A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5-40 and sulfinyl 41-62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63-82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53-/- (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates.

• Keywords
• DNA/RNA damage, Sulfanyl-Sulfinyl-Sulfonyl groups, antiproliferative activity, cell cycle, synthesis of 4-thioalkylquinoline,
• Publication type
• Journal Article MeSH

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

• Keywords
• COVID-19, Na+/K+-ATPase, cardiac steroids, coronavirus, digitoxin, digoxin, drug repurposing, lanatoside C, ouabain, virus entry,
• MeSH
• Antiviral Agents pharmacology   therapeutic use   MeSH
• COVID-19 MeSH
• Digitoxin MeSH
• Digoxin MeSH
• Virus Internalization drug effects   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Ouabain MeSH
• Pandemics MeSH
• Drug Repositioning methods   MeSH
• Virus Replication drug effects   MeSH
• SARS-CoV-2 MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides metabolism   therapeutic use   MeSH
• Heart Failure drug therapy   virology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Digitoxin MeSH
• Digoxin MeSH
• Ouabain MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides MeSH

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.

• Keywords
• Na+/K+ ATPase, antiviral potential, cancer treatment, cardenolides, digitoxin, digoxin, drug repositioning, immunogenic cell death, secondary plant metabolites, toxins,
• MeSH
• Molecular Targeted Therapy * MeSH
• Digitoxin pharmacology   toxicity   MeSH
• Digoxin pharmacology   toxicity   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Ouabain pharmacology   toxicity   MeSH
• Antineoplastic Agents pharmacology   toxicity   MeSH
• Cattle MeSH
• Sodium-Potassium-Exchanging ATPase antagonists & inhibitors   MeSH
• Cardiac Glycosides biosynthesis   pharmacology   toxicity   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Digitoxin MeSH
• Digoxin MeSH
• Ouabain MeSH
• Antineoplastic Agents MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides MeSH

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na+/K+-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

• Keywords
• NKA signalosome, Th17, anticancer compounds, calreticulin, cardiac steroids, immunogenic cell death, inflammation, interleukin 17, retinoic acid receptor-related orphan receptor γ thymus, sodium-potassium ATPase,
• MeSH
• Cytokines metabolism   MeSH
• Immunologic Factors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neoplasms drug therapy   immunology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Sodium-Potassium-Exchanging ATPase metabolism   MeSH
• Cardiac Glycosides pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cytokines MeSH
• Immunologic Factors MeSH
• Antineoplastic Agents MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides MeSH