Activity Of Analogues Research Articles

1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking.

Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.

Concentration-dependence of specific rotation of optically active glycerol analogues and structurally related compounds: The significance of intermolecular hydrogen bonding

Specific rotation of optically active glycerol analogues, (S)-3-(benzyloxy)propane-1,2-diol [(S)-1], (S)-3-methoxypropane-1,2-diol [(S)-6] and (S)-3-phenoxypropane-1,2-diol [(S)-13], changed its sign from (+) to (–) with increasing concentration in CHCl3, whereas no significant concentration-dependent change was observed in MeOH. The 1H NMR spectrum of (S)-1 showed concentration-dependent changes of the chemical shift in CDCl3. Intermolecular interaction by OH⋯OH hydrogen bonds was suggested by single crystal X-ray crystallography of (S)-13. The concentration-dependent changes of specific rotation of (S)-1, (S)-6, and (S)-13 in CHCl3 can therefore be presumed to be due to self-assembly of these compounds via intermolecular hydrogen bonding at high concentration. The remarkable concentration-dependent changes in specific rotation were also observed to occur in the compounds with related chemical structures, such as (S)-3-hydroxy-4-methoxy-4-oxobutanoic acid [(S)-10], (S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid [Boc-L-Pro-OH, (S)-14], (R)-3-hydroxy-4,4-dimethylhydrofran-2(3H)-one [(R)-15], (R)-tetrahydrofuran-2-carboxylic acid [(R)-16], (S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid [Boc-L-Val-OH, (S)-17], (R)-oxiran-2-ylmethanol [(R)-18], and (4S)-4-isopropyloxazolidin-2-one [(S)-19]. The existence of intermolecular interaction by C=O⋯HO hydrogen bonds was suggested by single crystal X-ray crystallography of (S)-10, (S)-13, and (S)-14. Thus, this series of chiral compounds have multiple functional groups in appropriate positions that serve as hydrogen-bond donors and/or acceptors, resulting in significant concentration-dependent changes of specific rotation.

S-Alkylated quinazolin-4(3H)-ones as dual EGFR/VEGFR-2 kinases inhibitors: design, synthesis, anticancer evaluation and docking study.

Dual targeting by a single molecule has emerged as a promising strategy for fighting cancer. In this study, a new set of 2-thioquinazolin-4(3H)-ones as potential anti-cancer surrogates endowed with dual EGFR/VEGFR-2 kinases inhibitory activities were synthesized. The anti-tumor potency of the newly synthesized candidates 4-27 was evaluated against a panel of four cancer cell lines. The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib. For instance, compound 4 (IC50 = 1.50-5.86 μM) and compound 20 (IC50 = 4.42-6.39 μM) displayed superior potencies against all cell lines compared to sorafenib (IC50 = 5.47-7.26 μM). Dual EGFR/VEGFR-2 inhibitory activities of the most active analogues (4, 11, and 20) were investigated. Compound 4 showed comparable EGFR/VEGFR-2 inhibitory activity to the used control drugs. Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.

Vitamin D3 exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in Sod1 knockout mice: a comparative study of two forms of vitamin D.

The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.

Computer-aided drug design of novel nirmatrelvir analogs inhibiting main protease of Coronavirus SARS-CoV-2

A computer-aided drug design of new derivatives of nirmatrelvir, an orally active inhibitor of the main-protease (Mpro) of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), was performed to identify its analogues with a higher antiviral potency. The following workflow was used: first, an evolutionary library composed of 1,866 analogues was generated starting from a parent nirmatrelvir scaffold and going through small mutation, fitness scoring, ranking, and selection. Second, the generated library was preprocessed and filtered against a 3-D pharmacophore model of nirmatrelvir built from its X-ray structure in a co-crystalized complex with the Mpro enzyme, allowing us to reduce the chemical space to 32 active analogues. Third, structure-based molecular docking against two different enzyme structures further ranked these active candidates, so that up to eight better-binding analogs were identified. The selected hit-analogues target the Mpro enzymes of SARS-CoV-2 with a higher binding affinity than a parent nirmatrelvir. The main structural modifications that increase the overall inhibitory affinity are identified at the azabicyclo[3.1.0] hexane and 2-oxopyrrolidine fragments. A characteristic structural feature of the inhibitor binding with the Mpro active centre is the similar location of the trifluoroacetylamino fragment, which is observed for most hit-analogues. The suggested workflow of the computer-aided rational design of new antiviral noncovalent inhibitors based on the scaffold of approved drugs is a promising, extremely low-cost, and time-efficient approach for the development of new potential pharmaceutical ingredients for the treatment of Coronavirus Disease 2019.

Peptide dendrimers transfecting CRISPR/Cas9 plasmid DNA: optimization and mechanism.

Gene editing by CRISPR/Cas9 offers great therapeutic opportunities but requires delivering large plasmid DNA (pDNA) into cells, a task for which transfection reagents are better suited than viral vectors. Here we performed a structure-activity relationship study of Z22, a d-enantiomeric, arginine containing, lipidated peptide dendrimer developed for pDNA transfection of a CRISPR/Cas9 plasmid co-expressing GFP. While all dendrimer analogs tested bound pDNA strongly and internalized their cargo into cells, d-chirality proved essential for transfection by avoiding proteolysis of the dendrimer structure required for endosome escape and possibly crossing of the nuclear envelope. Furthermore, a cysteine residue at the core of Z22 proved non-essential and was removed to yield the more active analog Z34. This dendrimer shows >83% GFP transfection efficiency in HEK cells with no detrimental effect on cell viability and promotes functional CRISPR/Cas9 mediated gene editing. It is accessible by solid-phase peptide synthesis and therefore attractive for further development.

EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model

Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A.In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity.

New Brassinosteroid Analogs with 23,24-Dinorcholan Side Chain, and Benzoate Function at C-22: Synthesis, Assessment of Bioactivity on Plant Growth, and Molecular Docking Study.

The synthesis and biological evaluation of brassinosteroids (BRs) analogs with chemical modification in the side alkyl chain is a matter of current interest. Recently, a series of BR analogs with phenyl or benzoate groups in the alkyl chain have been reported. The effect of substitution in the aromatic ring on the biological activities of these new analogs has been evaluated, and the results suggest that the bioactivity is enhanced by substitution with an F atom. In this context, we have synthesized, characterized, and evaluated a series of new analogs of 23,24-bisnorcholenic type in which the benzoate group at the C-22 position is substituted with an F atom at "ortho or para" positions. Plant growth-promoting activities were evaluated by using the rice lamina inclination test and bean second internode biotest. The results obtained with both bioassays indicate that the compound with an F atom in the para position on the aromatic ring is the most active BR analog and in some cases is even more active than brassinolide. The docking study confirmed that compounds with an F atom adopt an orientation similar to that predicted for brassinolide, and the F atom in the "para" position generates an extra hydrogen bond in the predicted binding position.

Artificial Intelligence-Based Diagnostic Support System for Functional Dyspepsia Based on Brain Activity and Food Preference.

Background and aim Disorders of gut-brain interaction (DGBI) aredisorders where no organic clinical abnormalities are detected such as functional dyspepsia (FD) and irritable bowel syndrome (IBS). The brain activity of individuals with FD and IBS differs from that of healthy controls. Artificial intelligence can distinguish healthy controls from individuals with DGBI using several biomarkers. This study aimed to establish an artificial intelligence-based diagnostic support system using food preferences and brain activity in patients with DGBI. Methods ROME IV criteria were used to diagnose patients with FD and IBS. Their food preference was scored using a visual analog scale, and brain activity in the prefrontal cortex was investigated using functional near-infrared spectroscopy (fNIRS). The diagnostic model was developed based on the brain activity and visual analog scale scores for food using an artificial neural network model. Results Forty-one participants, including 25 patients with DGBI were enrolled in the study. The accuracy of the artificial intelligence-based diagnostic model using an artificial neural network in differentiating between healthy controls and patients with DGBI and between healthy controls and those with FD were 72.3% and 77.1%, respectively. Conclusions The artificial intelligence-based diagnostic model using brain activity and preference to food images showed sufficiently high accuracy in distinguishing patients with DGBI from healthy controls, and those with FD from healthy controls. Therefore, the fNIRS system provides objective evidence for diagnosing DGBI.

Molecular hybrids of substituted phenylcarbamoylpiperidine and 1,2,4-triazole methylacetamide as potent 15-LOX inhibitors: Design, synthesis, DFT calculations and molecular docking studies

Inflammation is a multifaceted phenomenon triggered by potentially active mediators acutely released arachidonic acid metabolites partially in lipoxygenase (LOX) pathway which are primarily accountable for causing several diseases in humans. It is widely believed that an inhibitor of the LOX pathway represents a rational approach for designing more potent antiinflammatory leads with druggable super safety profiles. In our continual efforts in search for anti-LOX molecules, the present work was to design a new series of N-alkyl/aralkyl/aryl derivatives (7a-o) of 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol which was commenced in seriate formation of phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol (4). The aimed compounds were obtained by reacting 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol with assorted N-alkyl/aralkyl/aryl electrophiles. All compounds were characterized by FTIR, 1H-, 13C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX for their inhibitory potential using chemiluminescence method. All the compounds except 7m and 7h inhibited the said enzyme remarkably. Compounds 7c,7l, 7j and 7a displayed potent inhibitions ranging from IC50 1.92 ± 0.13 µM to 7.65 ± 0.12 µM. Other analogues 7g, 7o, 7e, 7b, 7d, 7k and 7n revealed excellent inhibitory values ranging from IC50 12.45 ± 0.38 µM to 24.81 ± 0.47 µM. All these compounds did not reveal DPPH radical scavenging activity. Compounds 7i-o maintained > 90 % human blood mononuclear cells (MNCs) viability at 0.125 mM as assayed by MTT whilst others were found toxic. Pharmacokinetic profiles predicted good oral bioavailability and drug-likeness properties of the active scaffolds. SAR investigations showed that phenyl substituted analogue on amide side decreased inhibitory activity due to inductive and mesomeric effects while the mono-alkyl substituted analogues were more active than disubstituted ones and ortho substituted analogues were more potent than meta substituted ones. MD simulation predicted the stability of the 7c ligand and receptor complex as shown by their relative RMSD (root mean square deviation) values. Molecular docking studies displayed hydrogen bonding between the compounds and the enzyme with Arg378 which was common in 7n, 7g, 7h and baicalein. In 7a and quercetin, hydrogen bonding was established through Asn375. RMSD values exhibited good inhibitory profiles in the order quercetin (0.73 Å) < 7 g < baicalein < 7a < 7n < 7 h (1.81 Å) and the binding free energies followed similar pattern. Density functional theory (DFT) data established good correlation between the active compounds and significant activity was associated with more stabilized LUMO (lowest unoccupied molecular orbitals) orbitals. Nevertheless, the present studies declare active analogues like 7c, 7 l, 7a, 7j as leads. Work is ongoing in derivatizing active molecules to explore more effective leads as 15-LOX inhibitors as antiinflammatory agents.

Design and synthesis of imidazo[1,2-a]pyridine-chalcone conjugates as antikinetoplastid agents.

A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using 1 H NMR, 13 C NMR and HRMS. The synthesized analogues were screened for their antikinetoplastid activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogues were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, 7f was found to be the most active against T. cruzi and T. b. brucei exhibiting IC50 values of 8.5 and 1.35 μM, respectively. Against T. b. rhodesiense, 7e was found to be the most active with an IC50 value of 1.13 μM. All synthesized active analogues were found to be non-cytotoxic against MRC-5 and PMM with selectivity indices of up to more than 50.

New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development.

Biosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising new antibiotic classes of the past decades. Here, we present a series of structure-driven biosynthetic modifications of our current frontrunner, darobactin 22 (D22), to investigate modifications at the understudied positions 2, 4, and 5 for their impact on bioactivity. Novel darobactins were found to be highly active against critical pathogens from the WHO priority list. Antibacterial activity data were corroborated by dissociation constants with BamA. The most active derivatives D22 and D69 were subjected to ADMET profiling, showing promising features. We further evaluated D22 and D69 for bioactivity against multidrug-resistant clinical isolates and found them to have strong activity.

Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment.

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the 'druggable' proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the 'bottom-up' development of PPI stabilizers (Molecular Glues). The hub protein 14-3-3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues. In this study, we employed a fragment extension strategy to discover stabilizers for the complex of 14-3-3 protein and an Estrogen Receptor alpha-derived peptide (ERα). A focused library of analogues derived from an amidine-substituted thiophene fragment enhanced the affinity of the 14-3-3/ERα complex up to 6.2-fold. Structure-activity relationship (SAR) analysis underscored the importance of the newly added, aromatic side chain with a certain degree of rigidity. X-ray structural analysis revealed a unique intermolecular π-π stacking binding mode of the most active analogues, resulting in the simultaneous binding of two molecules to the PPI binding pocket. Notably, analogue 11 displayed selective stabilization of the 14-3-3/ERα complex.

Isoxazole analogues of dibenzazepine as possible leads against ulcers and skin disease: In vitro and in silico exploration

Utilizing multi-target drugs shows great promise as an effective strategy against polygenic diseases characterized by intricate patho-mechanisms, such as ulcers, skin dermatitis, and cancers. The current research centers around the creation of hybrid compounds, connecting dibenzazepine and isoxazole, with the aim of exploring their potential as inhibitors for urease and tyrosinase enzymes. Analogs 6a, 6b, 6d, 6 h-6j, and 6 l demonstrated strong inhibitory potential against tyrosinase enzyme with IC50 values of 4.32 ± 0.31–12.36 ± 0.48. Whereas analogs 6a, 6c, 6e, 6f, 6h-6m, and 6r exhibited potent inhibitory activities against urease enzyme with IC50 values of 3.67 ± 0.91–15.60 ± 0.18 μM. Furthermore, compounds 6i, 6n, and 6r showed weak toxic effect in BJ-cell line, whereas the remaining compounds were found non-toxic to normal cell line. The mechanistic studies of potent inhibitors of both the enzymes showed competitive mode of inhibition. Molecular docking was employed to establish the relationship between structure and activity and to elucidate the interaction mechanism. This analysis revealed that the active analogs exhibited crucial interactions with the active site residues of urease and tyrosinase, thus corroborating our experimental results. Hence, the generated derivatives of dibenzazepine-linked isoxazoles present intriguing starting points for further investigations into their potential as inhibitors of urease and tyrosinase, with the potential for future modification and enhancement.

PmxPred: A data-driven approach for the identification of active polymyxin analogues against gram-negative bacteria

The multidrug-resistant Gram-negative bacteria has evolved into a worldwide threat to human health; over recent decades, polymyxins have re-emerged in clinical practice due to their high activity against multidrug-resistant bacteria. Nevertheless, the nephrotoxicity and neurotoxicity of polymyxins seriously hinder their practical use in the clinic. Based on the quantitative structure-activity relationship (QSAR), analogue design is an efficient strategy for discovering biologically active compounds with fewer adverse effects. To accelerate the polymyxin analogues discovery process and find the polymyxin analogues with high antimicrobial activity against Gram-negative bacteria, here we developed PmxPred, a GCN and catBoost-based machine learning framework. The RDKit descriptors were used for the molecule and residues representation, and the ensemble learning model was utilized for the antimicrobial activity prediction. This framework was trained and evaluated on multiple Gram-negative bacteria datasets, including Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and a general Gram-negative bacteria dataset achieving an AUROC of 0.857, 0.880, 0.756, 0.895 and 0.865 on the independent test, respectively. PmxPred outperformed the transfer learning method that trained on 10 million molecules. We interpreted our model well-trained model by analysing the importance of global and residue features. Overall, PmxPred provides a powerful additional tool for predicting active polymyxin analogues, and holds the potential elucidate the mechanisms underlying the antimicrobial activity of polymyxins. The source code is publicly available on GitHub (https://github.com/yanwu20/PmxPred).

Bimetallic Single-Atom Catalysts for Electrocatalytic and Photocatalytic Hydrogen Production

Electrocatalytic and photocatalytic hydrogen evolution reactions (HERs) provide a promising approach to clean energy generation. Bimetallic single-atom catalysts have been developed and explored to be advanced catalysts for HER. It is urgent to review and summarize the recent advances in developing bimetallic single-atom HER catalysts. Firstly, the fundamentals of bimetallic single-atom catalysts are presented, highlighting their unique configuration of two isolated metal atoms on their supports and resultant synergistic effects. Secondly, recent advances in bimetallic single-atom catalysts for electrocatalytic HER under acidic/alkaline conditions are then reviewed, including W-Mo, Ru-Bi, Ni-Fe, Co-Ag, and other dual-atom systems on graphene and transition metal dichalcogenides (TMDs) with enhanced HER activity versus monometallic analogs due to geometric and electronic synergies. Then, photocatalytic bimetallic single-atom catalysts on semiconducting carbon nitrides for solar H2 production are also discussed. Finally, an outlook is provided on opportunities and challenges in precisely controlling bimetallic single-atom catalyst synthesis and gaining in-depth mechanistic insights into bimetallic interactions. Further mechanistic and synthetic studies on bimetallic single-atom catalysts will be imperative for developing optimal systems for efficient and sustainable hydrogen production.

Frequency and determinants of serum calcium monitoring during eldecalcitol therapy in patients with osteoporosis.

Eldecalcitol (ELD) is an active vitamin D3 analog (AVD) commonly used to treat osteoporosis in Japan. Although routine monitoring of serum calcium levels during ELD therapy is recommended, little is known about the actual frequency and determinants of monitoring. This was a descriptive cohort study using a Japanese electronic medical records database. We identified osteoporosis patients who initiated treatment with ELD or other AVDs (alfacalcidol and calcitriol) between April 1, 2011 and September 10, 2021. The index date for cohort entry was the first prescription date of ELD or other AVDs. The frequency of serum calcium monitoring was evaluated every 6 months. Determinants of serum calcium monitoring were identified using multivariable logistic regression models. We also calculated the incidence of hypercalcemia and the frequency of serum calcium monitoring within 6 months before hypercalcemia. We identified 12,671 ELD users and 7867 other AVD users. Within 6 months after cohort entry, 45.9% of ELD users and 58.7% of other AVD users underwent serum calcium monitoring. Female sex, no use of systemic corticosteroids, moderate-to-good renal function, treatment in smaller hospitals, and treatment in orthopedic surgery departments were associated with a lower likelihood of receiving serum calcium monitoring during ELD therapy. The incidence of hypercalcemia among ELD users was 6.36 per 100 person-years, with 20.6% of cases not receiving serum calcium monitoring before hypercalcemia. Our findings suggest that serum calcium monitoring is not given adequate attention during ELD therapy in routine clinical practice.

Lipophilic Nucleoside Triphosphate Prodrugs of Anti-HIV Active Nucleoside Analogs as Potential Antiviral Compounds.

Nucleoside analogs require three phosphorylation steps catalyzed by cellular kinases to give their triphosphorylated metabolites. Herein, the synthesis of two types of triphosphate prodrugs of different nucleoside analogs is disclosed. Triphosphates comprising: i) a γ-phosphate or γ-phosphonate bearing a bioreversible acyloxybenzyl group and a long alkyl group and ii) γ-dialkyl phosphate/phosphonate modified nucleoside triphosphate analogs. Almost selective conversion of the former TriPPPro-compounds into the corresponding γ-alkylated nucleoside triphosphate derivatives is demonstrated in CEM/0 cell extracts that proved to be stable toward further hydrolysis. The latter γ-dialkylated triphosphate derivatives lead to the slow formation of the corresponding NDPs. Both types of TriPPPro-compounds are highly potent in wild-type CEM/0 cells and more importantly, they exhibit even better activities against HIV-2 replication in CEM/TK- cell cultures. A finding of major importance is that, in primer extension assays, γ-phosphate-modified-NTPs, γ-mono-alkylated-triphosphates, and NDPs prove to be substrates for HIV-RT but not for cellular DNA-polymerases α,γ.

Discovery of indole analogues from Periplaneta americana extract and their activities on cell proliferation and recovery of ulcerative colitis in mice

Background: As an important medicinal insect, Periplaneta americana (PA) has been applied for the treatment of wounds, burns, and ulcers with fewer side effects and a reduced recurrence rate, which provides great potential for developing new drugs based on its active constituents.Materials and methods: The main chromatographic peaks determined by high performance liquid chromatography (HPLC) in the PA concentrated ethanol-extract liquid (PACEL) were separated, purified, and identified by semi-preparative LC, mass spectrum, and 1H NMR spectroscopic analysis. The biological activities of the identified compounds were investigated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) method based on in vitro human skin fibroblasts (HSF) and in vivo experiments based on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model. Furthermore, RT-qPCR of six genes related to inflammation or intestinal epithelial cell proliferation was employed to investigate the molecular mechanism of the indole analogues recovering UC in mice.Results: Five indole analogues were purified and identified from PACEL, including tryptophan (Trp), tryptamine (pa01), 1,2,3,4-tetrahydrogen-β-carboline-3-carboxylic acid (pa02), (1S, 3S)-1-methyl-1,2,3,4-tetrahydrogen-β-carboline-3-carboxylic acid (pa03), and (1R, 3S)-1-methyl-1,2,3,4-tetrahydrogen-β-carboline-3-carboxylic acid (pa04), among which the pa02 and pa04 were reported in PA for the first time. In vitro and in vivo experiments showed that PACEL, Trp, and pa02 had promoting HSF proliferation activity and intragastric administration of them could alleviate symptoms of weight loss and colon length shortening in the UC mice. Although recovery activity of the compound pa01 on the colon length was not as obvious as other compounds, it showed anti-inflammatory activity in histological analysis. In addition, The RT-qPCR results indicated that the three indole analogues could alleviate DSS-induced intestinal inflammation in mice by inhibiting pro-inflammatory cytokines (MMP7, IL1α) and down-regulating BMP8B expression.Conclusion: This study reported the isolation, purification, structure identification, and biological activity of the active indole analogues in PACEL. It was found for the first time that the PA extract contained many indole analogues and Trp, which exhibited good proliferation activity on HSF fibroblasts as well as anti-UC activity in mice. These indole analogues probably are important components related to the pharmacological activity in PA.

Investigation of novel bis-thiadiazole bearing schiff base derivatives as effective inhibitors of thymidine phosphorylase: Synthesis, in vitro bioactivity and molecular docking study

Thymidine phosphorylase (TP) is an angiogenic enzyme. It is crucial for the development, invasion and metastasis of tumors as well as angiogenesis. In our current research, we examine how structurally changing bis-thiadiazole bearing bis-schiff bases affects their ability to inhibit TP. Through the oxidative cyclization of pyridine-based bis-thiosemicarbazone with iodine, a series of fourteen analogs of bis-thiadiazole-based bis-imines with pyridine moiety were developed. Newly synthesized scaffolds were assessed in vitro for their thymidine phosphorylase inhibitory potential and showed moderate to good inhibition profile. Eleven scaffolds such as 4a-4d,4f-4 h and 4j-4 m were discovered to be more effective than standard drug at inhibiting the thymidine phosphorylase enzyme with IC50 values of 1.16 ± 1.20, 1.77 ± 1.10, 2.48 ± 1.30, 12.54 ± 1.60, 14.63 ± 1.70, 15.53 ± 1.80, 17.47 ± 1.70, 18.98 ± 1.70, 19.53 ± 1.50, 22.73 ± 2.40 and 24.87 ± 2.80 respectively, while remaining three analogs such as 4n, 4i and 4ewere found to be more potent, but they were less potent than the standard drug. All analogs underwent SAR studies based on the pattern of substitutions around the aryl part of the bis-thiadiazole skeleton. The most active analogs in the synthesized series were then molecular docking study performed to investigate their interactions of active part of enzyme. The results showed that remarkable interactions were exhibited by these analogs with the targeted enzymes active sites. Furthermore, to confirm the structure of synthesized analogs by employing spectroscopic tools such as HREI-MS and NMR.