyl-3-H-imidazole-4-carboxylic acid (PIMA)

Among relevant metal ions in biological systems, zinc and iron play a key role as active partners of the catalytic machinery. In particular, the inhibition of metal enzymes that are involved in physiological and pathological processes has been deeply investigated for the rational design of selective and efficient drugs based on chelators. Since imidazole histidine residue is one of the most versatile sites in proteins, especially in enzymes acting in the presence of metal ions as cofactors, in this work the synthesis and characterization of a new imidazole derivative, namely 5-methyl-2-phenoxymethyl-3-H-imidazole-4-carboxylic acid (PIMA) is reported. PIMA was designed as metallo-β-lactamase inhibitor thanks to its similarity with penicillin V, a β-lactam antibiotic inactivated by metallo-β-lactamase, for which there are no commercially available inhibitors. The evaluation of PIMA coordinating ability toward iron, zinc, and gallium, these latter selected as a non-paramagnetic probe for iron, is performed by theoretical DFT calculations and in solution by experimental techniques, i.e. potentiometry, UV–vis and NMR spectroscopy. PIMA exhibits an efficient metal chelating ability; the prevailing species in physiological condition are ML3 for Fe3+ and Ga3+ and ML2 for Zn2+, in which chelation is due to deprotonated carboxylic oxygen and imidazole nitrogen in the N,O donor set. The demonstrated ability of PIMA to chelate zinc ion, combined with its structure similarity with penicillin V, supports further exploration of this imidazole-4-carboxylate as metallo-β-lactamase inhibitor

In vitro study on potential pharmacological activity of curcumin analogues and their copper complexes

Curcumin and its derivatives have attracted great interest in the prevention and treatment of Alzheimer's disease, thanks both to the ability to hinder the formation of amyloid-beta (Aβ) aggregates and the ability to bind Cu (II) ion. In this article, we explore the ability of curcumin derivatives of K2T series to affect amyloid Aβ1-40 aggregation. These derivatives were obtained by introducing the t-butyl ester group through a methylenic spacer on the central carbon atom of the β-diketo moiety of curcumin frame. The studied curcuminoids were demonstrated to inhibit Aβ1-40 fibrillization at substoichiometric concentrations with IC50 value near that of curcumin. In addition, the antioxidant properties and DNA interaction of their Cu(II) complexes is evaluated. The structure of Cu(II)-K2T31 complex is also proposed on the basis of DFT calculation

New curcumin-derived ligands and their affinity towards Ga3+, Fe3+and Cu2+: Spectroscopic studies on complex formation and stability in solution

The metal complexing ability in solution of four substituted curcumin (CUR)-derived ligands K3T, originated by the insertion of the -CH2CH2COOtBu branch on the central atom of the diketonic moiety of CUR and related derivatives with variable meta and para substituents (OH, OMe, H, OCOCH3) on the peripheral aromatic rings, is examined. These molecules can act as new chelators with biological properties comparable to those of CUR but with improved stability. In fact, curcuminoids represent new perspectives for the development of novel therapeutic agents for several diseases including Alzheimer's disease. CUR showed neuroprotective properties, and a probable mechanism of its action is related to the complexation ability towards endogenous metal ions Fe3+and Cu2+. K3T derivatives retain the solvent-dependent diketo-ketoenol tautomerism, with the prevalence of the diketonic form in aqueous solution. They show enhanced stability in simulated physiological conditions (phosphate buffered solution at pH = 7.4) compared to CUR, together with similar or even higher anti-proliferative activity against human colon carcinoma cells HCT116. The addition of the metal ion causes dissociation of the enolic proton creating chelate complexes and shift of the tautomeric equilibrium toward the keto-enol species. The formation of metal complexes was followed and confirmed by both NMR (using Ga3+as a diamagnetic probe for Fe3+) and UV-visible spectroscopy. All the ligands showed high affinity for Fe3+and Ga3+, forming M:L 1:2 species. In view of therapeutic applications, notable is the good affinity of K3T31, i.e. the ligand bearing only OH groups in para positions of the aromatic rings, for Cu2+, and the ability of the Cu:K3T31 1:1 complex to bind to DNA

Uptake of Ga-curcumin derivatives in different cancer cell lines: toward the development of new potential 68Ga-labelled curcuminoids-based radiotracers for tumour imaging.

Thanks to the ability to suppress the proliferation and to kill tumour cells, several studies have shown the anti-cancer effects of curcumin (CUR) and its derivatives, i.e. diacetylcurcumin (DAC) and bis-dehydroxycurcumin (bDHC). This study is focused onto the development of curcuminoid complexes with gallium-68 employed as potential new radio-labelled probes to detect neoplastic tissues through imaging techniques such as positron emission tomography. To this purpose, the uptake of three Ga-curcuminoid complexes, namely Ga(CUR)2+, Ga(DAC)2+, Ga(bDHC)2+, by various tumour cell lines was compared with the uptake of the same compounds by normal human lymphocytes by flow cytometry using the intrinsic fluorescence of the curcuminoids. Ga(CUR)2+, and particularly Ga(DAC)2+, showed a higher uptake by colorectal carcinoma (HT29) and lymphoma (K562) cell lines than lymphocytes, while the uptake of Ga(bDHC)2+ was higher in lymphocytes than in all the other cell lines. Based on the fluorescence data, Gallium-68 labelled complexes were then tested in HT29 cell line. 68Ga(DAC)2+ showed the highest uptake by HT29 cells (higher internalization with a lower externalization) and the highest affinity. The obtained results are promising and the findings foster further investigation on the development of curcumin-metal-based radiopharmaceuticals

Curcumin derivatives and A\u3b2-fibrillar aggregates: An interactions\u2019 study for diagnostic/therapeutic purposes in neurodegenerative diseases

Several neurodegenerative diseases, like Alzheimer's (AD), are characterized by amyloid fibrillar deposition of misfolded proteins, and this feature can be exploited for both diagnosis and therapy design. In this paper, structural modifications of curcumin scaffold were examined in order to improve its bioavailability and stability in physiological conditions, as well as its ability to interfere with \u3b2-amyloid fibrils and aggregates. The acid-base behaviour of curcumin derivatives, their pharmacokinetic stability in physiological conditions, and in vitro ability to interfere with A\u3b2 fibrils at different incubation time were investigated. The mechanisms governing these phenomena have been studied at atomic level by means of molecular docking and dynamic simulations. Finally, biological activity of selected curcuminoids has been investigated in vitro to evaluate their safety and efficiency in oxidative stress protection on hippocampal HT-22 mouse cells. Two aromatic rings, \u3c0-conjugated structure and H-donor/acceptor substituents on the aromatic rings showed to be the sine qua non structural features to provide interaction and disaggregation activity even at very low incubation time (2h). Computational simulations proved that upon binding the ligands modify the conformational dynamics and/or interact with the amyloidogenic region of the protofibril facilitating disaggregation. Significantly, in vitro results on hippocampal cells pointed out protection against glutamate toxicity and safety when administered at low concentrations (1 \u3bcM). On the overall, in view of its higher stability in physiological conditions with respect to curcumin, of his rapid binding to fibrillar aggregates and strong depolymerizing activity, phtalimmide derivative K2F21 appeared a good candidate for both AD diagnostic and therapeutic purposes