Transferrin-inspired iron delivery across the cell membrane using [(L2Fe)2(µ-O)] (L = chlorquinaldol) to harness anticancer activity of ferroptosis.

Although iron is a bio-essential metal, dysregulated iron acquisition and metabolism result in production of reactive oxygen species (ROS) due to the Fenton catalytic reaction, which activates ferroptotic cell death pathways. The lipophilic Fe(III)-chelator chlorquinaldol (L; i.e., 5,7-dichloro-8-hydroxy-2-methylquinoline) strongly favors the formation of a highly stable binuclear Fe(III) complex [(L2Fe)2(µ-O)] (1) that can mimic the function of the Fe(III)-transferrin complex in terms of the strong binding to Fe(III) and facile release of Fe(II) when the metal center is reduced. It should be noted that the cellular uptake of 1 is not transferrin receptor-mediated but enhanced by the high lipophilicity of chlorquinaldol. Once 1 is transported across the cell membrane, Fe(III) can be reduced by ferric reductase or other cellular antioxidants to be released as Fe(II), which triggers the Fenton catalytic reaction, thus harnessing the anticancer activity of iron. As the result, this transferrin-inspired iron-delivery strategy significantly reduces the cytotoxicity of 1 in normal human embryonic kidney cells (HEK 293) and the hemolytic activity of 1 in human red blood cells (hRBCs), giving rise to the unique tumor-specific anticancer activity of this Fe(III) complex.

Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2.

Histamine receptor 2 (HRH2) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HRH2. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HRH2-based sensor in yeast to evaluate the role of key residues in the HRH2 active site on histamine and 8HQ-based blocker binding. We find that the HRH2 mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HRH2:D186A and HRH2:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HRH2 blockers that interact with both ends of the HRH2 binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HRH2:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HRH2 therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.

Chlorquinaldol inhibits the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome and ameliorates imiquimod-induced psoriasis-like dermatitis in mice.

Psoriasis is a common chronic autoinflammatory/autoimmune skin disease associated with elevated pro-inflammatory cytokines. The pivotal role of interleukin (IL)-1ß and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of psoriasis has been widely described. Accordingly, the suppression of NLRP3-dependent IL-1ß release is a potential therapy for psoriasis. Repurposing marketed drugs is a strategy for identifying new inhibitors of NLRP3 inflammasome activation. Herein, chlorquinaldol (CQD), a historic antimicrobial agent used as a topical treatment for skin and vaginal infections, was found to have a distinct effect by inhibiting NLRP3 inflammasome activation at concentrations ranging from 2 to 6 µM. CQD significantly suppressed apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) oligomerization, NLRP3-ASC interaction, and pyroptosis in macrophages. The levels of cleaved IL-1ß and caspase-1 were reduced by CQD in the cell lysates of macrophages, suggesting that CQD acted on upstream of pore formation in the cell membrane. Mechanistically, CQD reduced mitochondrial reactive oxygen species production but did not affect the nuclear factor-κB (NF-κB) pathway. Intraperitoneal administration of CQD (15 mg/kg) for 6 days was found to improve the skin lesions in the imiquimod-induced psoriatic mouse model (male C57BL/6 mice), while secretion of pro-inflammatory cytokines (IL-17 and IL-1ß) and keratinocyte proliferation were significantly suppressed by CQD. In conclusion, CQD exerted inhibitory effects on NLRP3 inflammasome activation in macrophages and decreased the severity of psoriatic response in vivo. Such findings indicate that the repurposing of the old drug, CQD, is a potential pharmacological approach for the treatment of psoriasis and other NLRP3-driven diseases.

Chlorquinaldol targets the ß-catenin and T-cell factor 4 complex and exerts anti-colorectal cancer activity.

Aberrant activation of Wnt signaling plays a critical role in the initiation and progression of colorectal cancer (CRC). Chlorquinaldol (CQD) is a topical antimicrobial agent used to treat skin infections. Little is known about the anticancer activity of CQD and its underlying mechanisms. In this study, CQD was demonstrated to inhibit Wnt/ß-catenin signaling through targeting the downstream part of this pathway. The results showed that CQD could inhibit the acetylation of ß-catenin and disrupt the interaction of ß-catenin with T-cell factor 4 (TCF4), leading to reduced binding of ß-catenin to the promoters of Wnt target genes and downregulation of the expression of these target genes. Moreover, treatment with CQD suppressed the proliferation, migration, invasion and stemness of CRC cells. In APCmin/+ mice and CRC cell xenografts, administration of CQD suppressed tumor growth and the expression of Wnt target genes c-Myc and Leucine-rich G protein-coupled receptor-5 (LGR5). These results strongly suggest that CQD may be a promising therapeutic agent in the treatment of CRC.

Treatment of postscabies prurigo with diflucortolone and chlorquinaldol in a group of African refugees.

Postscabies prurigo (PSP) is caused by a delayed hypersensitivity reaction to antigens of the mite. Treatment is based on potent topical or intralesional corticosteroids. We present the results of a study on the effectiveness of a topical combination of diflucortolone and chlorquinaldol. Eighteen African patients who had been previously affected by scabies and treated with permethrin were enrolled. The diagnosis of PSP was made by excluding other causes through microscopic examinations. All patients were treated with the drug combination by two applications daily for two weeks. The primary study objective was to evaluate the itch by a visual analogue scale (VAS) of 0-100. Fifteen patients (83.3%) could be evaluated. All reported improvements: from 86/100 at the start to 29/100 (-57/100) at the end of treatment. Chlorquinaldol, known as an antiseptic agent, demonstrated, according to results of this study, an important anti-itch action.

High in vitro and in vivo antitumor activities of Ln(III) complexes with mixed 5,7-dichloro-2-methyl-8-quinolinol and 4,4'-dimethyl-2,2'-bipyridyl chelating ligands.

Three novel Ln(III) complexes, namely, [Pm(dmbpy)(ClQ)2NO3] (1), [Yb(dmbpy)(ClQ)2NO3] (2), and [Lu(dmbpy)(ClQ)2NO3] (3), with mixed 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 4,4'-dimethyl-2,2'-bipyridyl (dmbpy) chelating ligands were first synthesized. The cytotoxic activity of Ln(III) complexes 1-3, H-ClQ, and dmbpy against a panel of human normal and cancer cell lines, namely, human non-small cell lung cancer cells (NCI-H460), human cervical adenocarcinoma cancer cells, human ovarian cancer cells, and human normal hepatocyte cells, were evaluated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The three novel Ln(III) complexes showed a high in vitro antitumor activity toward the NCI-H460 with IC50 of 1.00 ±â€¯0.25 nM for 1, 5.13 ±â€¯0.44 µM for 2, and 11.87 ±â€¯0.79 µM for 3, respectively. In addition, Ln(III) complexes 1 and 2 exerted their in vitro antitumor activity/mechanism mainly via the mitochondrial death pathway and caused a G2/M phase arrest in the following order: 1 > 2. An NCI-H460 tumor xenograft mouse model was used to evaluate the Pm(III) complex 1in vivo antitumor activity. Pm(III) complex 1 showed a high in vivo antitumor activity, and the tumor growth inhibition rate (IR) was 56.0% (p < 0.05). In summary, our study on Pm(III) complex 1 revealed promising results in in vitro and in vivo antitumor activity assays.

Comparison of Chlorquinaldol-Promestriene Vaginal Tablets and Opin Suppositories Effect on Inflammatory Factors and Immune Function in Chronic HPV Cervicitis.

OBJECTIVE: To compare the effects of chlorquinaldol-promestriene vaginal tablets and opin suppositories on serum inflammatory factors and immune function in patients with chronic cervicitis complicated with HPV infection. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Gynaecology and Obstetrics, People's Hospital of Zhouzhi County, Shaanxi, China, from January 2016 to June 2017. METHODOLOGY: A total of 98 patients with chronic cervicitis complicated with HPV infection were randomly divided into the observation group and the control group with 49 cases in each group. Control group received vaginal administration of opin suppositories, and the observation group received chlorquinaldol-promestriene vaginal tablets. After treatment, the HPV-DNA negative conversion rate, levels of serum inflammatory factors (IL-1, IL-6 and hs-CRP) and indices of immune function (CD3 +,CD4 +, CD8 + and CD4 +/CD8 +) were compared between the two groups. RESULTS: At 6 and 9 months after treatment, the HPV-DNA negative conversion rate in the observation group was higher than that in the control group (p=0.001 and p<0.001, respectively). At 6 months after treatment, serum IL-1, IL-6, and hs-CRP levels in the observation group were lower than those in the control group (p<0.001, p=0.001 and p=0.002, respectively); serum CD3 +,CD4 +, CD8 + and CD4 +/CD8 + levels in the observation group were higher than those in the control group (all p<0.001). CONCLUSION: Chlorquinaldol-promestriene vaginal tablet is more effective than opin suppository in the treatment of patients with chronic cervicitis complicated with HPV infection. It can effectively improve the HPV-DNA negative conversion rate, reduce the level of serum inflammatory factors and improve the body's immune function.

A comparative study of novel spectrophotometric resolution techniques applied for pharmaceutical mixtures with partially or severely overlapped spectra.

Simultaneous determination of mixtures of lidocaine hydrochloride (LH), flucortolone pivalate (FCP), in presence of chlorquinaldol (CQ) without prior separation steps was applied using either successive or progressive resolution techniques. According to the concentration of CQ the extent of overlapping changed so it can be eliminated from the mixture to get the binary mixture of LH and FCP using ratio subtraction method for partially overlapped spectra or constant value via amplitude difference followed by ratio subtraction or constant center followed by spectrum subtraction spectrum subtraction for severely overlapped spectra. Successive ratio subtraction was coupled with extended ratio subtraction, constant multiplication, derivative subtraction coupled constant multiplication, and spectrum subtraction can be applied for the analysis of partially overlapped spectra. On the other hand severely overlapped spectra can be analyzed by constant center and the novel methods namely differential dual wavelength (D(1) DWL) for CQ, ratio difference and differential derivative ratio (D(1) DR) for FCP, while LH was determined by applying constant value via amplitude difference followed by successive ratio subtraction, and successive derivative subtraction. The spectra of the cited drugs can be resolved and their concentrations are determined progressively from the same ratio spectrum using amplitude modulation method. The specificity of the developed methods was investigated by analyzing laboratory prepared mixtures and were successfully applied for the analysis of pharmaceutical formulations containing the cited drugs with no interference from additives. The proposed methods were validated according to the ICH guidelines. The obtained results were statistically compared with those of the official or reported methods; using student t-test, F-test, and one way ANOVA, showing no significant difference with respect to accuracy and precision.

Purity determination of gynalgin bactericidal tablets with HPLC method.

The study was aimed at developing a simple HPLC method for the determination of the content of impurities in Gynalgin, a two-component preparation. A satisfactory separation was performed on 250 x 4.6 mm Symmetry C8 column in a gradient elution system: mobile phase A--acetonitrile/buffer, pH 5.5 in 10:90, v/v proportion, and mobile phase B--acetonitrile/buffer, pH 5.5 in 75:25 v/v proportion. Two wavelengths: 250 nm and 315 nm were used for detection. Validation confirmed that the method was linear in a required concentration range. The values of correlation coefficients for specific drug substances and the related impurities were as high as 0.999. The results of the purity tests proved that the method was sufficiently selective and precise.

Effects of highly active novel artemisinin-chloroquinoline hybrid compounds on ß-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum.

4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent ß-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials.

Therapeutic use of topical corticosteroids in the vesiculobullous lesions of incontinentia pigmenti.

Incontinentia pigmenti (IP) is a rare genodermatosis caused by a mutation of nuclear factor kappa B essential modulator gene. There is no specific treatment for IP, therefore it has been claimed that there is no effective treatment to hasten resolution of any of the phases of IP. However, the initial vesiculobullous stage of IP is characterized histopathologically by eosinophilic inflammation, which is expected to respond to corticosteroids. An 18-day-old female neonate was seen, with vesicles on her trunk and limbs diagnosed as the vesiculobullous stage of IP. The patient was treated with a double-compound cream containing a potent corticosteroid (difluocortolone valerate 0.1%) and an antiseptic (chlorquinaldol 1%), to be applied to the lesions twice daily. Five days later, resolution of the lesions was almost complete. As chlorquinaldol has no known anti-inflammatory activity, we attribute this improvement to difluocortolone valerate. This case shows that early lesions of IP with eosinophilic inflammation are treatable.

[Gynalgin--one more opportunity in the treatment of bacterial vaginosis].

The data of 30 nonpregnant women in reproductive age BV treated with Gynalgin were presented. On clinical and microbiological indicator Gynalgin showed a good effect on BV-associated microorganisms (80%). Only one of the cases of BV was not affected (4%). With nixed infection of BV and Candida we established clinical improvement and recovery of Lactobacillus spp. In 66.6%, but in all cases on Candida is not effect. We consider that Gynalgin is still one more easily applicable and clinically effective opportunity for treatment of BV.

Fluorimetric determination of chloroxine using manual and flow-injection methods.

A reliable and highly sensitive method is described for the determination of chloroxine in pharmaceutical preparations. It involves the formation of a complex between chloroxine and aluminum(III) in a micellar medium. The complex is a very fluorescent species, and there is a linear relationship between chloroxine concentration and fluorescence intensity over the range 2.0 x 10(-8)-5.1 x 10(-5) mol l-1. The limit of detection is 5 x 10(-9) mol l-1. The method can be easily adapted to a flow system using a three-channel manifold, the peak height being proportional to the chloroxine concentration over the range 5.6 x 10(-7)-5.6 x 10(-5) mol l-1. Manual and flow-injection procedures permit the determination of chloroxine in the presence of chlorquinaldol, and have been successfully applied to the determination of chloroxine in pharmaceutical preparations.

[The therapeutic potentials of the vaginal antimicrobial preparation Chlorchinaldin]. / Terapevtichni vuzmozhnosti na vaginalniia antimikroben preparat--Chlorchinaldin.

The aim of this study is the clinical testing of the vaginal wide-range, antimicrobial, quinolone--Chlorchinaldin/0,2/by POLFA, which has a strong antibacterial, antifungal, trichomonal and keratoplastic effect. The medicine was used on 43 patients with complaints of aggravated fluor. The clinical, colposcopic and microbiologic study showed: candidiasis--in 16 trichomoniasis--in 8, bacterial vaginalis--in 3 and anaerobic vaginitis--in 2 patients. The rest of the women (14) had various aerobic microbial findings. The treatment was daily using one vaginal tablet, every night for 10 days. A control examination was carried out one week after the any of therapy. The results showed a positive clinical effect, since in 67.4% there were negative microbiological findings. The lack of effect in cases with bacterial vaginosis and anaerobic vaginitis was painted out. These results give reason to believe that the wide antimicrobial range of Chlorchinaldin B will be complementary to the currently used drugs in the treatment of vaginal infections.

Tratamiento de la coalescencia de labios menores / Treatment of the labia minora coalescentia

Se trataron 203 casos de coalescencia de labios menores con crema de valerianato de difucortolona y clorquinaldol. Los resultados obtenidos en todas las pacientes fueron los esperados

[Microbiological evaluation of the effectiveness of gynalgin in the treatment of vaginitis]. / Ocena mikrobiologiczna skutecznosci Gynalginu w zapaleniach pochwy u kobiet.

The microbiological effectiveness of the preparation Gynalgin produced by POLFA Pharmaceutical Works in Rzeszów was assessed in cases of vulvovaginitis in 55 patients with clinically diagnosed inflammatory conditions of the lower genital tract, who were given Gynalgin tablets in 10-day courses. Vaginal smears were examined three times for the presence of bacteria, fungi and trichomonas vaginalis (before and immediately after the treatment, and two weeks later). In the initial examination in five vaginal smears mixed bacterial flora was found, in 6 smears trichomonas was present, in 4--bacteria and fungi, and in one--trichomonas and fungi. After the treatment in control examinations I and II the number of the isolated bacterial strains was lower, trichomonas was no longer present, and the number of fungi was reduced evidently. In the light of these microbiological examinations Gynalgin was found to exert a strong fungicidal, bactericidal and antitrichomonal activity, and the results of laboratory investigations agreed with those of clinical trials of Gynalgin effectiveness.