Metal Compounds against Neglected Tropical Diseases.

Many first-line treatments for neglected tropical diseases identified by the World Health Organization (WHO) are limited by one or more of the following: the development of drug resistance, toxicity, and side effects, lack of selectivity, narrow therapeutic indices, route of administration, and bioavailability. As such, there is an urgent need to develop viable alternatives to overcome these limitations. The following review provides an overview of all existing metal complexes studied and evaluates the status of these complexes on the respective disease of choice.

Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors.

Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 µM, and Topo II catalytic inhibitory effect at a concentration of10 µM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.

Innovative DNA-Targeted Metallo-prodrug Strategy Combining Histone Deacetylase Inhibition with Oxidative Stress.

Cancer remains a global health challenge. There is an urgent need to develop innovative therapeutics that can overcome the shortcomings of existing cancer therapies. DNA enzymes involved in nucleic acid compaction and organization are an attractive cancer drug target for therapeutic exploitation. In this work, a family of Cu(II) prodrugs containing suberoylanilide hydroxamic acid (SAHA), a well-established histone deacetylase inhibitor (HDACi) and clinically approved cancer drug, and phenanthrene ligands as DNA intercalative components have been rationally developed. The complexes, of general formula [Cu(SAHA-1H)( N, N'-phenanthrene)]+, exhibit excellent DNA recognition with binding affinity of lead agents in the order of ∼107 M(bp)-1. Biophysical studies involving nucleic acid polymers indicate intercalative binding at both adenine-thymine (A-T) and guanine-cytosine (G-C) rich sequences but thermodynamically stable interactions are favored in G-C tracts. The complexes mediate DNA damage by producing reactive oxygen species (ROS) with spin trapping experiments showing that superoxide, the hydroxyl radical, and hydrogen peroxide play critical roles in strand scission. The agents were found to have promising antiproliferative effects against a panel of epithelial cancers, and in two representative cell lines possessing mutated p53 (SK-OV-3 and DU145), enhanced cytotoxicity was observed. Significantly, mechanistic experiments with the most promising candidates revealed HDAC inhibition activity was achieved over a shorter time frame as compared to clinical standards with DNA damage-response markers identifying upregulation of both DNA synthesis and nucleotide excision repair (NER) pathways. Finally, confocal imaging and gene expression analysis show this metallodrug class exerts cytotoxic activity predominantly through an apoptotic pathway.

Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine.

BACKGROUND: Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine. METHODS: Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination. RESULTS: HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3 ubiquitin ligase activity. CONCLUSIONS: This study has revealed the ability of ruthenium complexes to inhibit cell proliferation, induce cell cycle progression and apoptosis. Ruthenium treatment upregulated the marker genes involved in apoptosis and cell cycle progression while it downregulated BRCA1 mRNA and replication of HCC1937 cells. Our results could provide an alternative approach to finding effective therapeutic ruthenium-based agents with promising anticancer activity, and demonstrated that the BRCA1 RING domain protein was a promising therapeutic target for breast cancers.

A novel DNA intercalator, 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline-4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor.

Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent.

DNA metalating-intercalating hybrid agents for the treatment of chemoresistant cancers.

Nonclassical platinum-based antitumor agents have shown enormous potential in the treatment of chemoresistant cancers. The design of these agents is based on the hypothesis that platinum-containing pharmacophores that react with nuclear DNA in cancer cells radically differently than the clinical agent cisplatin will produce a unique spectrum of biological activity. One such class of molecules are platinum-acridine hybrid agents derived from the prototypical complex [PtCl(en)(ACRAMTU)](NO(3))(2), en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea ("PT-ACRAMTU"). This article summarizes milestones in the development of these agents and reviews critical key concepts that have guided their design and that of related compounds.

Eeyarestatin I, an inhibitor of the valosin-containing protein, exhibits potent virucidal activity against the flaviviruses.

Cellular responses to stress generally lead to the activation of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Several lines of study support that ERAD may be playing a proviral role during flaviviral infection. A key host factor in ERAD is the valosin-containing protein (VCP), an ATPase which ushers ubiquitin-tagged proteins to degradation by the proteasome. VCP exhibits different proviral activities, such as engaging in the biogenesis of viral replication organelles and facilitating flavivirus genome uncoating after the viral particle entry. To investigate the possible antiviral value of drugs targeting VCP, we tested two inhibitors: eeyarestatin I (EEY) and xanthohumol (XAN). Both compounds were highly effective in suppressing Zika virus (ZIKV) and Usutu virus (USUV) replication during infection in cell culture. Further analysis revealed an unexpected virucidal activity for EEY, but not for XAN. Preincubation of ZIKV or USUV with EEY before inoculation to cells resulted in significant decreases in infectivity in a dose- and time-dependent manner. Viral genomes in samples previously treated with EEY were more sensitive to propidium monoazide, an intercalating agent, with 10- to 100-fold decreases observed in viral RNA levels, supporting that EEY affects viral particle integrity. Altogether, these results support that EEY is a strong virucide against two unrelated flaviviruses, encouraging further studies to investigate its potential use as a broad-acting drug or the development of improved derivatives in the treatment of flaviviral infection.

In vitro anticancer activity and evaluation of DNA duplex binding affinity of phenyl-substituted indoloquinolines.

Phenyl-substituted indoloquinolines were studied for their biological activity and their DNA binding affinity. Water-soluble aminoalkyl derivatives were prepared and have shown significant in vitro anticancer activity. Unlike previous reports on the potential role of duplex DNA as target for various indoloquinoline based drugs, duplex UV melting experiments and fluorescence titrations suggest only weak and moderately strong binding of the phenyl-substituted indoloquinolines at 120 mM and 20 mM Na(+) concentrations, respectively. Binding is suggested by ethidium displacement and circular dichroism experiments to be associated with drug intercalation between base pairs.

Covalent and noncovalent interactions of coordination compounds with DNA: An overview.

Deoxyribonucleic acid plays a central role in crucial cellular processes, and many drugs exert their effects through binding to DNA. Since the discovery of cisplatin and its derivatives considerable attention of researchers has been focused on the development of novel anticancer metal-based drugs. Transition metal complexes, due to their great diversity in size and structure, have a big potential to modify DNA through diverse types of interactions, making them the prominent class of compounds for DNA targeted therapy. In this review we describe various binding modes of metal complexes to duplex DNA based on covalent and noncovalent interactions or combination of both. Specific examples of each binding mode as well as possible cytotoxic effects of metal complexes in tumor cells are presented.

ß-Carbolines as potential anticancer agents.

ß-Carbolines are indole alkaloids having a tricyclic pyrido[3,4-b]indole ring in their structure. Since the isolation of first ß-carboline from Peganum harmala in 1841, the isolation and synthesis of various ß-carboline derivatives surged in the following centuries. ß-Carboline derivatives due to their widespread availability from natural sources, structural flexibility, quick reactivity and interaction with varied anticancer targets such as DNA (intercalation, groove binding, etc.), enzymes (GPX4, topoisomerases, kinases, etc.) and proteins (tubulin, ABCG2/BRCP1, etc.) have established themselves as promising lead compounds for the synthesis of various anticancer active agents. The current review covers the synthesis and isolation, anticancer activity, mechanism of action and SAR of various ß-carboline containing molecules, its derivatives and congeners.

Photon activation therapy and brachytherapy.

PURPOSE: In photon activation therapy (PAT), energy deposition at critical sites within a tumor can be increased by complexing the DNA with higher Z atoms, and provoking the emission of Auger electrons after inducing a photoelectric effect. This in vivo study evaluates the hypothesis using X-rays from palladium-103 seeds to excite the L-edge of platinum (Pt) atoms bound to the DNA of cancerous cells. METHODS AND MATERIALS: Pt (II) tetrakis(N-methyl-4-pyridyl) porphyrin chloride was used to locate Pt atoms adjacent to the DNA of the KHJJ murine mammary carcinoma; a 2.3-mCi palladium-103 seed was implanted in the tumor. RESULTS: The tumor periphery received subtherapeutic doses. The rate of tumor growth in mice treated with PAT was slower than in mice treated with brachytherapy only. CONCLUSIONS: The tumor growth delay for PAT-treated mice is attributed to Auger emission from Pt atoms that produced substantial local damage. However, other co-existing mechanisms cannot be ruled out.

Efficacy and tolerability of mitoxantrone for neuromyelitis optica spectrum disorder: A systematic review.

The review assessed the efficacy and tolerability of mitoxantrone in patients with neuromyelitis optica spectrum disorder (NMOSD). Eight articles were reviewed with a total of 117 patients. Annualized relapse rate and progression of disability dramatically decreased post-treatment in most studies. Mitoxantrone was generally tolerated. Only one patient developed acute myeloid leukemia, which lead to septicemia and death. No serious cardiotoxicity was reported. Mitoxantrone may be effective in reducing the frequency of relapse and slowing down the progression of disability in patients with NMOSD. The risk of cardiotoxicity and leukemia detains it as a second-line agent for NMOSD.

Boronated DNA-binding compounds as potential agents for boron neutron capture therapy.

Boron Neutron Capture Therapy (BNCT) is a binary cancer treatment that exploits the short range particles released from a nuclear fission reaction involving the non-radioactive 10B nucleus and low-energy (thermal) neutrons for the destruction of tumour cells. If boronated agents are targeted towards chromosomal DNA, the efficiency of BNCT is greatly enhanced. This article presents a concise review of DNA-binding compounds that have been functionalised with boron.

DNA intercalators in cancer therapy: organic and inorganic drugs and their spectroscopic tools of analysis.

Since the discovery of the DNA intercalation process by Lerman in 1961 thousands of organic, inorganic octahedral (particularly ruthenium(II) and rhodium(III)) and square-planar (particularly platinum(II)) compounds have been developed as potential anticancer agents and diagnostic agents. The design and synthesis of new drugs is focused on bis-intercalators which have two intercalating groups linked via a variety of ligands, and synergistic drugs, which combine the anticancer properties of intercalation with other functionalities, such as covalent binding or boron-cages (for radiation therapy). Advances in spectroscopic techniques mean that the process of DNA intercalation can be examined in far greater detail than ever before, yielding important information on structure-activity relationships. In this review we examine the history and development of DNA intercalators as anticancer agents and advances in the analysis of DNA-drug interactions.

Phase I clinical investigation of 1,4-dihydroxy-5,8-bis (( (2-[(2-hydroxyethyl)amino]ethyl) amino))-9,10-anthracenedione dihydrochloride (NSC 301739), a new anthracenedione.

1,4-Dihydroxy-5,8-bis(( (2-[(2-hydroxyethyl)amino]ethyl)-amino))-9,10-anthracenedione dihydrochloride is a new anthracenedione derivative that was evaluated in a Phase I clinical trial. The schedule of administration consisted of a single i.v. injection, repeated at 4-week intervals. Twenty-five patients received a total of 41 courses of the drug in a dose range of 1.2 to 14 mg/sq m. Leukopenia and thrombocytopenia were dose limiting but were of short duration and rapidly reversible. Mild degrees of phlebitis were observed in 10% of courses, and a green discoloration of the urine was noted with doses of greater than or equal to 10 mg/sq m. One patient with adenocarcinoma of the lung experienced a partial response of his tumor secondary to the drug. Phase II studies of 1,4-dihydroxy-5,8-bis(( (2-[(2-hydroxyethyl)amino]ethyl)amino))-9,10-anthracenedione dihydrochloride are planned at a starting dose of 12 mg/sq m as a single dose repeated at 21- to 28-day intervals.

Anthrapyrazoles, a new class of intercalating agents with high-level, broad spectrum activity against murine tumors.

A series of 5-[(aminoalkyl)amino]-substituted anthra[1,9-cd] pyrazol-6(2H)ones (anthrapyrazoles) were synthesized. These compounds, which differ from the anthracenediones in that an additional pyrazole ring has been fused to the anthracene system in place of one carbonyl group, were evaluated in vivo for their anticancer activity in eight different mouse tumor systems. Compounds were selected for testing primarily on the basis of their high levels of activity P388 leukemia and occasionally for structural considerations. Sixty-seven % of the 21 analogues studied were curative in the National Cancer Institute P388 screen. Many of the compounds tested were highly active against each of the tumors of the National Cancer Institute panel. Thus 82, 73, 45, and 80% of the compounds tested were curative for L1210 leukemia, B16 melanoma, M5076 sarcoma, and the MX-1 mammary xenograft, respectively. Several of the compounds studied were curative against every tumor of the above panel. Because of the high activity of the anthrapyrazole series as a class in the National Cancer Institute tumor panel, additional testing was necessary to allow selection of clinical candidates. Twenty-one anthrapyrazoles were tested against mammary adenocarcinoma 16C, colon adenocarcinoma 11a, and the Ridgway osteogenic sarcoma. Four compounds, PD 113,309 (Cl-937), PD 113,785 (Cl-941), PD 111,815 (Cl-942), and PD 115,593, were judged superior to the rest on the basis of the expanded panel testing. The preclinical data to date suggest that these anthrapyrazoles are similar to doxorubicin in both degree and spectrum of activity. Each of these anthrapyrazoles were significantly more active than were the other synthetic intercalating agents, the anthracenediones mitoxantrone and ametantrone, against the tumors of the expanded panel. On the basis of their high level of broad spectrum activity in preclinical systems, ease of formulation, possible lack of cross-resistance with doxorubicin, and potential lack of cardiotoxicity, Cl-937, Cl-941, and Cl-942 have been selected for further preclinical evaluation and possible clinical development.

Phase I study of amonafide dosing based on acetylator phenotype.

Amonafide is extensively metabolized, including N-acetylation to an active metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxicity at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately for slow and fast acetylators. Twenty-six patients with advanced cancer underwent acetylator phenotyping with caffeine and were assigned to a dose level. Slow acetylators were treated at 375 mg/m2 (daily for 5 days) and had a median WBC nadir of 1600/microliters. Fast acetylators were treated at both 200 and 250 mg/m2, resulting in median WBC nadirs of 5300 and 2000/microliter, respectively. Two patients were not typeable, and two patients appear to have been misphenotyped, one in each phenotype category. Pharmacodynamic analysis yielded a model for nadir WBC including acetylator phenotype, 24-h N-acetyl-amonafide plasma concentration, gender, and pretreatment WBC. We recommend doses of 250 and 375 mg/m2 (for 5 days) for further phase II testing of amonafide in fast and slow acetylators, respectively.

Noncovalent Binding to DNA: Still a Target in Developing Anticancer Agents.

DNA-binding compounds are of extraordinary importance in medicine, accounting for a substantial portion of antitumor drugs in clinical usage. However, their mechanisms of action remain sometimes incompletely understood. This review critically examines two broad classes of molecules that bind noncovalently to DNA: intercalators and groove binders. Intercalators bind to DNA by inserting their chromophore moiety between two consecutive base pairs, whereas groove binders fit into the grooves of DNA. Noncovalent DNAinteractive drugs can recognize certain supramolecular DNA structures such as the Gquadruplexes found in telomeres and in numerous gene promoters, and they can act as topoisomerase I and II poisons. We discuss how DNA-binding compounds affect transcription and compete with protein factors for binding to consensus binding sites in gene promoters both in vitro and in cultured cancer cells. Moreover, we comment on the design of molecules that can tightly and specifically bind to any desired target DNA, such as various hairpin polyamides which efficacy as chemotherapeutic agents is being evaluated. At present, genome-wide studies, which provide details of events that may influence both cancer progression and therapeutic outcome, are a common way used to analyze the effects of DNA-binding compounds. A conclusive feature that emerges from reviewing the information on DNA-binding compounds is that both natural sources and chemical approaches can be productively used to obtain drugs to manipulate gene expression in cancer cells.