Synthesis,Characterization and Evaluation of the Antibacterial and Antitumor Activity of HalogenatedSalen Copper (II) Complexes derived from Camphoric Acid

Platinum metal complexes are the most common chemotherapeutics currently used in cancer treatment. However, the frequent adverse effects, as well as acquired resistance by tumor cells, urge the development of effective alternatives. In the recent past, copper complexes with Schiff base ligands have emerged as good alternatives, showing interesting results. Accordingly, and in continuation of previous studies in this area, three new camphoric acid-derived halogenated salen ligands and their corresponding Cu (II) complexes were synthesized and their antitumor activity was evaluated in order to determine the influence of the type and number of halogens present (Br, Cl). The in vitro cytotoxic activity was screened against colorectal WiDr and LS1034 and against breast MCF-7 and HCC1806 cancer cell lines. The results proved the halogenated complexes to be very efficient, the tetrachlorinated Cu (II) complex being the most promising, presenting IC₅₀ of 0.63–1.09 μM for the cell lines studied. The complex also shows selectivity to colorectal cancer cells compared to non-tumor colon cells. It is worth highlighting that the tetrachlorinated Cu (II) complex, our most efficient complex, shows a significantly more powerful antitumor effect than the reference drugs currently used in conventional chemotherapy. The halogenated salen and corresponding complexes were also screened for their antimicrobial activity against four bacterial species-Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa-and four fungal species-Candida albicans, Candida glabrata, Aspergillus fumigatus and Alternaria alternata. The compounds were found to exhibit moderate to strong antibacterial activity against the bacterial strains studied. NMR studies and theoretical calculations provided some insight into the structure of the ligands and copper complexes. Considering the results presented herein, our work validates the potential use of copper-based chemotherapeutics as alternatives for cancer treatment.     

Retracted: Synthesis,Molecular Properties,and Biological Evaluation of Hybrid 1,2,3‐Triazolylpolyaza Heterocyclic Compounds

In this research article, a highly efficient, cost‐effective synthesis of various hybrid molecules possessing 1,2,3‐triazolyltetrazoles and evaluation of their biological activity have been addressed. The structure elucidation of these new library hybrid molecules has been carried out by IR, ¹H NMR, ¹³C NMR, and mass spectral analysis. The compounds have been screened for their anticancer activity against human colon cancer cell line Colo‐205 and human lung cancer cell line HOP‐205, and the results attest that most of the compounds have shown very good therapeutic nature. In particular, compounds 3d , 3j , 6a , and 6e were more cytotoxic than Adriamycin against all tested human cancer cell lines with 68%, 101.8%, 94%, and 104.5% growth, respectively. In the present investigation, a series of 3a – j and 6a – h were subjected to molecular properties prediction, drug likeness by Molinspiration, and toxicity risks by Molsoft software programs. All the 18 analogues were chosen on the basis of Lipinski “Rule of five” for the synthesis, screening their antibacterial and anticancer as oral bioavailable drugs/leads.     

Response of Osteosarcoma Cell Metabolism to Platinum and Palladium Chelates as Potential New Drugs

This paper reports the first metabolomics study of the impact of new chelates Pt₂Spm and Pd₂Spm (Spm = Spermine) on human osteosarcoma cellular metabolism, compared to the conventional platinum drugs cisplatin and oxaliplatin, in order to investigate the effects of different metal centers and ligands. Nuclear Magnetic Resonance metabolomics was used to identify meaningful metabolite variations in polar cell extracts collected during exposure to each of the four chelates. Cisplatin and oxaliplatin induced similar metabolic fingerprints of changing metabolite levels (affecting many amino acids, organic acids, nucleotides, choline compounds and other compounds), thus suggesting similar mechanisms of action. For these platinum drugs, a consistent uptake of amino acids is noted, along with an increase in nucleotides and derivatives, namely involved in glycosylation pathways. The Spm chelates elicit a markedly distinct metabolic signature, where inverse features are observed particularly for amino acids and nucleotides. Furthermore, Pd₂Spm prompts a weaker response from osteosarcoma cells as compared to its platinum analogue, which is interesting as the palladium chelate exhibits higher cytotoxicity. Putative suggestions are discussed as to the affected cellular pathways and the origins of the distinct responses. This work demonstrates the value of untargeted metabolomics in measuring the response of cancer cells to either conventional or potential new drugs, seeking further understanding (or possible markers) of drug performance at the molecular level.     

Thermal degradation of platinum(IV) precursors to antitumor drugs

Organoplatinum antitumor agents are very effective, broad-spectrum drugs used for the treatment of a variety of cancerous conditions. The two most prominent of these, Cisplatin [cis-diamminodichloroplatinum(II)] and Carboplatin [diammino(1,1-cyclobutanedicarboxylato)platinum(II)], are large scale commercial successes. The third, Oxaliplatin [((trans-1,2-diamminocyclohexane)oxalato)platinum(II)], is now commercially available. The administration of all these drugs is accompanied by severe side effects. For Cisplatin, the most debilitating of these is kidney damage and extreme nausea. Several approaches to generate drug-release formulations that might mitigate toxic side effects have been explored. Now, platinum(IV) compounds which are more inert than platinum(II) compounds, and consequently less toxic, but which may be reduced to platinum(II) species within the cell are being evaluated for effectiveness in the treatment of cancer. The thermal stability of several precursors to compounds of this kind has been examined by thermogravimetry. In general, these materials lose ligands sequentially to generate a residue of platinum. This behavior may be generally useful for the characterization of such materials.     

Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin

Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual‐responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the Pt^IV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the Pt^IV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells.     

A Dogma in Doubt: Hydrolysis of Equatorial Ligands of PtIV Complexes under Physiological Conditions

Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, Pt^IV complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato Pt^IV complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of Pt^IV drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact Pt^IV complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of Pt^IV compounds and needs to be considered in the screening and design for novel platinum‐based anticancer drugs.     

Imine‐N‐Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p‐Cymene Anticancer Complexes: A Structure–Activity Relationship Study

A family of novel imine‐N‐heterocyclic carbene ruthenium(II) complexes of the general formula [(η⁶‐p‐cymene)Ru(C^N)Cl]PF₆⁻ (where C^N is an imine‐N‐heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine‐N‐heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD⁺ is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC₅₀=14.36 μm ), with an approximately 1.5‐fold better activity than the clinical platinum drug cisplatin (IC₅₀=21.30 μm ) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy.     

Novel bis(thiosemicarbazones) of the 3,5-diacetyl-1,2,4-triazol series and their platinum(II) complexes: chemistry, antiproliferative activity and preliminary nephrotoxicity studies

The preparation and characterization of three novel (4)N-monosubstituted bis(thiosemicarbazone) ligands of 3,5-diacetyl-1,2,4-triazol series and their dinuclear platinum complexes are described. The crystal and molecular structure of the [Pt(μ-H(3)L(3))](2) complex derived of 3,5-diacetyl-1,2,4-triazol bis((4)N-p-tolylthiosemicarbazone), H(5)L(3), has been resolved by single crystal X-ray diffraction. The ligands coordinate, in an asymmetric dideprotonate form, to the platinum ions in a tridentate fashion (NNS) and S-bridging bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that these compounds may be endowed with important antitumour properties since are capable of not only circumventing cisplatin resistance in A2780cisR cells but also exhibit high antiproliferative activity in human non-small cell lung cancer NCI-H460 cells. The interactions of these compounds with calf thymus DNA was investigated by UV-vis absorption and a nephrotoxic study, in LLC-PK1 cells, has also been carried out.     

Synthesis,characterization, and biological activity of new mixed ammine/amine platinum(IV) complexes

A series of mixed ammine/amine platinum(IV) complexes with lipophilic ligands in their axial positions were designed, synthesized, and spectrally characterized. In vitro cytotoxicity evaluation of these complexes and their lead compounds have been carried out against A549, SMMC-7721, MCF-7, and SW480 human cancer cell lines. The introduction of carboxylate ions as leaving group can improve the aqueous solubility and stability of the platinum(II) complexes. The carboxylato ligands and chloride ligands in the axial position markedly increased the lipophilicity and cytotoxicity of compounds C4 and C5. Particularly, compound C5 showed two to eight times higher cytotoxicity than cisplatin and satraplatin against selected cell lines. For its oral activity and no cross-resistance potentiality, C5 is expected to be an antitumor platinum drug candidate. This novel class of platinum compounds represents a valuable lead in the development of new-generation agents capable of demonstrating cytotoxicity superior to that of the clinically established cisplatin.     

Metals in Medicine

Not only the 24 or so essential elements , but also nonessential and even radioactive elements have enormous potential for applications in medicine. In the fight against cancer cisplatin, one of the world's best selling anticancer drugs, is being joined by other platinum, titanium, and ruthenium complexes. Gadolinium(III ) complexes can be safely injected as magnetic resonance imaging contrast agents, and ligand design allows targeting of paramagnetic ions as well as radiodiagnostic (e.g. ^99mTc) and radiotherapeutic isotopes (e.g. ¹⁸⁶Re). Manganese superoxide dismutase mimics, vanadium insulin mimics, ruthenium nitric oxide scavengers, lanthanide-based photosensitizers, and metal-targeted organic agents show exciting clinical potential.     

Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models—S. cerevisiae, five cancer cell lines, and the parasite L. mexicana—were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.     

Can an Elusive Platinum(III) Oxidation State be Exposed in an Isolated Complex?

Platinum(IV) complexes are extensively studied for their activity against cancer cells as potential substitutes for the widely used platinum(II) drugs. Pt^IV complexes are kinetically inert and need to be reduced to Pt^II species to play their pharmacological action, thus acting as prodrugs. The mechanism of the reduction step inside the cell is however still largely unknown. Gas‐phase activation of deprotonated platinum(IV) prodrugs was found to generate products in which platinum has a formal +3 oxidation state. IR multiple photon dissociation spectroscopy is thus used to obtain structural information helping to define the nature of both the platinum atom and the ligands. In particular, comparison of calculations at DFT, MP2 and CCSD levels with experimental results demonstrates that the localization of the radical is about equally shared between the d_xz orbital of platinum and the p_z of nitrogen on the amino group, the latter acting as a non‐innocent ligand.     

Synthesis,Docking, ADME‐Tox Study of 2‐(2‐(2‐Chlorophenyl)quinoline‐4‐carbonyl)‐N‐substituted hydrazinecarbothioamide Derivatives and Their Biological Evaluation

A series of 2‐(2‐(2‐chlorophenyl)quinoline‐4‐carbonyl)‐N‐substituted hydrazinecarbothioamide derivatives were synthesized by facile and efficient conventional method. The structures of the compounds were elucidated with the aid of an elemental analysis, IR, ESI‐MS, ¹H‐NMR, and ¹³C‐NMR spectral data. The synthesized compounds were evaluated for their in vitro antibacterial, antifungal, antimalarial, and antituberculosis activity against standard drugs. The bacterial studies were determined against gram‐positive and negative bacteria. These compounds were found to a broad spectrum of activity against the screened bacteria, but poor activity was observed against Pseudomonas aeruginosa and Escherichia coli. Compounds 8d , 8f , 8i , 8l , and 8n showed the potent activity against Staphylococcus aureus. Compounds 8d , 8g , 8k , 8l , and 8q show the potent activity against antimalarial as compared with the standard drugs Chloroquine, Quinine and compounds 8h , 8n , and 8o shows mild activity against H37Rv strain. Molecular docking revealed that synthesized derivatives and target proteins were actively involved in a binding pattern and had a significant corelation with biological activity. We have also performed a molecular dynamics and ADME‐Tox parameters for the synthesized compounds.     

Synthesis,in vitro biological evaluation and in silico docking studies of new quinazolin-2,4-dione analogues as possible anticarcinoma agents

Today, cancer is considered as one of the major reasons of death in human beings worldwide. We reported herein the synthesis, anticancer activity, and in silico docking studies of a series of nine quinazolindione-based scaffolds bearing pyrimidine, pyridine, pyran, and pyrazole moieties ( 1 - 9 ) through Michael addition, Vilsmeier-Haack, Claisen-Schmidt, and nucleophilic addition reactions. The chemical structures of the newly prepared compounds were ascertained by means of their spectral analysis techniques like IR, ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, mass spectroscopy, and elemental analysis. This work was conducted to investigate the implication of Rho7 protein in breast and hepatocellular cancer cells aggressively. MCF-7 and HepG2 cells have been selected as models for the effect of protein expression on breast and hepatocellular cancers cell growth. All prepared compounds were biologically evaluated for their antiproliferative efficacy on hepatic cancer cell lines (HepG2) and breast cancer cell lines (MCF-7); also, their effects on normal cell lines (BALB/3T3) were studied. Moreover, in silico molecular docking studies were studied for the compounds against the binding site of Homo sapiens Rho7 protein. The pharmacokinetic properties of the newer compounds were also evaluated using various computational tools. The compounds showed interesting interactions with satisfactory docking scores to the target Rho7; thus, they may act as promising potent drug candidates against cancer.     

Towards the rational design of platinum(II) and gold(III) complexes as antitumour agents

Metal complexes afford an opportunity for the discovery of new antitumour drugs with truly novel mechanisms of action. Various tactics and some new concepts have been employed to improve the physico-chemical and biological properties of metal complexes. Recent advances in this area demonstrate a bright prospect for the utilization of metal complexes in cancer chemotherapy. The theme of this article focuses on the approaches towards the rational design of platinum(II) and gold(III) complexes with antitumour properties based on the updated understanding of the mechanism of action of these compounds. The complexes summarized in this work include monofunctional platinum(II) complexes, multinuclear platinum(II) complexes, hybrid and targeted platinum(II) complexes, and gold(III) complexes. Most of them violate the established structure-activity relationships and demonstrate different reactivities from cisplatin and thereby show some potential for the prevention of detoxification.     

Identification and In Silico Characterization of Novel Helicobacter pylori Glucose-6-Phosphate Dehydrogenase Inhibitors

Helicobacter pylori (H. pylori) is a pathogen that can remain in the stomach of an infected person for their entire life. As a result, this leads to the development of severe gastric diseases such as gastric cancer. In addition, current therapies have several problems including antibiotics resistance. Therefore, new practical options to eliminate this bacterium, and its induced affections, are required to avoid morbidity and mortality worldwide. One strategy in the search for new drugs is to detect compounds that inhibit a limiting step in a central metabolic pathway of the pathogen of interest. In this work, we tested 55 compounds to gain insights into their possible use as new inhibitory drugs of H. pylori glucose-6-phosphate dehydrogenase (HpG6PD) activity. The compounds YGC-1; MGD-1, MGD-2; TDA-1; and JMM-3 with their respective scaffold 1,3-thiazolidine-2,4-dione; 1H-benzimidazole; 1,3-benzoxazole, morpholine, and biphenylcarbonitrile showed the best inhibitory activity (IC₅₀ = 310, 465, 340, 204 and 304 μM, respectively). We then modeled the HpG6PD protein by homology modeling to conduct an in silico study of the chemical compounds and discovers its possible interactions with the HpG6PD enzyme. We found that compounds can be internalized at the NADP⁺ catalytic binding site. Hence, they probably exert a competitive inhibitory effect with NADP⁺ and a non-competitive or uncompetitive effect with G6P, that of the compounds binding far from the enzyme’s active site. Based on these findings, the tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori.     

Novel antitumor dinuclear platinum (II) complexes with a new chiral tetradentate ligand as the carrier group

Seven dinuclear platinum(II) complexes with a novel chiral tetradentate ligand, (1R,1′R,2R,2′R)‐N¹,N^1′‐(1,4‐phenylenebis(methylene))dicyclohexane‐1,2‐diamine, were designed, synthesized and spectrally characterized. All the complexes were evaluated for their in vitro cytotoxicity against human HepG‐2, A549, HCT‐116 and MCF‐7 cancer cell lines. The results indicated that all compounds showed positive biological activity against HepG‐2, A549 and HCT‐116 cancer cell lines. In particular, compounds D7 and D2 showed better activity than carboplatin against HepG‐2 and A549 and compound D7 also showed an activity close to that of oxaliplatin. Copyright © 2015 John Wiley & Sons, Ltd.     

Current Status,Distribution, and Future Directions of Natural Products against Colorectal Cancer in Indonesia: A Systematic Review

In 2020, an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths have occurred worldwide, with colorectal cancer ranking as the third most frequently diagnosed (10.0%). Several attempts have been conducted against cancer, including surgery, radiation, monoclonal antibodies, and chemotherapy. Many people choose natural products as alternatives against cancer. These products will not only help in human life preservation but also work as a source of up-to-date information, leading people away from incorrect information. We discuss the current status, distribution, and future implications of protecting populations with natural products as an alternative against colorectal cancer in Indonesia. Thirty-eight studies were included in this review for data extraction. The distribution of natural products in Indonesia that have potential activity against colorectal cancer cells was predominated by terpenoids, followed by phytosterols, phenolics, alkaloids, and polyisoprenoids. The type of cell line utilized in the cytotoxic activity analysis of natural products was the WiDr cell line, followed by HT-29 cells and HCT-116 cells. This review showed that MTT in vitro assay is a general method used to analyze the cytotoxic activity of a natural product against colorectal cancer cells, followed by other in vitro and in vivo methods. The systematic review provided predictions for several secondary metabolites to be utilized as an alternative treatment against colorectal cancer in Indonesia. It also might be a candidate for a future co-chemotherapy agent in safety, quality, and standardization. In addition, computational methods are being developed to predict the drug-likeness of compounds, thus, drug discovery is already on the road towards electronic research and development.     

Tridentate bipyrazole compounds with a side-arm as a new class of antitumor agents

Eight tridentate bipyrazole derivatives with different side arms have been prepared in one step and with good yields. The products were screened for their cytotoxic activity against three tumor cell lines—human breast cancer cell line MDA-MB231, human prostate cancer cell line PC3, and human colorectal cell line LoVo, by use of colorimetric MTT assay. Structure–activity relationships reflected the effect of substituted drugs. Among this series, two compounds had remarkable in-vitro antiproliferative activity against the LoVo cell line with IC50 values ranging from 2.6 to 2.7 μg ml^?1. All the compounds had suitable drug-like characteristics according to Lipinski’s rule.     

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Dual- or multi-action Pt^IV prodrugs represent a new generation of platinum anticancer drugs. The important property of these Pt^IV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a “triple-action” prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the Pt^IV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC₅₀ values in the screened malignant cell lines ranged from as low as 9 nm (HCT-116) to 74 nm (MDA-MB-231)]. It is also demonstrated that cellular activation of the Pt^IV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the Pt^IV prodrug introduced in this study acts as a true “multi-action” prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells.