Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine.

In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system.

Erratum: Correction of Text in the Article "The Impact of COVID-19 on the Use of Radiology Resources in a Tertiary Hospital".

This corrects the article on p. e368 in vol. 35, PMID: 33075859.

Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin.

To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4-7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 µM = 81.6%), 4w (CMA at 10 µM = 71.2%) and 6b (CMA at 10 µM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 µM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure-activity relationship (SAR) studies were conducted. Para substitution (-Cl, -OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 µM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.

The Impact of COVID-19 on the Use of Radiology Resources in a Tertiary Hospital.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has escalated to be a global threat to public health. Analysis of the use of radiology resources may render us insight regarding the public health behavior during pandemic. We measured the influence COVID-19 had on the use of radiology resources in terms of the number of examinations performed, and turnaround time for portable radiography. METHODS: This study was conducted at a tertiary hospital located in area where the prevalence of COVID-19 infection was low (0.01%). We compared the number of radiology examinations 1) before pandemic (in 2019) vs. during peak of pandemic (January to March 2020), and 2) before pandemic vs. after the peak of pandemic (April to June 2020) via t-tests. We repeated similar analyses for subgroups as follows: gender, age, department (outpatient, inpatient, emergency, screening), body parts, and modality. We also performed a survey of radiologic technologists regarding the turnaround time and rate-limiting step of portable radiography for patients with and without suspicion or confirmation of COVID-19. RESULTS: Although not statistically significant, the daily number of examinations during the peak of pandemic decreased by 9 percentage points (2,638 vs. 2,413; difference [95% CI], -225 [-489, 38]; P = 0.094). The percentage change was especially notable for children, emergency, and screening department (25, 19, and 44 percentage points, respectively). After the peak of the pandemic, the number of examinations increased back to near the pre-pandemic level (2,638 vs. 2,588; -50 [-317, 218]; P = 0.71). The turnaround time for portable radiography tended to be longer for patients with suspicion or confirmation of COVID-19, with donning personal protective equipment being the major rate-limiting step. CONCLUSION: The number of examinations decreased during the pandemic, reflecting the tendency of the public to refrain from seeking medical care even in a community of low infection risk. Nevertheless, burden of healthcare providers may not have decreased as much, considering longer turnaround time required for COVID-19 related examinations.

Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator.

The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure.

Ileostomy versus fecal diversion device to protect anastomosis after rectal surgery: a randomized clinical trial.

PURPOSE: Patients with rectal anastomosis commonly experience various ileostomy-related complications. This study aimed to elucidate the usefulness of a fecal diversion device (FDD) as an alternative to ileostomy for protecting rectal anastomosis. METHODS: Patients with rectal anastomosis were randomly assigned to the ileostomy and FDD groups except in cases of emergency surgery. The primary endpoint was the clinical safety and effectiveness of FDD. The mean operation time, delay of diet advancement, length of hospital stay, FDD and stoma durations, and anastomotic leakage (AL) management methods were compared. RESULTS: A total of 54 patients were enrolled in this study. No cases of mortality occurred. Overall morbidity was similar between groups (P = 0.551). Six patients (22.2%) in the FDD group and nine (29.0%) in the stoma group (P = 0.555) had AL. The mean total hospital stay was 16.4 ± 6.7 and 23.4 ± 8.7 days in the FDD and stoma groups, respectively (P = 0.002). The mean total hospital cost was 12,726.8 ± 3422.8 USD and 17,954.9 ± 9040.3 USD in the FDD and stoma groups, respectively (P = 0.008). The mean FDD and stoma durations were 21.6 ± 6.1 days and 114.9 ± 41.3 days, respectively (P < 0.0001). CONCLUSIONS: This study demonstrated FDD safety and effectiveness. We identified the possibility of FDD as an alternative technique to conventional stoma procedures.

Fecal diverting device for the substitution of defunctioning stoma: preliminary clinical study.

BACKGROUND: A novel fecal diverting device (FDD) made for the prevention of sepsis resulting from anastomotic leakage (AL) was tested successfully in an animal study. This study was undertaken to evaluate the clinical safety and effectiveness of the FDD. METHODS: A prospective observation trial was implemented in a tertiary referral university hospital. The study enrolled patients who needed a defunctioning stoma to preserve low-lying rectal anastomosis. The FDD was fixed to the proximal colon 15 cm from the anastomosis and scheduled to divert feces for 3 weeks. The duration could be extended for more than 3 weeks if AL was noted. Postoperative evaluations of AL were performed by obtaining a computed tomography (CT) scan after 1 week and a contrast study after 3 weeks. The outcomes were FDD-related complications, and the capacity of the FDD to preserve the anastomosis. The median follow-up period was 10 (range 5-40) months. RESULTS: Thirty-one patients, including 5 benign cases, were evaluated. There was no case of stoma conversion or surgical re-intervention. Evidence of AL was identified in 10 (32%) patients using the CT scan at 1 week after surgery. However, in the contrast study at 3 weeks after surgery, only 5 cases of AL sinus were noted. Conservative treatments including 1-3 weeks prolongation of FDD maintenance were enough to preserve the anastomosis. There were 3 cases of partial colonic wall erosions at the FDD attachment area. All of these patients showed improvement with conservative treatment. The limitations were that the study was performed in a single institute and without a control group. CONCLUSIONS: The FDD showed a sufficient capacity of fecal diversion and maintenance duration that prevented aggravation of sepsis in the case of AL without significant complications.

Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator.

To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.

Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity.

To establish the structure-activity relationship of 5-hydroxy-1,4-naphthoquinones toward anticancer activity, a series of its derivatives were prepared and tested for the activity (IC50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among them 2 (IC50: 2.3; 2.0; 1.4 µM), 6 (IC50: 1.9; 2.2; 1.3 µM), 9 (IC50: 0.7; 1.7; 0.9 µM) and 10 (IC50:1.7; 1.0; 1.2 µM) showed moderate to excellent activity. Our perception toward the DNA substitution of alkoxy groups at the C2 position of these naphthoquinones for the anticancer activity led us to investigate their reactivity of substitution toward dimethylamine as a nucleophile. The ease of the substitution of alkoxy groups at the C2 position with dimethylamine is strongly accelerated by hydroxyl group at C5 position and is well correlated with the found anticancer activity results.

Melanogenesis inhibitory pregnane glycosides from Cynanchum atratum.

Bioassay-guided fractionation of the methanolic extract from the roots of Cynanchum atratum has resulted in the isolation of three new pregnane glycosides (1-3) along with four known compounds (4-7). Their structures were identified by analysis of the spectroscopic data including extensive 2D NMR. All of the isolates were evaluated for their potential to inhibit the melanin production in α-melanocyte stimulating hormone (α-MSH)-activated B16 melanoma cells. Of these, compounds 4-7 dose-dependently inhibited the melanin production with the IC50 values ranging from 4 µM to 33 µM.

Promotion of hair growth by newly synthesized ceramide mimetic compound.

Based on the crucial roles of ceramides in skin barrier function, use of ceramides or their structural mimetic compounds, pseudoceramides, as cosmetic ingredients are getting more popular. While currently used pseudoceramides are intended to substitute the structural roles of ceramides in stratum corneum, development of bioactive pseudoceramides has been repeatedly reported. In this study, based on the potential involvement of sphingolipids in hair cycle regulation, we investigated the effects of newly synthesized pseudoceramide, bis-oleamido isopropyl alcohol (BOI), on hair growth using cultured human hair follicles and animal models. BOI treatment promoted hair growth in cultured human hair follicles ex vivo and induced earlier conversion of telogen into anagen. Although we did not find a significant enhancement of growth factor expression and follicular cell proliferation, BOI treatment resulted in an increased sphinganine and sphingosine contents as well as increased ceramides contents in cultured dermal papilla (DP) cells. Taken together, our data strongly suggest that biologically active pseudoceramide promotes hair growth by stimulating do novo synthesis of sphingolipids in DP cells.

Novel analogs of N-acylhydroxyethylaminomethyl-4H-chromen-4-one scaffold as IL-5 inhibitors.

A number of N-acyl substituted hydroxyethylaminomethyl-4H-chromen-4-ones 6a-u were prepared and evaluated for their IL-5 inhibitory activity. Among them, the compound 6r (95.0% inhibition at 30µM, IC50=10.0µM, ClogP=4.1549) showed most potent inhibitory activity. The structure activity relationship revealed that the bulkier or hydrophobic substituents at urea, carbamate or amide group resulted in good inhibitory activity against IL-5. Moreover, electron donating group at phenyl ring (6g and 6s) is much more active than electron withdrawing group (6f). Finally, replacement of cyclohexylmethoxy group at 5th position of ring A with bulky aliphatic substituents resulted in the loss of activity.

IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid.

Mice lacking the IL-1R-associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine-induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti-inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d-galactosamine-challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist-, IL-1α-, or high-mobility group box-1-stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity-related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses.

Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors.

Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model.

Exploration of 2-benzylbenzimidazole scaffold as novel inhibitor of NF-κB.

For finding the novel inhibitor of nuclear factor κB activity, a series of benzimidazole derivatives were rationally designed, synthesized and systematically studied for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay based on the flexible chalcone JSH ((E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxy phenyl)prop-2-en-1-one) which was previously reported. Although most of the benzimidazole derivatives showed strong inhibitory activity in low micromolar potency, 2-(4-methoxybenzyl)-1H-benzo[d]imidazole (3m; IC50=1.7 µM) and 2-(2-methoxybenzyl)-1H-benzo[d]imidazole (3n; IC50=2.4 µM) showed the best inhibition. The structure activity relationship revealed that 2-benzylbenzimidazole scaffold with hydrogen bonding acceptor on phenyl ring appears as a pharmacophore.

Synthesis and anti-proliferative activity of novel azazerumbone conjugates with chalcones.

The conjugation of azazerumbone ((3E,7E,11E)-5,5,8,12-tetramethylazacyclododeca-3,7,11-trien-2-one (7)) and 2,4-dihydroxychalcones was carried out for the preparation of novel target compounds 9a-g with 1-ethylene-4-methylene-1,2,3-triazole linker and 10a-f with propylene linker between amide nitrogen of azazerumbone and 4-hydroxy group of chalcone. The anti-proliferative activity of these compounds against the LU-1, Hep-G2, MCF-7 and SW480 human cancer cell lines were significantly improved compared to those of azazerumbone or zerumbone. The anti-proliferative activities of (3E,7E,11E)-1-((1-(2-(3-hydroxy-4-((E)-3-(3-methoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-5,5,8,12-tetramethyl azacyclododeca-3,7,11-trien-2-one (9b) and (3E,7E,11E)-1-(3-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenoxy)propyl)-5,5,8,12-tetramethylazacyclododeca-3,7,11-trien-2-one (10d) are nearly comparable to those of ellipticine.

Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors.

Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy.

Exploration of benzamidochromenone derivatives with conformational restrictor as interleukin-5 inhibitors.

Novel amidochromen-4-one analogs 8a-k and 9a-f were prepared and studied for their IL-5 inhibitory activity. Among the synthesized compounds, (6-benzamido-2-cyclohexyl-4-oxo-4H-chromen-3-yl)methyl acetate (8a, 95% inhibition at 30 µM, IC50=6.1 µM) exhibited potent IL-5 inhibitory activity. The conformational restrictor at position 2 like bulky cyclohexyl group is favorable for the formation of effective conformer of side chain small ester like acetoxymethyl at position 3 of these chromenone analogs 8. In addition the hydrophobic planarity of benzamido group at position 6 should be important for the potent IL-5 inhibitory activity. Since replacing acetoxymethyl moiety with hydroxymethyl group at position 3 of chromenone decreases the activity, which indicates that the location of hydrogen bonding group should be near 4 atom distances away from chromenone ring is more optimum for the activity. Therefore, these benzamidochromen-4-one analogs 8 are novel scaffold for finding potent interleukin-5 inhibitors.

Comparison of oncologic outcomes of metastatic rectal cancer patients with or without neoadjuvant chemoradiotherapy.

PURPOSE: The aim of this study is to evaluate the effect of neoadjuvant chemoradiotherapy in stage IV rectal cancer. METHODS: Primary rectal cancer patients with synchronous distant metastases between September 2001 and August 2011 were enrolled. Of 86 patients, 40 patients underwent neoadjuvant chemoradiotherapy (RTX group) and the remaining 46 patients underwent postoperative systemic chemotherapy without radiotherapy (NRTX group). Sharp mesorectal excision according to tumor location was performed. Oncologic outcomes were compared. RESULTS: The lower tumor location was more common in RTX group than NRTX group (60.0 vs. 28.3%, P = 0.003). Clinical T and N status and American Society of Anesthesiologist (ASA) score were similar in both groups. The incidence of pathologic LN metastases in the NRTX group was 93.5% compared with 70.0% in RTX group (P = 0.007). Pattern of distant metastasis was similar between groups. However, metastatectomy was frequently performed in RTX group than NRTX group (57.5 vs. 30.4%, P = 0.020). There was no statistical difference in local recurrence rate between groups (10.0% in RTX vs. 15.2% in NRTX, P = 0.470). The median PFS was similar in both groups (12.00 months in RTX vs. 12.00 months in NRTX, P = 0.768). The median OS between groups was also not different (24.00 months in RTX vs. 27.00 months in NRT, P = 0.510). CONCLUSIONS: Neoadjuvant chemoradiotherapy may not affect local control and overall survival in locally advanced rectal cancer with distant metastasis.

Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula.

Fistula is a representative devastating complication in Crohn's patients due to refractory to conventional therapy and high recurrence. In our phase I clinical trial, adipose tissue-derived stem cells (ASCs) demonstrated their safety and therapeutic potential for healing fistulae associated with Crohn's disease. This study was carried out to evaluate the efficacy and safety of ASCs in patients with Crohn's fistulae. In this phase II study, forty-three patients were treated with ASCs. The amount of ASCs was proportioned to fistula size and fistula tract was filled with ASCs in combination with fibrin glue after intralesional injection of ASCs. Patients without complete closure of fistula at 8 weeks received a second injection of ASCs containing 1.5 times more cells than the first injection. Fistula healing at week 8 after final dose injection and its sustainability for 1-year were evaluated. Healing was defined as a complete closure of external opening without any sign of drainage and inflammation. A modified per-protocol analysis showed that complete fistula healing was observed in 27/33 patients (82%) by 8 weeks after ASC injection. Of 27 patients with fistula healing, 26 patients completed additional observation study for 1-year and 23 patients (88%) sustained complete closure. There were no adverse events related to ASC administration. ASC treatment for patients with Crohn's fistulae was well tolerated, with a favorable therapeutic outcome. Furthermore, complete closure was well sustained. These results strongly suggest that autologous ASC could be a novel treatment option for the Crohn's fistula with high-risk of recurrence.