Synthesis and biological evaluation of artemisinin derivatives as potential MS agents.

In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4+ T cells and IL-17A secreted by Th17 CD4+ T cells played critical roles in the treatment of multiple sclerosis. We used different concentrations of artemisinin derivatives to inhibit Th1 / Th17 differentiation in naive CD4+ T cells and to characterize IFN-γ / IL-17A in in vitro experiments. The preliminary screening results showed that ester compound 5 exhibited obvious inhibitory activities on Th1 and Th17 (IFN-γ decreased from 41% to 3% and IL-17A decreased from 24% to 8% at the concentration of 10 nM to 10 µM), and carbamate compounds also had obvious inhibitory activities against Th17 at high concentration. Moreover, we investigated the effect of compound 5 on myelin oligodendrocyte glycoprotein (MOG)-induced mice experimental autoimmune encephalomyelitis (EAE) model in vivo. 100 mg/kg compound 5 effectively reduced the disease severity of EAE compared with the vehicle group. This research revealed that compound 5 could be a promising avenue as potential MS inhibitor.

Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate.

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.

Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2.

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.

Synthesis and anticancer activity of ethyl 5-amino-1-N-substituted-imidazole-4-carboxylate building blocks.

A series of 5-amino-1-N-substituted-imidazole-4-carboxylate building blocks was synthesized and assayed for their antiproliferative potential against human cancer cell lines, including HeLa (cervical), HT-29, HCT-15 (colon), A549 (lung), and MDA-MB-231 (breast) cells. The preliminary screening results revealed that several derivatives containing alkyl chains at the N-1 position of the imidazole core demonstrate a certain inhibitory effect on growth and proliferation. A significant effect was observed following ethyl 5-amino-1-dodecyl-1H-imidazole-4-carboxylate (5e) treatment for 72 h. The IC50 value for HeLa cells was 0.737 ± 0.05 µM, whereas that for HT-29 cells was 1.194 ± 0.02 µM. Further investigations revealed that 5e significantly inhibited tumor cell colony formation and migration, and it exhibited antiadhesive effects on HeLa cells as well as antitubulin activity along with the induction of early apoptosis of HeLa and HT-29 cells. In addition, derivative 5e significantly reduced the cell mitochondrial membrane potential in a dose-dependent manner and induced early apoptosis of HeLa and HT-29 cells, indicating that 5e may serve as a lead compound for further drug discovery and development.

Synthesis of CBD and Its Derivatives Bearing Various C4'-Side Chains with a Late-Stage Diversification Method.

A novel synthetic route for making (-)-CBD and its derivatives bearing various C4'-side chains is developed by a late-stage diversification method. Starting from commercially available phloroglucinol, the key intermediate (-)-CBD-2OPiv-OTf is efficiently and regioselectively prepared and further undergoes Negishi cross-coupling to furnish (-)-CBD. This approach allowed an efficient synthesis of (-)-CBD in a five-step total 52% yield on a 10 g scale. Furthermore, diversification on the C4'-side chain with this method can be realized in a wide range.

Oxidative Aromatization of 3,4-Dihydroquinolin-2(1 H)-ones to Quinolin-2(1 H)-ones Using Transition-Metal-Activated Persulfate Salts.

Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1 H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1 H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1 H)-one derivatives with various functional groups were demonstrated in 52-89% yields.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview.

The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using 'click' chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the 'linker' property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.

Qualitative analysis of Schizonepeta annua (Pall.) Schischk essential oil by gas chromatography-quadrupole time-of-flight mass spectrometry.

In this study, a method for the qualitative analysis of small molecular compounds in Schizonepeta annua (Pall.) Schischk essential oil was established based on gas chromatography-quadrupole time-of-flight mass spectrometry. In addition to an automated search of the NIST library, the identification of oxygenated monoterpenes, phenolic esters, and phenolic compounds was achieved by two additional strategies. One strategy involved comparing the relative errors of accurate masses measured for ions in the experimental spectra with those calculated for fragments identified from the NIST database of candidate matches. The second strategy involved combination of the product ion scans and positive chemical ionisation spectra for structural elucidation. Overall, 95.45% of the total essential oil volatile chemical content of Schizonepeta annua (Pall.) Schischk was identified, with phenolic monoterpenes dominating.

Terpenoids from Euphorbia soongarica and Their Multidrug Resistance Reversal Activity.

Ten new terpenoids, including five diterpenoids (1-5), three nortriterpenoids (6-8), and two triterpenoids (9, 10), and 15 known terpenoids (11-25) were isolated from an acetone extract of Euphorbia soongarica. Sooneuphoramine (1) is the first example of a euphoractine B-type diterpenoid alkaloid, while sooneuphanones A-C (6-8) are rare nortriterpenoids from the Euphorbia genus. The isolated terpenoids were tested for their cytotoxicity and multidrug resistance (MDR) reversal activity, 10 of which showed moderate cytotoxicity against the KB and KBv200 cell lines, while 11 compounds exhibited P-gp modulating potential. The triterpenoid sooneuphanone D (9) possessed a remarkable MDR reversal activity much higher than the positive control, verapamil.

Upregulation of Melanogenesis and Tyrosinase Activity: Potential Agents for Vitiligo.

Melanin, the compound primarily responsible in humans for hair, eye and skin pigmentation, is produced by melanocytes through a complicated process called melanogenesis that is catalyzed by tyrosinase and other tyrosinase-related proteins. The abnormal loss of melanin causes dermatological problems such as vitiligo. Hence the regulation of melanogenesis and tyrosinase activity is very important for treating hypopigmentary disorders. Many melanogenesis stimulators have been discovered during the past decade. This article reviews recent advances in research on extracts and active ingredients of plants, synthesized compounds with stimulating effect on melanin synthesis and tyrosinase activity, as well as their influence on the expression of related proteins and possible signaling pathways for the design and development of novel anti-vitiligo agents.

Elderly patients have more infectious complications following laparoscopic colorectal cancer surgery.

AIM: Elderly patients may be at higher risk of postoperative complications, particularly infective, than younger patients. METHOD: We prospectively followed 163 consecutive patients undergoing elective laparoscopic resection for cancer. We compared patients < 65, 65-80 and > 80 years of age at the time of surgery. RESULTS: Seventy (42.9%) patients had no complication; 93 (57.1%) had at least one complication following surgery and in 20 (12.3%) this was major. There was no difference in major complications between the groups (P = 0.47). Patients over 65 years of age were more likely to have a complication of any severity [< 65 years, 39.3%; 65-80 years, 69.3%; and > 80 years, 63.0% (P = 0.002)]. The frequency of gastrointestinal complications (30.1%) was similar in the groups (P = 0.29), as was wound infection (25.2%) (P = 0.65). There was an increase in the frequency of infectious complications, especially chest infection, with age, from 14.8% in patients < 65 years, to 22.7% in patients 65-80 years, to 44.4% in patients > 80 years (P = 0.01). Multivariate analysis showed no increase in overall complications in elderly patients, but Stage II or Stage III cancer (OR = 2.59, P = 0.04) and increasing body mass index (BMI) (OR = 1.07 for each unit increase in BMI, P = 0.04) were related to complications. Age remained the only predictor of an infective complication on multivariate analysis. Patients > 80 years of age had 4.21 times the OR of an infective complication (P = 0.03). CONCLUSION: Older patients are more susceptible to infective complications postoperatively, particularly chest complications. Surgeons should alter their practice to reduce morbidity, such as adopting protocols requiring early physiotherapy.

Mini-probe ultrasonography for the staging of colon cancer: a systematic review and meta-analysis.

AIM: With an increasing array of treatment modalities available for colon cancer, it is increasingly important to stage tumours accurately to allocate the appropriate management. This study evaluated the accuracy of mini-probe endoscopic ultrasound (EUS) in assigning clinical stage to colon cancer. METHOD: An electronic search was performed in January 2013 using the Embase, MEDLINE and Cochrane databases. This was supplemented by a hand search of published abstracts from scientific meetings. Trials evaluating the accuracy of the mini-probe EUS compared with histopathological grade in determining the clinical stage of colon cancer were included in this pooled analysis. The main outcome measures included accuracy, sensitivity and specificity for T and N staging. RESULTS: Ten studies were identified which compared the mini-probe EUS staging of 642 colon or rectal cancers with the histopathological specimen. The pooled sensitivity and specificity for staging were 0.91 and 0.98 for T1 tumours, 0.78 and 0.94 for T2 tumours, 0.97 and 0.90 for T3/T4 tumours and 0.63 and 0.82 for nodal staging. Eight per cent of T1/T2 tumours were upstaged to T3/T4 tumours and 5% of T3/T4 tumours were downstaged. CONCLUSION: Mini-probe EUS is highly effective for assigning clinical stage in colon cancer and in identifying patients who may be suitable for nonsurgical treatment including neoadjuvant chemotherapy or endoscopic resection.

Direct esterification of amides by the dimethylsulfate-mediated activation of amide C-N bonds.

Amides are important intermediates in organic chemistry and the pharmaceutical industry, but their low reactivity requires catalysts and/or severe reaction conditions for esterification. Here, a novel approach was devised to convert amides into esters without the use of transition metals. The method effectively overcomes the inherent low reactivity of amides by employing dimethylsulfate-mediated reaction to activate the C-N bonds. To confirm the proposed reaction mechanism, control experiments and density functional theory (DFT) calculations were conducted. The method demonstrates a wide array of substrates, including amides with typical H/alkyl/aryl substitutions, N,N-disubstituted amides, amides derived from alkyl, aryl, or vinyl carboxylic acids, and even amino acid substrates with stereocentres. Furthermore, we have shown the effectiveness of dimethylsulfate in removing acyl protective groups in amino derivatives. This study presents a method that offers efficiency and cost-effectiveness in broadening the esterification capabilities of amides, thereby facilitating their increased utilization as synthetic compounds in diverse transformations.

Improved and ligand-free copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles.

We present an improved copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles, under mild and ligand-free conditions. The optimal conditions yielded exceptional products of up to 98%, demonstrating the broad applicability of this synthetic strategy in generating a wide range of valuable imidazole derivatives. This methodology enables the efficient synthesis of various substituted benzimidazole derivatives and offers an environmentally friendly alternative to conventional methods. By eliminating the use of harsh reagents and high temperatures associated with traditional synthesis approaches, this method proves to be more efficient and robust. Notably, we successfully applied this synthetic approach to the synthesis of bendazol and thiabendazole, yielding 82% and 78%, respectively, on a 100 gram scale.

High-frequency mini-probe ultrasound as a useful adjunct in the management of patients with malignant colorectal polyps.

AIM: Colorectal polyps with a focus of malignancy, identified postpolypectomy, pose a management challenge of whether endoscopic treatment is adequate or whether further surgical resection is required. This study assessed 12- and 20-MHz colonoscopic ultrasound to evaluate the presence of residual disease and local lymph nodes. METHOD: Consecutive cases of all colorectal polyps with a focus of malignancy were included. Colonoscopic high-frequency ultrasound was performed (20-MHz mini-probes for residual polyps and 12-MHz ultrasound for local lymph nodes) in the region of previous polypectomy. Biopsies were taken of the polypectomy site if any abnormalities were seen. RESULTS: Twenty-one malignant polyps (sigmoid, n = 10; rectum, n = 8; transverse colon, n = 1; ascending colon, n = 1; and caecum, n = 1) were identified. All were invasive adenocarcinomas; 12 were intramucosal and nine were submucosal (seven sm1 lesions in the upper third of the submucosa; and two sm2 lesions in the middle third of the submucosa). Excision was histologically complete in 12 patients, four had involved margins and histology was uncertain in five owing to diathermy artefacts. Further colonoscopy revealed a residual abnormality in eight patients. The 12- and 20-MHz ultrasound imaging revealed mucosal irregularity with normal bowel-wall layers and no lymph-node involvement, with normal histology. High-frequency ultrasound was normal in the remaining 13 patients. At the time of writing, 15 (72%) of the 21 patients were disease free without further surgery. Six of the 21 patients underwent surgery, despite normal high-frequency ultrasound findings, because of submucosal invasion (sm1 or sm2) and uncertain completeness of resection. The specimens were free of cancer in all six patients. CONCLUSION: High-frequency ultrasound is feasible for the assessment of colorectal malignant polyps.

A clinicopathological study of serotonin of sigmoid colon mucosa in association with chronic symptoms in uncomplicated diverticulosis.

INTRODUCTION: Neurotransmitter imbalance is hypothesised as a pathogenetic mechanism in several bowel conditions. We previously reported increased 5-HT in the sigmoid mucosa of colon resected for complicated diverticular disease (DD). We aimed to identify if abnormal 5-HT expression is associated with symptoms of uncomplicated DD. METHODS: This was a prospective, comparative study and follow-up survey of symptoms. We examined the differences in 5-HT between DD patients and controls, as well as the presence of bowel symptoms at time of endoscopy and also 2 years later. Sigmoid biopsies were collected at colonoscopy. Immunohistochemical staining for 5-HT cells was performed. RESULTS: Eighty-seven patients were recruited, 37 (42.5 %) DD and 50 (57.5 %) controls. No patients underwent surgery. There was no significant difference in total mean number of 5-HT-positive cells in DD compared to controls or between patients and controls with abdominal symptoms. Forty-one patients (47.1 %) responded to questionnaires at median 57.8 months from biopsy. Eighteen (43.9 %) were DD and 23(56.1 %) controls. 5-HT counts showed no significant association to symptom persistence. DISCUSSION: Although 5-HT expression has previously been found to be increased in complicated DD in whole bowel-resected specimens, the same is not confirmed on colonic mucosal biopsies. This raises the suggestion that 5-HT may be involved in the development of acute complications but may not be involved in the pathogenesis of chronic symptoms.

Colonoscopic high frequency mini-probe ultrasound is more accurate than conventional computed tomography in the local staging of colonic cancer.

AIM: Colonoscopic high frequency mini-probe ultrasound was compared prospectively with CT in the local staging of colonic cancer. METHOD: Consecutive patients undergoing surgical resection for colonic cancer were recruited. Preoperative 64-slice CT staging with multiplanar reconstruction was compared with colonoscopic high frequency mini-probe ultrasound using 12 MHz and 20 MHz probes. The three methods of staging (CT, 12 MHz ultrasound and 20 MHz ultrasound) were compared with the histological stage of the resected specimen. This was done using weighted kappa coefficients where weights of 0.7-0.8 were given to penalize disagreements of one level in either direction and weights of zero were given to penalize disagreements of more than one level in any direction. RESULTS: In total, 38 patients with colonic cancer were included. They were located in the sigmoid (n = 20), descending (n = 5), ascending (n = 2) and transverse colon (n = 1) and in the caecum (n = 7) and splenic (n = 2) and hepatic (n = 1) flexure. Histopathological assessment revealed seven pT1, four pT2, 25 pT3 and two pT4 cancers. In relation to the pathology the weighted kappa coefficients were 0.36 (SE = 0.14), 0.81 (SE = 0.16) and 0.81 (SE = 0.17) for CT, ultrasound 12 MHz and ultrasound 20 MHz. Histopathologically 15 (39.5%) patients were lymph node positive. The sensitivity, specificity and kappa coefficient for detection of nodal disease for CT were 80%, 47.8% and 0.25 (SE = 0.14) compared with 80%, 82.5% and 0.62 for 12 MHz ultrasound (SD = 0.14) and 23%, 90.5% and 0.15 (SD = 0.13) for 20 MHz ultrasound. CONCLUSION: Colonoscopic ultrasound is significantly more accurate than CT for T staging of colonic cancers. With respect to nodal status, 12 MHz ultrasound offers superior accuracy to CT or 20 MHz ultrasound.

Recent advancement of observing living cells in the esophagus using CM double staining: endocytoscopic atypia classification.

Magnification endoscopy enables in vivo evaluation of gastrointestinal mucosa. Furthermore, endocytoscopy (ECS) with ultra-high magnification enables in vivo observation of cellular atypia during routine endoscopic examination. The purpose of this study is to clarify the efficacy of ECS and endocytoscopic atypia (ECA) classification in various types of benign and malignant pathology in the esophagus. Consecutive 110 patients, who underwent ECS in our institution from March 2003 to December 2009, were included in this study. One hundred and forty-six esophageal lesions were classified according to ECA classification, and these endocytoscopic images were compared with histological images. We categorized endocytoscopic images into five categories according to size and uniformity of nuclei, number of cells and regularity of cellular arrangement. Eighty-one out of 89 ECA-1 to ECA-3 lesions (91.0%) corresponded to Vienna categories 1 to 3. Seventy-one out of 84 ECA-4 or ECA-5 lesions (91.2%) corresponded to Vienna category 4 or 5. Overall accuracy of ECS was 91.3%, providing images similar to conventional hematoxylin and eosin staining. In addition, with ECS, we can take an 'optical biopsy' even in patients with cardiovascular disease without interrupting anticoagulant therapy. A newly designed single charge-coupled device endocytoscope allows observation of target tissue noninvasibly from regular magnification to ultra-high magnification. The development of ECS has opened the door to in vivo cellular imaging, enabling endoscopic diagnosis of tissue cytological atypia during routine endoscopic examination.

Practical and Highly Efficient Synthesis of Remdesivir from GS-441524.

A three-step sequence for preparing remdesivir, an important anti-SARS-CoV-2 drug, is described. Employing N,N-dimethylformamide dimethyl acetal (DMF-DMA) as a protecting agent, this synthesis started from (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-2-carbonitrile (GS-441524) and consisted of three reactions, including protection, phosphoramidation, and deprotection. The advantages of this approach are as follows: (1) the protecting group could be removed under a mild deprotection condition, which avoided the generation of the degraded impurity; (2) high stereoselectivity was achieved in the phosphorylated reaction; (3) this synthesis could be performed successively without purification of intermediates. Moreover, the overall yield of this approach on a gram scale could be up to 85% with an excellent purity of 99.4% analyzed by high-performance liquid chromatography (HPLC).

Facile Synthesis of Benzimidazoles via N-Arylamidoxime Cyclization.

A facile synthesis of benzimidazoles was described by a one-pot process containing acylation-cyclization of N-arylamidoxime. This method provided an alternative synthesis of benzimidazoles with a certain diversity of substituted groups in acceptable yields (up to 96%). More importantly, the construction of bis-benzimidazole (8), the key intermediate for making telmisartan, was achieved by adopting this method that enabled avoiding the undesired nitration with nitric/sulfuric acid and the cyclization in polyphosphoric acid in the existing operations.