Binding Affinity, Selectivity, and Pharmacokinetics of the Oxytocin Receptor Antagonist L-368,899 in the Coyote (Canis latrans).

L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.

Economic and Health Value of Delaying Atrial Fibrillation Progression Using Radiofrequency Catheter Ablation.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is an established treatment for atrial fibrillation (AF) refractory to antiarrhythmic drugs. The economic value of RFCA in delaying disease progression has not been quantified. METHODS: An individual-level, state-transition health economic model estimated the impact of delayed AF progression using RFCA versus antiarrhythmic drug treatment for a hypothetical sample of patients with paroxysmal AF. The model incorporated the lifetime risk of progression from paroxysmal AF to persistent AF, informed by data from the ATTEST (Atrial Fibrillation Progression Trial). The incremental effect of RFCA on disease progression was modeled over a 5-year duration. Annual crossover rates were also included for patients in the antiarrhythmic drug group to mirror clinical practice. Estimates of discounted costs and quality-adjusted life years asssociated with health care utilization, clinical outcomes, and complications were projected over patients' lifetimes. RESULTS: From the payer's perspective, RFCA was superior to antiarrhythmic drug treatment with an estimated mean net monetary benefit per patient of $8516 ($148-$16 681), driven by reduced health care utilization, cost, and improved quality-adjusted life years. RFCA reduced mean (95% CI) per-patient costs by $73 (-$2700 to $2200), increased mean quality-adjusted life years by 0.084 (0.0-0.17) and decreased the mean number of cardiovascular-related health care encounters by 24%. CONCLUSIONS: RFCA is a dominant (less costly and more effective) treatment strategy for patients with AF, especially those with early AF for whom RFCA could delay progression to advanced AF. Increased utilization of RFCA-particularly among patients earlier in their disease progression-may provide clinical and economic benefits.

Cost-effectiveness of catheter ablation versus medical therapy for the treatment of atrial fibrillation in the United Kingdom.

INTRODUCTION: Research evidence has shown that catheter ablation is a safe and superior treatment for atrial fibrillation (AF) compared to medical therapy, but real-world practice has been slow to adopt an early interventional approach. This study aims to determine the cost effectiveness of catheter ablation compared to medical therapy from the perspective of the United Kingdom. METHODS: A patient-level Markov health-state transition model was used to conduct a cost-utility analysis. The population included patients previously treated for AF with medical therapy, including those with heart failure (HF), simulated over a lifetime horizon. Data sources included published literature on utilization and cardiovascular event rates in real world patients, a systematic literature review and meta-analysis of randomized controlled trials for AF recurrence, and publicly available government data/reports on costs. RESULTS: Catheter ablation resulted in a favorable incremental cost-effectiveness ratio (ICER) of £8614 per additional quality adjusted life years (QALY) gained when compared to medical therapy. More patients in the medical therapy group failed rhythm control at any point compared to catheter ablation (72% vs. 24%) and at a faster rate (median time to treatment failure: 3.8 vs. 10 years). Additionally, catheter ablation was estimated to be more cost-effective in patients with AF and HF (ICER = £6438) and remained cost-effective over all tested time horizons (10, 15, and 20 years), with the ICER ranging from £9047-£15 737 per QALY gained. CONCLUSION: Catheter ablation is a cost-effective treatment for atrial fibrillation, compared to medical therapy, from the perspective of the UK National Health Service.

Economic Evaluation of Contact Force Catheter Ablation for Persistent Atrial Fibrillation in the United States.

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it increases the risk of stroke, heart failure, and other cardiac complications. Catheter ablation is well-established as a treatment for paroxysmal AF, and the recent PRECEPT (Prospective Review of the Safety and Effectiveness of the THERMOCOOL SMARTTOUCH SF Catheter Evaluated for Treating Symptomatic Persistent AF) clinical trial resulted in the catheter gaining approval for the treatment of persistent AF in the United States. Objectives: To construct an economic simulation model, based on the results of the PRECEPT trial, to monetize the impact of radiofrequency catheter ablation (RFCA) compared with medical therapy (MT). Methods: Cost-offset and break-even analyses were performed to assess the economic impact of RFCA vs MT for adult persistent AF patients. Three perspectives were considered: commercial payers, Medicare, and self-insured employers. A cohort-level decision tree model was developed and validated in TreeAge Pro 2019. Sensitivity analyses were performed to determine the robustness of findings. Results: For all 3 types of payer, RFCA had a higher initial cost compared with MT. However, reductions in health care utilization after ablation, driven by decreased cardiovascular hospitalizations, led to an annual cost offset of between $5037 and $8402 after the first year. Projecting this forward resulted in an estimated cost break-even after 5.9, 4.2, and 5.1 years for commercial payers, Medicare, and self-insured employers, respectively. Conclusion: In addition to providing clinical benefits, RFCA may be a valuable economic investment for U.S. payers, substantially reducing utilization after the first year.

Effectiveness of Radiofrequency Catheter Ablation Using Ablation Index Versus Second Generation Cryoballoon in the Treatment of Persistent Atrial Fibrillation: A Matching-Adjusted Indirect Comparison.

INTRODUCTION: Both radiofrequency (RF) and cryoballoon (CB) ablation are treatment options for persistent atrial fibrillation (PsAF). An important recent innovation in RF ablation is Ablation Index (AI), known also as the VISITAG SURPOINT™ Module, a composite lesion quality marker whose use has been shown to significantly reduce the incidence of acute and late pulmonary vein (PV) reconnection and the recurrence of atrial arrhythmias in PsAF. Due to a lack of direct comparative evidence between the latest generations of technologies, there is uncertainty regarding the best treatment option in PsAF. The objective of the present study was to conduct a matching-adjusted indirect treatment comparison (MAIC) using individual patient-level data (IPD) to assess the comparative effectiveness of the THERMOCOOL SMARTTOUCH™ Catheter or the THERMOCOOL SMARTTOUCH™ SF Catheter with AI/VISITAG SURPOINT™ Module (STAI) versus the second-generation CB catheter (Arctic Front Advance™; herein referred to as CB) with respect to 12-month atrial arrhythmia recurrence, fluoroscopy time, and procedural efficiency. METHODS: IPD for STAI were obtained from four investigator-initiated studies and were pooled. Comparable CB studies identified from a systematic literature review were also pooled. In the absence of a common treatment arm between STAI and CB studies, an unanchored MAIC was conducted. The primary analysis compared the pooled STAI IPD to the pooled CB cohort, with corrections for differences across trials, including eligibility criteria and patient baseline characteristics. Scenario and sensitivity analyses were conducted to assess the robustness of the primary analysis. RESULTS: In the primary analysis, which was adjusted for left atrial diameter (LAD), age, diabetes, and sex, STAI was associated with a statistically significant 65% relative reduction in the rate of arrhythmia recurrence compared to CB at 12-month follow-up (HR 0.35; 95% CI 0.23, 0.52). STAI was associated with shorter total fluoroscopy time than CB but longer procedure time. Results were consistent across scenario and sensitivity analyses. CONCLUSION: Radiofrequency ablation with AI significantly reduced atrial arrhythmia recurrence at 12-month follow-up and fluoroscopy time compared to CB, with longer procedure times.

Scalable and cost-effective tosylation-mediated synthesis of antifungal and fungal diagnostic 6″-Modified amphiphilic kanamycins.

Amphiphilic kanamycins bearing hydrophobic modifications at the 6″ position have attracted interest due to remarkable antibacterial-to-antifungal switches in bioactivity. In this report, we investigate a hurdle that hinders practical applications of these amphiphilic kanamycins: a cost-effective synthesis that allows the incorporation of various connecting functionalities to which the hydrophobic moieties are connected to the kanamycin core. A cost-effective tosylation enables various modifications at the 6″ position, which is scalable to a 90-g scale. The connecting functionalities, such as amine and thiol, were not the dominant factor for biological activity. Instead, the linear chain length played the decisive role. Amphiphilic kanamycin attached with tetradecyl (C14) or hexadecyl (C16) showed strong antifungal and modest antibacterial activities than with shorter chains (C6-C10). However, increases in chain length were closely correlated with an increase in HeLa cell toxicity. Thus, a compromise between the antimicrobial activities and cytotoxicities, for optimal efficacy of amphiphilic kanamycins may contain chain lengths between C8 and C12. Finally, the described synthetic protocol also allows the preparation of a fluorescent amphiphilic kanamycin selective toward fungi.

Cationic Anthraquinone Analogs as Selective Antimicrobials.

Development of new antibiotics is always needed in the fight against growing threat from multiple drug-resistant bacteria, such as resistant Gram-negative (G-) Escherichia coli and Klebsiella pneumoniae. While the development of broad-spectrum antibiotics has attracted great attention, careful administration of these antibiotics is important to avoid adverse effects, like Clostridium difficile infection (CDI). The use of broad-spectrum antibiotics, for example, quinolones, can increase the risk of CDI by eradicating the protective bacteria in intestine and encouraging C difficile spore germination. Many common intestine bacteria are G- or anaerobic, including Enterococcus faecalis, Bacteroides fragilis, and E coli. Hence, it may be advantageous in certain therapeutic practices to employ selective antimicrobials. For instance, Gram-positive (G+) methicillin-resistant Staphylococcus aureus (MRSA) that can cause life-threatening sepsis can be controlled with the use of selective antibiotic, vancomycin. Nevertheless, its effectiveness has been limited with the emerging of vancomycin-resistant Staphylococcus aureus (VRSA). A recent report on antimicrobial cationic anthraquinone analogs (CAAs) that show tunable activity and selectivity may provide new hope in the search for selective antimicrobials. In particular, the lead CAA displays prominent activity against MRSA while manifesting low activity against E coli and low cytotoxicity toward normal mammalian cells.

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation.

Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure-activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans, and several Candida sp., and also significant antibacterial activities. With fluorescence-based whole cell assays, the aryl amphiphilic kanamycins were observed to permeabilize fungal surface membranes at faster rates than bacterial surface membranes. Also, the antifungal action of the amphiphilic kanamycins was observed to occur in a biphasic mode with an initial fast phase correlated with rapid membrane permeabilization at subminimal inhibitory concentrations and a slower phase membrane permeabilization that elevates the reactive oxygen species production leading to cell death. Inactive hydrophobic amphiphilic kanamycins displayed no membrane permeabilization. The results offer cost-effective methods for producing amphiphilic kanamycins and reveal insights into how nonfungal specific amphiphilic kanamycins can be employed for fungal specific diagnostic and therapeutic applications.

Antifungal amphiphilic kanamycins: new life for an old drug.

Classical aminoglycoside antibiotics are obsolete or hampered by the emergence of drug resistant bacteria. Recent discoveries of antifungal amphiphilic kanamycins offer new strategies for reviving and repurposing these old drugs. A simple structural modification turns the clinically obsolete antibacterial kanamycin into an antifungal agent. Structure-activity relationship studies have led to the production of K20, an antifungal kanamycin that can be mass-produced for uses in agriculture as well as in animals. This review delineates the path to the discovery of K20 and other related antifungal amphiphilic kanamycins, determination of its mode of action, and findings in greenhouse and field trials with K20 that could lead to crop disease protection strategies.

Synthesis and biological activity investigation of azole and quinone hybridized phosphonates.

Phosphonates, azoles and quinones are pharmacophores found in bioactive compounds. A series of phosphonates conjugated to azoles and quinones with variable carbon chain lengths were synthesized in 3-4 steps with good yield. Antifungal assay of these compounds showed that ethyl protected phosphates have excellent inhibitory activity against phytopathogenic fungus Fusarium graminearum, and the free-base phosphates have good activity against human pathogenic fungi Aspergillus flavus and Candida albicans. Structure- activity relationship (SAR) studies showed activity increases with longer carbon chain length between phosphonate and anthraquinone analogs consisting of azole and quinone moieties. These newly synthesized compounds also have mild antibacterial activities to Gram positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Cytotoxicity analysis of these compounds against HeLa cells reveals that the phosphoric acid analogs are less toxic compared to ethyl protected phosphonates. Three leads compounds have been identified with prominent antifungal activity and low cytotoxicity.

Tuning the biological activity of cationic anthraquinone analogues specifically toward Staphylococcus aureus.

Development of new antibacterial agents against drug resistant bacteria is an imminent task, especially against methicillin-resistant Staphylococcus aureus (MRSA). While MRSA can still be treated with broad spectrum antibiotics, the use of which often leads to the disruption of normal microbial flora leading to Clostridium difficile infection (CDI). Herein, a new class of antibacterial agent, cationic anthraquinone analogues specifically against MRSA, has been developed. Through the variation and optimization of substituents, these agents are selective toward MRSA, and not Gram negative bacteria which may avoid the problem of CDI. In addition, newly discovered lead compounds also show significantly reduced cytotoxicity against normal mammalian cells than cancerous cells. This interesting finding can alleviate the toxicity and side effect problems often associate with the use of antibiotics.

One-step synthesis of carbohydrate esters as antibacterial and antifungal agents.

Carbohydrate esters are biodegradable, and the degraded adducts are naturally occurring carbohydrates and fatty acids which are environmentally friendly and non-toxic to human. A simple one-step regioselective acylation of mono-carbohydrates has been developed that leads to the synthesis of a wide range of carbohydrate esters. Screening of these acylated carbohydrates revealed that several compounds were active against a panel of bacteria and fungi, including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Candida albicans, Cryptococcus neoformans, Aspergillus flavus and Fusarium graminearum. Unlike prior studies on carbohydrate esters that focus only on antibacterial applications, our compounds are found to be active against both bacteria and fungi. Furthermore, the synthetic methodology is suitable to scale-up production for a variety of acylated carbohydrates. The identified lead compound, MAN014, can be used as an antimicrobial in applications such as food processing and preservation and for treatment of bacterial and fungal diseases in animals and plants.

Aminoglycoside interactions and impacts on the eukaryotic ribosome.

Aminoglycosides are chemically diverse, broad-spectrum antibiotics that target functional centers within the bacterial ribosome to impact all four principle stages (initiation, elongation, termination, and recycling) of the translation mechanism. The propensity of aminoglycosides to induce miscoding errors that suppress the termination of protein synthesis supports their potential as therapeutic interventions in human diseases associated with premature termination codons (PTCs). However, the sites of interaction of aminoglycosides with the eukaryotic ribosome and their modes of action in eukaryotic translation remain largely unexplored. Here, we use the combination of X-ray crystallography and single-molecule FRET analysis to reveal the interactions of distinct classes of aminoglycosides with the 80S eukaryotic ribosome. Crystal structures of the 80S ribosome in complex with paromomycin, geneticin (G418), gentamicin, and TC007, solved at 3.3- to 3.7-Å resolution, reveal multiple aminoglycoside-binding sites within the large and small subunits, wherein the 6'-hydroxyl substituent in ring I serves as a key determinant of binding to the canonical eukaryotic ribosomal decoding center. Multivalent binding interactions with the human ribosome are also evidenced through their capacity to affect large-scale conformational dynamics within the pretranslocation complex that contribute to multiple aspects of the translation mechanism. The distinct impacts of the aminoglycosides examined suggest that their chemical composition and distinct modes of interaction with the ribosome influence PTC read-through efficiency. These findings provide structural and functional insights into aminoglycoside-induced impacts on the eukaryotic ribosome and implicate pleiotropic mechanisms of action beyond decoding.

Synthesis and bioactivity investigation of quinone-based dimeric cationic triazolium amphiphiles selective against resistant fungal and bacterial pathogens.

A series of synthetic dimeric cationic anthraquinone analogs (CAAs) with potent antimicrobial activities against a broad range of fungi and bacteria were developed. These compounds were prepared in 2-3 steps with high overall yield and possess alkyl chain, azole, quinone, and quaternary ammonium complexes (QACs). In vitro biological evaluations reveal prominent inhibitory activities of lead compounds against several drug-susceptible and drug-resistant fungal and bacterial strains, including MRSA, VRE, Candida albicans and Aspergillus flavus. Mode of action investigation reveals that the synthesized dimeric CAA's can disrupt the membrane integrity of fungi. Computational studies reveal possible designs that can revive the activity of QACs against drug-resistant bacteria. Cytotoxicity assays in SKOV-3, a cancer cell line, show that the lead compounds are selectively toxic to fungi and bacteria over human cells.

Divergent Synthesis of Three Classes of Antifungal Amphiphilic Kanamycin Derivatives.

A concise and novel method for site-selective alkylation of 1,3,6',3″-tetraazidokanamycin has been developed that leads to the divergent synthesis of three classes of kanamycin A derivatives. These new amphiphilic kanamycin derivatives bearing alkyl chains length of 4, 6, 7, 8, 9, 10, 12, 14, and 16 have been tested for their antibacterial and antifungal activities. The antibacterial effect of the synthesized kanamycin derivatives declines or disappears as compared to the original kanamycin A. Several compounds, especially those with octyl chain at O-4″ and/or O-6″ positions on the ring III of kanamycin A, show very strong activity as antifungal agents. In addition, these compounds display no toxicity toward mammalian cells. Finally, computational calculation has revealed possible factors that are responsible for the observed regioselectivity. The simplicity in chemical synthesis and the fungal specific property make the lead compounds ideal candidates for the development of novel antifungal agents.

Characterization of Three Tailoring Enzymes in Dutomycin Biosynthesis and Generation of a Potent Antibacterial Analogue.

The anthracycline natural product dutomycin and its precursor POK-MD1 were isolated from Streptomyces minoensis NRRL B-5482. The dutomycin biosynthetic gene cluster was identified by genome sequencing and disruption of the ketosynthase gene. Two polyketide synthase (PKS) systems are present in the gene cluster, including a type II PKS and a rare highly reducing iterative type I PKS. The type I PKS DutG repeatedly uses its active sites to create a nine-carbon triketide chain that is subsequently transferred to the α-l-axenose moiety of POK-MD1 at 4″-OH to yield dutomycin. Using a heterologous recombination approach, we disrupted a putative methyltransferase gene (dutMT1) and two glycosyltransferase genes (dutGT1 and dutGT2). Analysis of the metabolites of these mutants revealed the functions of these genes and yielded three dutomycin analogues SW140, SW91, and SW75. The major product SW91 in Streptomyces minoensis NRRL B-5482-ΔDutMT1 was identified as 12-desmethyl-dutomycin, suggesting that DutMT1 is the dedicated 12-methyltransferase. This was confirmed by the in vitro enzymatic assay. DutGT1 and DutGT2 were found to be responsible for the introduction of ß-d-amicetose and α-l-axenose, respectively. Dutomycin and SW91 showed strong antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus, whereas POK-MD1 and SW75 had no obvious inhibition, which revealed the essential role of the C-4″ triketide chain in antibacterial activity. The minimal inhibitory concentration of SW91 against the two strains was 0.125 µg mL(-1), lower than that of dutomycin (0.25 µg mL(-1)), indicating that the antibacterial activity of dutomycin can be improved through biosynthetic structural modification.

Three new fusidic acid derivatives and their antibacterial activity.

Two steroid acids, cephalosporin P1 and isocephalosporin P1, were isolated from Hapsidospora irregularis FERM BP-2511. These compounds are structurally related to fusidic acid. Their NMR data were completely assigned on the basis of the 2D NMR spectra. Incubation of these two compounds with Microbacterium oxydans CGMCC 1788 in Luria-Bertani broth yielded the same set of three new 3-dehydrogenated products, 3-keto-isocephalosporin P1, 3-keto-cephalosporin P1 and 6-deacetyl-3-keto-cephalosporin P1. The final pH of the bacterial culture was 9.0. Incubation of 3-keto-isocephalosporin P1 or 3-keto-cephalosporin P1 in Tris-HCl buffer (pH 9.0) revealed that these two compounds can convert to each other by shifting the acetyl group between C-6 and C-7. The acetyl group at C-6 or C-7 can also be removed by hydrolysis to yield the minor product 6-deacetyl-3-keto-cephalosporin P1. These fusidic acid derivatives were tested for the antibacterial activity against the Gram-positive pathogen Staphylococcus aureus. 3-Keto-cephalosporin P1 showed the highest activity among the five compounds, with a minimal inhibition concentration (MIC) of 4 µg/mL, which is more potent than the substrate cephalosporin P1. Both cephalosporin P1 and 3-keto-cephalosporin P1 were active against methicillin-resistant S. aureus, with the same MIC of 8 µg/mL.

Structure-activity relationships for antibacterial to antifungal conversion of kanamycin to amphiphilic analogues.

Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4″ position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3″-NH2 group of kanamycin B was synthesized. FG03's antifungal activity and synthetic scheme inspired the synthesis of a library of kanamycin B analogues alkylated at various hydroxyl groups. SAR studies of the library revealed that for antifungal activity the O-4″ position is the optimal site for attaching a linear alkyl chain and that the 3″-NH2 and 6″-OH groups of the kanamycin B parent molecule are not essential for antifungal activity. The discovery of lead compound, FG03, is an example of reviving clinically obsolete drugs like kanamycin by simple chemical modification and an alternative strategy for discovering novel antimicrobials.

Cyclopamine: from cyclops lambs to cancer treatment.

In the late 1960s, the steroidal alkaloid cyclopamine was isolated from the plant Veratrum californicum and identified as the teratogen responsible for craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in the western United States. Cyclopamine was found to inhibit the hedgehog (Hh) signaling pathway, which plays a critical role in embryonic development. More recently, aberrant Hh signaling has been implicated in several types of cancer. Thus, inhibitors of the Hh signaling pathway, including cyclopamine derivatives, have been targeted as potential treatments for certain cancers and other diseases associated with the Hh signaling pathway. A brief history of cyclopamine and cyclopamine derivatives investigated for the treatment of cancer is presented.

Synthesis and anticancer structure activity relationship investigation of cationic anthraquinone analogs.

We have synthesized a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium salts, which can be viewed as analogs of cationic anthraquinones. Unlike the similar analogs that we have reported previously, these compounds show relatively weak antibacterial activities but exert strong anticancer activities (low µM to nM GI50), in particular, against melanoma, colon cancer, non-small cell lung cancer and central nervous system (CNS) cancer. These compounds are structurally different from their predecessors by having the aromatic group, instead of alkyl chains, directly attached to the cationic anthraquinone scaffold. Further investigation in the structure-activity relationship (SAR) reveals the significant role of electron donating substituents on the aromatic ring in enhancing the anticancer activities via resonance effect. Steric hindrance of these groups is disadvantageous but is less influential than the resonance effect. The difference in the attached groups at N-1 position of the cationic anthraquinone analog is the main structural factor for the switching of biological activity from antibacterial to anticancer. The discovery of these compounds may lead to the development of novel cancer chemotherapeutics.