Selective Anticancer Activity Research Articles

Evaluation of the anticancer activity and chemiluminescence of a halogenated coelenterazine analog

Chemiluminescence is a remarkable process in which light is emitted due to a chemical reaction, without the need for photoexcitation. Among some of the most well-known chemiluminescent systems is that of marine Coelenterazine. Herein, we report the synthesis of a novel halogenated Coelenterazine analog, as well as the characterization of its potential anticancer activity and chemiluminescence. We have found that this analog is capable of significantly enhanced emission in aqueous solution when triggered by superoxide anion while being compatible with human cell lines. So, this compound presents great potential for the sensitive and dynamic sensing of a molecule of interest in biological media. Furthermore, the analysis of its cytotoxicity provided structural insight into the properties of brominated Coelenterazines, which were previously found to possess selective anticancer activity. Namely, the introduction of bromine heteroatoms is not enough to provide cytotoxicity, while the introduction of electro-withdrawing groups eliminates all previously reported anticancer activity. Finally, while this compound is not active, its use in a combination approach allowed to improve the profile of a known chemotherapeutic agent. These results should be useful to guide future optimizations of halogenated Coelenterazine analogs.

Synthesis of Novel Arsonolipids and Development of Novel Arsonoliposome Types.

Arsonolipids represent a class of arsenic-containing compounds with interesting biological properties either as monomers or as nanostructure forming components, such as arsonoliposomes that possess selective anticancer activity as proven by in vitro and in vivo studies. In this work, we describe, for the first time, the synthesis of novel arsono-containing lipids where the alkyl groups are connected through stable ether bonds. It is expected that this class of arsonolipids, compared with the corresponding ester linked, will have higher chemical stability. To accomplish this task, a new methodology of general application was developed, where a small arsono compound, 2-hydroxyethylarsonic acid, when protected with thiophenol, can be used in an efficient and simple way as a building block for the synthesis of arsono-containing lipids as well as other arsono-containing biomolecules. Thus, besides the above-mentioned arsonolipid, an arsono cholesterol derivative was also obtained. Both ether arsonolipid and arsono cholesterol were able to form liposomes having similar physicochemical properties and integrity to conventional arsonoliposomes. Furthermore, a preliminary in vitro anticancer potential assessment of the novel ether arsonolipid containing liposomes against human prostate cancer (PC-3) and Lewis lung carcinoma (LLC) cells showed significant activity (dose- and time-dependent), which was similar to that of the conventional arsonoliposomes (studied before). Given the fact that novel arsonolipids may be more stable compared to the ones used in conventional arsonoliposomes, the current results justify further exploitation of the novel compounds by in vitro and in vivo studies.

Investigating anticancer potency of in vitro propagated endemic Thymus cilicicus Boiss. & Bal. extract on human lung, breast, and prostate cancer cell lines

Cancer is the leading cause of death in the world, accounting for nearly 10 million deaths in 2020 alone and surpassing all other categories by a large margin. Several different strategies have been and are still being deployed to combat different types of cancers and among the common clinical approaches are the use of synthetic and natural compounds as anticancer agents within chemotherapy regimens. Thymus cilicicus Boiss. & Bal is a spice endemic to Turkey, the Northern Aegean Islands, Lebanon, and Syria, while several species of the Thymus genus are known to exhibit different clinically valuable properties, the research on T. cilicicus is rather scarce, therefore, in this study, the wound healing properties of in vitro propagated T. cilicicus ethanolic extracts were investigated on murine fibroblast (NIH-3T3), and its anticancer potency was investigated on the human alveolar basal epithelial adenocarcinoma (A549), human breast adenocarcinoma (MDA-MB-213), and human prostate cancer (DU-145) cell lines via colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The wound healing property assessments didn’t lead to any significant results, however, T. cilicicus yielded selective and promising anticancer potency on the A549 cell line. Furthermore, molecular docking analyses on the proteins of 9 genes confirmed to be upregulated in both 3D and 4D A549 cultures against 48 compounds found in the essential oils of T. cilicicus were performed and yielded results acquiescent with previous findings in the scientific literature. This study provides in vitro evidence to the selective anticancer activity of T. cilicicus extracts on A549 cells enhanced with computational evidence on the molecular mechanism involved in this selective activity. This study serves as a precursor for further in vivo and clinical research on the constituents of T. cilicicus as potent anticancer agents and their potential use in cancer therapies.

Target-Agnostic P-Glycoprotein Assessment Yields Strategies to Evade Efflux, Leading to a BRAF Inhibitor with Intracranial Efficacy

The blood-brain barrier (BBB) presents a major hurdle in the development of central nervous system (CNS) active therapeutics, and expression of the P-glycoprotein (P-gp) efflux transporter at the blood-brain interface further impedes BBB penetrance of most small molecules. Designing efflux liabilities out of compounds can be laborious, and there is currently no generalizable approach to directly transform periphery-limited agents to ones active in the CNS. Here, we describe a target-agnostic, prospective assessment of P-gp efflux using diverse compounds. Our results demonstrate that reducing the molecular size or appending a carboxylic acid in many cases enables evasion of P-gp efflux in cell-based experiments and in mice. These strategies were then applied to transform a periphery-limited V600EBRAF inhibitor, dabrafenib, into versions that possess potent and selective anti-cancer activity but now also evade P-gp-mediated efflux. When compared to dabrafenib, the compound developed herein (everafenib) has superior BBB penetrance and superior efficacy in an intracranial mouse model of metastatic melanoma, suggesting it as a lead candidate for the treatment of melanoma metastases to the brain and gliomas with BRAF mutation. More generally, the results described herein suggest the actionability of the trends observed in these target-agnostic efflux studies and provide guidance for the conversion of non-BBB-penetrant drugs into versions that are BBB-penetrant and efficacious.

The Synthesis, Characterization, Molecular Docking and In Vitro Antitumor Activity of Benzothiazole Aniline (BTA) Conjugated Metal-Salen Complexes as Non-Platinum Chemotherapeutic Agents.

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L, MnL, FeL, CoL, and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC50 than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL, CoL, and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL, remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy.

In situ synthesis, crystal structure, selective anticancer and proapoptotic activity of complexes isolated from the system containing zerovalent nickel and pyrazole derivatives

New nickel(II) complexes [NiLS(NCS)2]∙CH3CN (1) [Ni(dmpz)2(NCS)2]n (2), where LS is N,N,N-tris(1-(3,5-dimethylpyrazolylmethyl)amine) and dmpz is 3,5-dimethylpyrazole, have been isolated in a one-pot synthesis by reacting zerovalent-powered nickel, 1-hydroxymethyl-3,5-dimethylpyrazole (HL1) and 1-carboxamide-3,5-dimethylpyrazole (HL2) as precursors. The complexes were characterized by elemental analysis, IR and UV–Vis spectra, thermal investigations and single crystal diffraction studies. The anti-proliferative activity of the described Ni(II) complexes was studied in vitro against selected human tumour cell lines and normal human cells (fibroblasts). The monomeric complex [NiLS(NCS)2]∙CH3CN (1) expressed more potent anti-proliferative activity towards cancer cells with the relevant cytotoxicity, while the polymeric complex [Ni(dmpz)2(NCS)2]n (2) was very toxic towards normal cells and was also characterized by mild inhibitory potency against tumour cells and poor selectivity. Complex (1) causes massive death of cancer cells due to programmed cell death, apoptosis. The obtained results demonstrated potent cytotoxic activity of the isolated [NiLS(NCS)2]∙CH3CN complex combined with strong selectivity towards cancer cells, and the mechanism of its actions included apoptosis.

Dinuclear silver and gold bisNHC complexes as drug candidates for cancer therapy

We report four dinuclear silver(I) and gold(I) complexes containing two different bidentate N-heterocyclic carbene ligands (bisNHC). One of these complexes 4, shows strong and selective anticancer activity against the human ovarian cancer cell line A2780. Mechanistically, 4 enhances the oxidative stress by stimulating reactive oxygen species production and inhibiting the scavenging activity of thioredoxin reductase. Our findings provide evidence that tuning ligand and electronic properties of metal-NHC complexes can modulate their reactivity and selectivity and it may result in potential novel anticancer drugs.

Green fabrication of copper oxide nanoparticles by Tragopogon collinus leaf extract: Characterization and exploring their selective anticancer effects against human leukemia cell line

Extending the studies on the preparation of nanoparticles using green chemistry, we present here a facile and simple method for the fabrication of copper oxide (CuO) nanoparticles using Tragopogon collinus leaf extract. The characteristics of biologically synthesized CuO nanoparticles were determined by several techniques including UV–vis spectroscopy, FITR, XRD, XPS, TEM, and DLS. Subsequently, the anticancer activity of bio-fabricated CuO nanoparticles against human leukemia (K562) cell line was assessed through MTT, ROS, apoptosis, caspase-9/-3, mitochondrial membrane potential (MMP), and qPCR analyses, whereas lymphocytes were used as control. The outcomes demonstrated that crystalline CuO nanoparticles had an average size of 50 nm, a zeta potential of - 33.91 mV, and a hydrodynamic radius of 88.31 nm with a PDI of 0.193, revealing the high dispersion ability of the nanoparticles. The cytotoxic activity against K562 cell line and lymphocytes showed that fabricated CuO nanoparticles had a selective anticancer activity against K562 cells through generation of ROS, apoptosis induction, elevation of caspase-9/-3 activity, reduction of MMP, overexpression of Bax and caspase-9/-3, and downregulation of Bcl-2 at mRNA level, determining the anticancer effects of biosynthesized CuO nanoparticles through mitochondrial-mediated apoptosis signaling pathway. Therefore, based on the scientific achievements it can be concluded that fabricated CuO nanoparticles may be used in future studies to augment the activities of anticancer drugs in vivo and in clinical trials.

Green Synthesized Bismuth Oxide Nanoparticles Using Aqueous Rhizome Extract ofCurcuma longaMitigate the Proliferation of Human U87 Glioblastoma Cells by Regulation of the Wnt/β-Catenin Signaling Pathway

The low biocompatibility of inorganic nanoparticles (NPs) is a main concern in their wide applications in the biomedical field. Therefore, the green synthesis of NPs from plant extracts can provide safe NPs for biomedical applications. The present study was aimed to assess the anticancer activity of bismuth oxide (Bi2O3) NPs fabricated using aqueous plant extracts from the rhizome ofCurcuma longa(C. longa). Characterization of green Bi2O3NPs was done using TEM, DLS, and X-ray diffraction analyses. Selective anticancer activity of green Bi2O3NPs against human glioblastoma (U87) cells was assessed using MTT, GSH, MDA, ROS, apoptosis, and caspase-3 assays. Also, qPCR analysis was done to explore the expression ofβ-catenin, cyclin D1, and c-myc at mRNA level as the important genes of the Wnt/β-catenin signaling pathway. The results showed that the green Bi2O3NPs have a crystalline nature with a size of around 30 nm with good colloidal stability attributed to potential bio-fabrication of Bi2O3NPs. Cellular study indicated that green Bi2O3NPs triggered selective anticancer activity against U87 cells through reduction of GSH level and increase of MDA level, ROS level, Annexin+cells, and caspase-3 activity. Also, it was found that IC50concentration of biosynthesized Bi2O3NPs (20μg/mL) resulted in a significant downregulation in the expression ofβ-catenin, cyclin D1, and c-myc genes involved in the Wnt/β-catenin signaling pathway. This study concludes that green Bi2O3NPs bio-fabricated from rhizome ofC. longashow potential selective anticancer activity.

Structure-Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity.

Simple SummaryCancer is the leading cause of death worldwide and responsible for killing approximately 10 million people per year. Fused heterocyclic ring systems such as benzofuran have emerged as important scaffolds with many biological properties. Furthermore, derivatives of benzofurans demonstrate a wide range of biological and pharmacological activities, including anticancer properties. The main aim of this review is to highlight and discuss the contribution of benzofuran derivatives as anticancer agents by considering and discussing the chemical structure of 20 different compounds. Evaluating the chemical structure of these compounds will guide future medicinal chemists in designing new drugs for cancer therapy that might give excellent results in in vivo/in vitro applications.Benzofuran is a heterocyclic compound found naturally in plants and it can also be obtained through synthetic reactions. Multiple physicochemical characteristics and versatile features distinguish benzofuran, and its chemical structure is composed of fused benzene and furan rings. Benzofuran derivatives are essential compounds that hold vital biological activities to design novel therapies with enhanced efficacy compared to conventional treatments. Therefore, medicinal chemists used its core to synthesize new derivatives that can be applied to a variety of disorders. Benzofuran exhibited potential effectiveness in chronic diseases such as hypertension, neurodegenerative and oxidative conditions, and dyslipidemia. In acute infections, benzofuran revealed anti-infective properties against microorganisms like viruses, bacteria, and parasites. In recent years, the complex nature and the number of acquired or resistant cancer cases have been largely increasing. Benzofuran derivatives revealed potential anticancer activity with lower incidence or severity of adverse events normally encountered during chemotherapeutic treatments. This review discusses the structure–activity relationship (SAR) of several benzofuran derivatives in order to elucidate the possible substitution alternatives and structural requirements for a highly potent and selective anticancer activity.

Core-Sheath-Like Poly(Ethylene Oxide)/Beeswax Composite Fibers Prepared by Single-Spinneret Electrospinning. Antibacterial, Antifungal, and Antitumor Activities.

Composite fibrous materials are prepared from poly(ethylene oxide) (PEO) and beeswax (BW) by single-spinneret electrospinning using chloroform as a common solvent. The obtained fibers have core-sheath-like structure, as evidenced by the water contact angle values and corroborated by the results on the elemental composition of the fiber's surface determined by X-ray photoelectron spectroscopy (XPS) and by analyses with scanning electron microscopy of fibers before and after selective extraction of PEO or BW. Furthermore, the core-sheath-like structure is proven by transmission electron microscopy. This is attributed to self-assembly of BW molecules on the surface of the formed fibers driven by the incompatibility between PEO and BW. 5-Nitro-8-hydroxyquinoline (NQ) is embedded as a model drug with antibacterial, antifungal, and anticancer properties in the PEO/BW fibrous materials. XPS analyses reveal that NQ is present on the surface of the PEO/BW/NQ materials. Using a purposely designed cell for fixation of the fibrous materials the NQ release in phosphate buffer solution with рН 7.4 is followed. The new PEO/BW/NQ fibrous materials exhibit antibacterial activity against S. aureus and E. coli, antifungal effect against C. albicans, and selective anticancer activity against HeLa (human cervical adenocarcinoma cells) and SH-4 (human melanoma cells) cell lines.

Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 9–16 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16.

The Secreted Metabolome of Hela Cells under Effect of Crotamine, a Cell-Penetrating Peptide from a Rattlesnake Using NMR-Based Metabolomics Analyses

Sequestering and reprogramming of cellular metabolism represents one of the principal hallmarks of several cells. Antimicrobial peptides have been shown to exhibit selective anticancer activities. In this study, the secreted metabolome of HeLa cells under action of the antimicrobial peptide Crotamine from the venom of the South American rattlesnake Crotalus durissus terrificus was evaluated. Crotamine has been shown to be selective for highly proliferating cells and is able to extend the in vivo lifespan. The present study using a cell line of cervical cancer, HeLa cells, provide insights into how Crotamine acts in cell metabolism. NMR spectroscopy was used to identify and quantify relative metabolite levels, which are associated with Crotamine uptake. Statistical analysis reveals that Crotamine dramatically affects metabolites related to glycolysis, metabolism and biosynthesis of amino acids and pyruvate metabolism. The developed machine learning model is found to be robust by ROC curve analysis, suggesting that the metabolic state of HeLa cells treated with Crotamine is different from the control samples. To account for metabolite levels, it is suggested that Crotamine would have to act on glycolysis, which, in turn, affects several other metabolic pathways, such as, glutathione metabolism, TCA cycle and pyruvate metabolism. The observed metabolic changes shed light into the mode of Crotamine function.

Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis

While the anti-inflammatory activities of Eriodictyol, a plant-derived flavonoid is well-known, reports on its anti-cancer efficacy and selective cytotoxicity in cancer cells are still emerging. However, little is known regarding its mechanism of selective anti-cancer activities. Here, we show the mechanism of selective cytotoxicity of Eriodictyol towards cancer cells compared to normal cells. Investigation reveals that Eriodictyol significantly upregulates TNFR1 expression in tumor cells (HeLa and SK-RC-45) while sparing the normal cells (HEK, NKE and WI-38), which display negligible TNFR1 expression, irrespective of the absence or presence of Eriodictyol. Further investigation of the molecular events reveal that Eriodictyol induces apoptosis through expression of the pro-apoptotic DISC components leading to activation of the caspase cascade. In addition, CRISPR-Cas9 mediated knockout of TNFR1 completely blocks apoptosis in HeLa cells in response to Eriodictyol, confirming that Eriodictyol induced cancer cell apoptosis is indeed TNFR1-dependent. Finally, in vivo data demonstrates that Eriodictyol not only impedes tumor growth and progression, but also inhibits metastasis in mice implanted with 4T1 breast cancer cells. Thus, our study has identified Eriodictyol as a compound with high selectivity towards cancer cells through TNFR1 and suggests that it can be further explored for its prospect in cancer therapeutics.

Induction of apoptosis in human colorectal cancer cells by nanovesicles from fingerroot (Boesenbergia rotunda (L.) Mansf.).

Colorectal cancer is the leading cause of cancer-related deaths worldwide, warranting the urgent need for a new treatment option. Plant-derived nanovesicles containing bioactive compounds represent new therapeutic avenues due to their unique characteristics as natural nanocarriers for bioactive molecules with therapeutic effects. Recent evidence has revealed potential anticancer activity of bioactive compounds from Boesenbergia rotunda (L.) Mansf. (fingerroot). However, the effect and the underlying mechanisms of fingerroot-derived nanovesicles (FDNVs) against colorectal cancer are still unknown. We isolated the nanovesicles from fingerroot and demonstrated their anticancer activity against two colorectal cancer cell lines, HT-29 and HCT116. The IC50 values were 63.9 ± 2.4, 57.8 ± 4.1, 47.8 ± 7.6 μg/ml for HT-29 cells and 57.7 ± 6.6, 47.2 ± 5.2, 34 ± 2.9 μg/ml for HCT116 cells at 24, 48, and 72 h, respectively. Interestingly, FDNVs were not toxic to a normal colon epithelial cell line, CCD 841 CoN. FDNVs exhibited selective uptake by the colorectal cancer cell lines but not the normal colon epithelial cell line. Moreover, dose- and time-dependent FDNV-induced apoptosis was only observed in the colorectal cancer cell lines. In addition, reactive oxygen species levels were substantially increased in colorectal cancer cells, but total glutathione decreased after treatment with FDNVs. Our results show that FDNVs exhibited selective anticancer activity in colorectal cancer cell lines via the disruption of intracellular redox homeostasis and induction of apoptosis, suggesting the utility of FDNVs as a novel intervention for colorectal cancer patients.

Three New Dihydrophenanthrene Derivatives from Cymbidium ensifolium and Their Cytotoxicity against Cancer Cells.

From the aerial parts of Cymbidium ensifolium, three new dihydrophenanthrene derivatives, namely, cymensifins A, B, and C (1–3) were isolated, together with two known compounds, cypripedin (4) and gigantol (5). Their structures were elucidated by analysis of their spectroscopic data. The anticancer potential against various types of human cancer cells, including lung, breast, and colon cancers as well as toxicity to normal dermal papilla cells were assessed via cell viability and nuclear staining assays. Despite lower cytotoxicity in lung cancer H460 cells, the higher % apoptosis and lower % cell viability were presented in breast cancer MCF7 and colon cancer CaCo2 cells treated with 50 µM cymensifin A (1) for 24 h compared with the treatment of 50 µM cisplatin, an available chemotherapeutic drug. Intriguingly, the half-maximum inhibitory concentration (IC50) of cymensifin A in dermal papilla cells at >200 µM suggested its selective anticancer activity. The obtained information supports the further development of a dihydrophenanthrene derivative from C. ensifolium as an effective chemotherapy with a high safety profile for the treatment of various cancers.

Plasmalemmal V-ATPase as a Potential Biomarker for Lactoferrin-Based Anticancer Therapy.

Lactoferrin (Lf) is a milk-derived protein with well-recognized potential as a therapeutic agent against a wide variety of cancers. This natural protein exhibits health-promoting effects and has several interesting features, including its selectivity towards cancer cells, good tolerability in humans, worldwide availability, and holding a generally recognized as safe (GRAS) status. To prompt the rational clinical application of this promising anticancer compound, previous works aimed to unveil the molecular mechanisms underlying its selective anticancer activity, where plasmalemmal V-ATPase was identified as an Lf target in cancer cells. V-ATPase is a proton pump critical for cellular homeostasis that migrates to the plasma membrane of highly metastatic cancer cells contributing to the acidity of the tumor microenvironment. Cancer cells were found to be susceptible to Lf only when this proton pump is present at the plasma membrane. Plasmalemmal V-ATPase can thus be an excellent biomarker for driving treatment decisions and forecasting clinical outcomes of Lf-based anticancer strategies. Future research endeavors should thus seek to validate this biomarker by thorough preclinical and clinical studies, as well as to develop effective methods for its detection under clinical settings.

Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity.

Development of targeted anticancer modalities has prompted a new era in cancer treatment that is notably different from the age of radical surgery and highly toxic chemotherapy. Behind each effective compound is a rich and complex history from first identification of chemical matter, detailed optimization, and mechanistic investigations, ultimately leading to exciting molecules for drug development. Herein we review the history and on-going journey of one such anticancer scaffold, the 3-(4-hydroxyphenyl)indoline-2-ones. With humble beginnings in 19th century Bavaria, we review this scaffold's synthetic history and anticancer optimization, including its recent demonstration of tumor eradication of drug-resistant, estrogen receptor-positive breast cancer. Compounds containing the 3-(4-hydroxyphenyl)indoline-2-one pharmacophore are emerging as intriguing candidates for the treatment of cancer.

Structure-antitumor activity relationship of hybrid acetogenins focusing on connecting groups between heterocycles and the linker moiety.

We studied hybrid molecules of annonaceous acetogenins and mitochondrial complex I-inhibiting insecticides to develop a novel anticancer agent. A structure–antitumor activity relationship study focusing on the connecting groups between the heterocycles and the linker moiety bearing the tetrahydrofuran moiety was conducted. Eleven hybrid acetogenins with 1-methylpyrazole instead of γ-lactone were synthesized and their growth inhibitory activities against 39 human cancer cell lines were evaluated. The nitrogen atom at the 2′-position of the linker moiety was essential for inhibiting cancer growth. The 1-methylpyrazole-5-sulfonamide analog showed potent growth inhibition of NCI-H23, a human lung cancer cell line, in a xenograft mouse assay without critical toxicity. Hence, the results of this study may pave the way for the development of novel anticancer agents, with both selective and broad anticancer activities.

Potent and selective anticancer activity of half-sandwich ruthenium and osmium complexes with modified curcuminoid ligands.

We have recently reported a series of half-sandwich ruthenium(II) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(II) and osmium(II) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(II)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(II)(cym)(p-curc)/(p-bdcurc)(PTA)][SO3CF3] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(II) and Os(II) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes.