Analogues of Anticancer Natural Products: Chiral Aspects.

Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates-equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate.

Antiproliferative Ruthenium Complexes Containing Curcuminoid Ligands Tested In Vitro on Human Ovarian Tumor Cell Line A2780, towards Their Capability to Modulate the NF-κBTranscription Factor, FGF-2 Growth Factor, and MMP-9 Pathway.

So far, the polyphenolic components of turmeric have shown a significant pharmacological preventative activity for a wide spectrum of diseases, including oncological disorders. This type of natural product could be of great interest for the inhibition of cancer cell proliferation, displaying less side effects in comparison to classical chemotherapeutics. The poor bioavailability and quick metabolism of such natural compounds require new investigative methods to improve their stability in the organisms. A synthetic approach to increase the efficiency of curcuminoids is to coordinate them to metals through the beta-dicarbonyl moiety. We report the synthesis and the biological attempts on human ovarian carcinoma A2780 of ruthenium(II) complexes 1-4, containing curcuminoid ligands. The cytotoxicity of complexes 1-4 proves their antiproliferative capability, and a correlation between the IC50 values and NF-κB transcription factor, FGF-2, and MMP-9 levels was figured out through the principal component analysis (PCA).

Evaluation of Antiproliferative Palladium(II) Complexes of Synthetic Bisdemethoxycurcumin towards In Vitro Cytotoxicity and Molecular Docking on DNA Sequence.

Metallodrugs form a large family of therapeutic agents against cancer, among which is cisplatin, a paradigmatic member. Therapeutic resistance and undesired side effects to Pt(II) related drugs, prompts research on different metal-ligand combinations with potentially enhanced biological activity. We present the synthesis and biological tests of novel palladium(II) complexes containing bisdemethoxycurcumin (BDMC) 1 and 2. Complexes were fully characterized and their structures were determined by X-ray diffraction. Their biological activity was assessed for several selected human tumor cell lines: Jurkat (human leukaemic T-cell lymphoma), HCT-116 (human colorectal carcinoma), HeLa (human cervix epitheloid carcinoma), MCF-7 (human breast adenocarcinoma), MDA-MB-231 (human mammary gland adenocarcinoma), A549 (human alveolar adenocarcinoma), Caco-2 (human colorectal carcinoma), and for non-cancerous 3T3 cells (murine fibroblasts). The cytotoxicity of 1 is comparable to that of cisplatin, and superior to that of 2 in all cell lines. It is a correlation between IC50 values of 1 and 2 in the eight studied cell types, promising a potential use as anti-proliferative drugs. Moreover, for Jurkat cell line, complexes 1 and 2, show an enhanced activity. DFT and docking calculations on the NF-κB protein, Human Serum Albumin (HSA), and DNA were performed for 1 and 2 to correlate with their biological activities.

Modulatory effect of curcumin analogs on the activation of metalloproteinases in human periodontal stem cells.

Periodontitis progresses due to increased levels of active metalloproteinases (MMPs) and the imbalance between MMPs and their tissue inhibitors (TIMPs). Natural curcumin limits the lytic activity of MMPs but has low cellular uptake. Use of synthetic curcumin analogs could be a means of overcoming this limitation of treatment efficiency. Human periodontal stem cells were isolated from gingival tissue, gingival ligament fibers, periodontal ligament, and alveolar bone. The effect of five synthetic curcumin analogs was compared with that of natural curcumin by assessing cytotoxicity [by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay], the cellular uptake (by fluorometry), the proteolytic activities of MMP-2 and -9 (by zymography), and the levels of TIMP-1 (by ELISA). Our results indicated increased cytotoxicity of synthetic curcumins for doses between 100 and 250 µM. At a concentration of 10 µM, cellular uptake of synthetic curcumins varied depending on their chemical structure. The curcumin compounds modulated pro-MMP-2 levels and increased TIMP-1 production. There was no detectable synthesis of pro-MMP-9 and no activation of MMPs 2 and 9. Gingival tissue and gingival ligament fiber stem cells were most responsive to treatment, showing inverse correlations between pro-MMP-2 and TIMP-1 levels. In conclusion, synthetic curcumins influenced the balance between pro-MMP-2 and TIMP-1 in human periodontal stem cells in vitro, and this could open perspectives for their application as adjuvants in periodontal therapy.

A three-armed cryptand with triazine and pyridine units: synthesis, structure and complexation with polycyclic aromatic compounds.

The aromatic nucleophilic substitution reaction based synthesis of a three-armed cryptand displaying 2,4,6-triphenyl-1,3,5-triazine units as caps and pyridine rings in the bridges, along with NMR, MS and molecular modelling-based structural analysis of this compound are reported. Appropriate NMR and molecular modelling investigations proved the formation of 1:1 host-guest assemblies between the investigated cryptand and some polynuclear aromatic hydrocarbons or their derivatives.

Synthesis, structural characterization and biological activity of novel Knoevenagel condensates on DLD-1 human colon carcinoma.

Biologically active Knoevenagel condensates (1-14) of diarylheptanoids: 1,7-bis(3-methoxy-4-hydroxyphenyl)hepta-1,7-diene-3,5-dione and 1,7-bis(3-ethoxy-4-hydroxyphenyl)hepta-1,7-diene-3,5-dione, were synthesized and structurally characterized. Compounds 1-14 exhibited cytotoxicity against colon carcinoma cells, and their antiproliferative effect was associated with a significant decrease of multidrug resistance proteins. One of the underlying mechanisms of these effects is the reduction of intracellular and extracellular SOD enzymes by compounds 1, 12 and 14, which render the tumor cells more vulnerable to oxidative stress.

Novel Palladium(II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells.

New Pd(II) complexes of 1,7-bis(2-methoxyphenyl)hepta-1,6-diene-3,5-dione were synthesized and structurally characterized. The complexes were tested in vitro on human colon and hepatic carcinoma cell lines, normal hepatic cells and hematopoietic progenitor cells. Biological tests proved that Pd(II) complexes 1 and 2 (containing a curcumin derivative) exhibit a strong in vitro antitumor effect against the cells derived from human colorectal carcinoma and the hepatic metastasis of a colorectal carcinoma. Complex 1 has an outstanding inhibitory effect against BRAF-mutant colon carcinoma and hepatocarcinoma cell growth; 1 and 2 are both more active than the free ligand and have the capacity to trigger early apoptotic processes. By flow cytometric measurements, an important decrease of prominin-1 (CD133) molecule expression on tumor cells membrane was identified in cell populations subjected to 1 and 2. Quantitative immune enzymatic assay proved restrictions in stem cell factor (SCF) release by treated tumor cells. Although less cytotoxic, the free ligand inhibits the surface marker CD133 expression in hepatocarcinoma cells, and in HT-29 colon carcinoma. The new synthesized Pd(II) complexes 1 and 2 exhibit an important potential through their selective cytotoxic activity and by targeting the stem-like tumor cell populations, which leads to the tumor growth arrest and prevention of metastasis.

Iron, inflammation and invasion of cancer cells.

Chronic inflammation is associated with the metastasis of tumor cells evolving from a benign tumor to disseminating cancer. Such a metastatic progression is fostered by the angiogenesis propelled by various mediators interacting at the site of tumor growth. Angiogenesis causes two major changes that are assisted by altered glycosylation and neo-antigen presentation by the cancer cells. The angiogenesis-promoted pathological changes include enhanced inflammation and degradation of tissue matrices releasing tumor cells from the site of its origin. The degraded tumor cells release the neo-antigens resulting from altered glycosylation. Presentation of neo-antigens to T cells escalates metastasis and inflammation. Inflammasome activation and inflammation in several infections are regulated by iron. Based on the discrete reports, we propose a link between iron, inflammation, angiogenesis and tumor growth. Knowing the link better may help us formulate a novel strategy for cancer immunotherapy.

Antiproliferative effect of novel platinum(II) and palladium(II) complexes on hepatic tumor stem cells in vitro.

Novel platinum and palladium complexes with (2-isopropoxyphenyl)dicyclohexylarsine and (2-methoxyphenyl)dicyclohexylarsine ligands were synthesized and tested on different tumor cells. Adducts with general formula MX(2)L(2) (M = Pt(II), Pd(II); X = Cl or I; L = organoarsenic ligand) were fully characterized. According to the crystallographic data, in all complexes the organoarsenic ligands coordinate the metal center through the arsenic atom only, in a trans arrangement with the halogen atoms. The antiproliferative potential of complexes 1-4 was evaluated in vitro on human tumor cell lines. A markedly biological activity was observed against the chemoresistant hepatic tumor stem cell line, the normal hepatic stem cells and towards the hepatocellular carcinoma (non-stem) cells. The new compounds toxicity is selectively limited in normal liver cells, unlikeness with the oxaliplatin, which displays a more intense effect in normal cells, compared with the two tumor cell lines. The stem cells treatment with compounds 1-4 causes DNA damages; the antimitotic effect of these compounds is based on their genotoxicity and on the capacity to form crosslinks with the DNA interstrand. In the case of platinum complexes 1 and 3 this mechanism gives rise to specific lesions on DNA that induces apoptosis in stem cells, influencing their selectivity in tumor cell growth inhibition. Compounds 1, 2 and 4 display higher activity against tumor stem cells. The novel platinum complexes 1 and 3 are more efficient against tumor stem cells than oxaliplatin, and if used in combination with sorafenib-based monoclonal anticancer therapy, complexes 1, 3 and 4 have the ability to induce superior chemosensitivity relative to sorafenib than the standard platinum-based drug, making them promising candidates for prodrug development.

Synthesis and biological activity of dialkylphosphocholines.

A series of dialkylphosphocholines were prepared and evaluated for their biological activity. The antiprotozoal activity was determined against Acanthamoeba lugdunensis. Compound 15 exhibited excellent trophocidal activity. None of the tested dialkylphosphocholines exhibited better fungicidal activity against Candida albicans than miltefosine. The antineoplastic activity was determined against HeLa. The most cytotoxic was compound 10, which was more active against tumor cells as against normal cells.

Antiproliferative effect and genotoxicity of novel synthesized palladium complexes with organoarsenic ligands.

Three new palladium complexes with general formula [PdCl(2)L(2)], where L=heterofunctional organoarsenic ligand: (2-isopropoxyphenyl)diphenylarsine (1), (2-methoxyphenyl)-diphenylarsine (2) and (2-hydroxyphenyl)diphenylarsine (3) have been synthesized and fully characterized, including X-ray crystallographic data. Their potential antitumor effect and genotoxicity have been studied as well. The viability test performed on human tumor (MLS) and normal (Hfl-1) cell lines indicates significant cytotoxicity of complexes, which is higher in tumor cells than in normal cells. The lethal doses are comparable with those of standard metal-based chemotherapeutical drugs (carboplatin and oxaliplatin). These palladium complexes exhibit a higher cytotoxicity against tumor cells as against normal cells in vitro. A new static cytometric method was developed and simultaneously the classic AnnexinV test was performed. Complex 2 has an important capacity to induce apoptosis in tumor cells. The apoptotic process is triggered due to the interaction of these complexes with secondary structure of DNA in treated cells. The alkaline single-cell gel assay shows that the level of DNA damages induced by compounds 2 and 3 are significantly higher in tumor cells as in normal cells. These studies shown that complexes 1, 2 and 3 have biologic activity, the effect of complex 2 being superior to its platinum analogues, attributable to its structure.

Determination of molecular structure of bisphenylene homologues of BINOL-based phosphoramidites by chiroptical methods.

Vibrational (VCD), electronic circular dichroism (ECD), and IR absorption spectra together with transparent spectral region optical rotation (OR) of two derivatives of bisphenylene 1,1'-binaphthyl-based phosphoramidites containing three stereogenic axes were measured and the results were compared with simulated data obtained by ab initio calculations with density functional theory. An excellent agreement between experimental and predicted B3LYP/6-31G** and BPW91/6-31G** VCD spectra enabled the assignment of all VCD bands in the experimental spectra, while the Gibbs free energy of all the conformers allowed the determination of their relative populations. The calculation of ECD spectra showed that CAM-B3LYP/6-311G** provided results superior to those of B3LYP/6-311G**. The theoretical results for the OR at the B3LYP/6-311G** and CAM-B3LYP/6-311G** levels were in good agreement with experimental optical rotations, but exhibited lower sensitivity in determining particular conformers than VCD and ECD. By a careful comparison of experimental VCD, IR, and ECD spectra and OR with calculated data, it was possible to assign the absolute configuration of all three stereogenic axes and to determine the molecular structure of the studied bisphenylene 1,1'-binaphthyl-based phosphoramidites in solution with a high degree of confidence.