-
Molecules (Basel, Switzerland) Nov 2018A series of novel 5'-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against...
A series of novel 5'-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of was completely inhibited by the most active compounds at a MIC of 67 μg/mL (mc²155) and a MIC of 6.7⁻67 μg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of ATCC 25177 (MIC 28⁻61 μg/mL) and ATCC 35737 (MIC 50⁻60 μg/mL), as well as two virulent strains of ; a laboratory strain H37Rv (MIC 20⁻50 μg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC 20⁻50 μg/mL). Transmission electron microscopy (TEM) evaluation of H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls.
Topics: Anti-Bacterial Agents; Antitubercular Agents; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Pyrimidines; Structure-Activity Relationship; Uracil
PubMed: 30477147
DOI: 10.3390/molecules23123069 -
International Journal of Molecular... Mar 2020Riboswitches are naturally occurring RNA aptamers that control the expression of essential bacterial genes by binding to specific small molecules. The binding with both...
Riboswitches are naturally occurring RNA aptamers that control the expression of essential bacterial genes by binding to specific small molecules. The binding with both high affinity and specificity induces conformational changes. Thus, riboswitches were proposed as a possible molecular target for developing antibiotics and chemical tools. The adenine riboswitch can bind not only to purine analogues but also to pyrimidine analogues. Here, long molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) computational methodologies were carried out to show the differences in the binding model and the conformational changes upon five ligands binding. The binding free energies of the guanine riboswitch aptamer with C74U mutation complexes were compared to the binding free energies of the adenine riboswitch (AR) aptamer complexes. The calculated results are in agreement with the experimental data. The differences for the same ligand binding to two different aptamers are related to the electrostatic contribution. Binding dynamical analysis suggests a flexible binding pocket for the pyrimidine ligand in comparison with the purine ligand. The 18 μs of MD simulations in total indicate that both ligand-unbound and ligand-bound aptamers transfer their conformation between open and closed states. The ligand binding obviously affects the conformational change. The conformational states of the aptamer are associated with the distance between the mass center of two key nucleotides (U51 and A52) and the mass center of the other two key nucleotides (C74 and C75). The results suggest that the dynamical character of the binding pocket would affect its biofunction. To design new ligands of the adenine riboswitch, it is recommended to consider the binding affinities of the ligand and the conformational change of the ligand binding pocket.
Topics: Adenine; Bacterial Proteins; Guanine; Ligands; Models, Molecular; Molecular Dynamics Simulation; Mutation; Nucleic Acid Conformation; Purines; Pyrimidines; Riboswitch
PubMed: 32168940
DOI: 10.3390/ijms21061926 -
Chemical & Pharmaceutical Bulletin 2014A series of diarylureas and diarylamides possessing pyrrolo[2,3-d]pyrimidine scaffold was designed and synthesized. The in vitro antiproliferative activities of a...
A series of diarylureas and diarylamides possessing pyrrolo[2,3-d]pyrimidine scaffold was designed and synthesized. The in vitro antiproliferative activities of a selected group of the target compounds against NCI-60 cell line panel were tested and compared with Sorafenib and Imatinib as reference compounds. Most of the compounds showed strong and broad-spectrum antiproliferative activities. Compounds IVa, IVb, and IVd with benzamido moiety at position 4 of the pyrrolo[2,3-d]pyrimidine nucleus, para-disubstituted phenyl ring at N1-position of pyrrolo[2,3-d]pyrimidine scaffold, and urea linker showed strong and broad-spectrum anticancer results with high potencies and efficacies. In addition, the amide derivatives Vb and Vc demonstrated one-digit nanomolar IC50 values over two and one cell line(s), respectively. Amid all the target compounds, compound IVa demonstrated the best results in both one-dose and five-dose testing modes. It showed 109.18% mean % inhibition over the NCI-60 cancer cell line panel at 10 µM concentration, submicromolar 50% inhibitory concentration (IC50) values over eight cell lines of eight different cancer types, and high efficacy with total growth inhibition (TGI) and 50% lethal concentration (LC50) values less than 4.22 µM over three colon, ovarian, and prostate cancer cell lines. It showed superior potency and efficacy to Sorafenib and Imatinib over most of the tested cell lines.
Topics: Antineoplastic Agents; Benzamides; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Imatinib Mesylate; Niacinamide; Phenylurea Compounds; Piperazines; Pyrimidines; Pyrroles; Sorafenib
PubMed: 24390490
DOI: 10.1248/cpb.c13-00249 -
Acta Poloniae Pharmaceutica 2004Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer... (Review)
Review
Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer nucleosides include analogs of physiologic pyrimidine and purine nucleosides. They are used in oncology in the treatment of both, solid tumors and hematological malignancies. These agents have many intracellular targets, e.g. they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis and as inhibitors of key cell enzymes. Understanding of the mechanisms of action of these compounds and synthesis of new analogs provides the possibility to further expand the spectrum of their clinical use and enhance their antitumor activity. In this paper we describe mechanisms of action and possible clinical use in the treatment of hematological malignancies of these nucleoside analogs, which are now in different stages of clinical trials, namely tezacitabine, troxacitabine, clofarabine, nelarabine, decitabine, CNDAC and ECyD.
Topics: Adenine Nucleotides; Animals; Antineoplastic Agents; Arabinonucleosides; Clinical Trials as Topic; Clofarabine; Cytarabine; Cytosine; Deoxycytidine; Dioxolanes; Half-Life; Hematologic Neoplasms; Humans; Purine Nucleosides; Pyrimidine Nucleosides; Stereoisomerism
PubMed: 15481249
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Oct 2013Cryptosporidiosis, a gastrointestinal disease caused by a protozoan Cryptosporidium hominis is often fatal in immunocompromised individuals. There is little clinical...
Cryptosporidiosis, a gastrointestinal disease caused by a protozoan Cryptosporidium hominis is often fatal in immunocompromised individuals. There is little clinical data to show that the existing treatment by nitazoxanide and paromomycin is effective in immunocompromised individuals. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer and malaria. A novel series of classical antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines have been evaluated as Cryptosporidium hominis thymidylate synthase (ChTS) inhibitors. Crystal structure in complex with the most potent compound, a 2'-chlorophenyl with a sulfur bridge with a Ki of 8.83±0.67 nM is discussed in terms of several Van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5-fluorodeoxyuridine monophosphate. Of these interactions, two interactions with the non-conserved residues (A287 and S290) offer an opportunity to develop ChTS specific inhibitors. Compound 6 serves as a lead compound for analog design and its crystal structure provides clues for the design of ChTS specific inhibitors.
Topics: Antiprotozoal Agents; Cryptosporidium; Crystallography, X-Ray; Enzyme Activation; Enzyme Inhibitors; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Pyrimidines; Pyrroles; Thymidylate Synthase
PubMed: 23927969
DOI: 10.1016/j.bmcl.2013.07.037 -
Chemistry, An Asian Journal Mar 2009The enzymatic incorporation of a series of emissive pyrimidine analogues into RNA oligonucleotides is explored. T7 RNA polymerase is challenged with accepting three...
The enzymatic incorporation of a series of emissive pyrimidine analogues into RNA oligonucleotides is explored. T7 RNA polymerase is challenged with accepting three non-natural, yet related, triphosphates as substrates and incorporating them into diverse RNA transcripts. The three ribonucleoside triphosphates differ only in the modification of their uracil nucleus and include a thieno[3,2-d]pyrimidine nucleoside, a thieno[3,4-d]pyrimidine derivative, and a uridine containing a thiophene ring conjugated at its 5-position. All thiophene-containing uridine triphosphates (UTPs) get incorporated into RNA oligonucleotides at positions that are remote to the promoter, although the yields of the transcripts vary compared with the transcript obtained with only native triphosphates. Among the three derivatives, the 5-modified UTP is found to be the most "polymerase-friendly" and is well accommodated by T7 RNA polymerase. Although the fused thiophene analogues cannot be incorporated next to the promoter region, the 5-modified non-natural UTP gets incorporated near the promoter (albeit in relatively low yields) and even in multiple copies. Labeling experiments shed light on the mediocre incorporation of the fused analogues, suggesting the enzyme frequently pauses at the incorporation position. When incorporation does take place, the enzyme fails to elongate the modified oligonucleotide and yields aborted transcripts. Taken together, these results highlight the versatility and robustness, as well as the scope and limitation, of T7 RNA polymerase in accepting and incorporating reporter nucleotides into modified RNA transcripts.
Topics: Base Sequence; DNA-Directed RNA Polymerases; Fluorescent Dyes; Isotope Labeling; Oligonucleotides; Pyrimidine Nucleotides; Ribonucleotides; Substrate Specificity; Transcription, Genetic; Uridine Triphosphate; Viral Proteins
PubMed: 19072942
DOI: 10.1002/asia.200800370 -
Journal of Controlled Release :... Jan 2019Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity,...
Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab' conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholino oligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization.
Topics: Antigens, CD20; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Deoxycytidine; Docetaxel; Drug Resistance, Neoplasm; Epirubicin; Humans; Pyrimidines; Serum Albumin, Human; Gemcitabine
PubMed: 30465822
DOI: 10.1016/j.jconrel.2018.11.015 -
Biochemical Pharmacology Mar 2021The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the...
The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the treatment of cardiovascular, gastrointestinal, and metabolic disorders. However, no non-peptidic molecules targeting this receptor have yet been disclosed. Using a high-throughput screening campaign directed at SCTR to identify small molecule modulators, we have identified three structurally related scaffolds positively modulating SCTRs. Here we outline a comprehensive study comprising a structure-activity series based on commercially available analogs of the three hit scaffold sets A (2-sulfonyl pyrimidines), B (2-mercapto pyrimidines) and C (2-amino pyrimidines), which revealed determinants of activity, cooperativity and specificity. Structural optimization of original hits resulted in analog B2, which substantially enhances signaling of truncated secretin peptides and prolongs residence time of labeled secretin up to 13-fold in a dose-dependent manner. Furthermore, we found that investigated compounds display structural similarity to positive allosteric modulators (PAMs) active at the glucagon-like peptide-1 receptor (GLP-1R), and we were able to confirm cross-recognition of that receptor by a subset of analogs. Studies using SCTR and GLP-1R mutants revealed that scaffold A, but not B and C, likely acts via two distinct mechanisms, one of which constitutes covalent modification of Cys-347 known from GLP-1R-selective modulators. The scaffolds identified in this study might not only serve as novel pharmacologic tools to decipher SCTR- or GLP-1R-specific signaling pathways, but also as structural leads to elucidate allosteric binding sites facilitating the future development of orally available therapeutic approaches targeting these receptors.
Topics: Allosteric Regulation; Amino Acid Sequence; Animals; CHO Cells; Cell Line, Tumor; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Protein Binding; Pyrimidines; Rats; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Structure-Activity Relationship
PubMed: 33545115
DOI: 10.1016/j.bcp.2021.114451 -
Journal of Enzyme Inhibition and... Dec 2020Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling...
Design, synthesis and biological evaluation of a new thieno[2,3-]pyrimidine-based urea derivative with potential antitumor activity against tamoxifen sensitive and resistant breast cancer cell lines.
Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-]pyrimidine based urea derivative, . It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Structure-Activity Relationship; Tamoxifen; Urea
PubMed: 32781854
DOI: 10.1080/14756366.2020.1804383 -
Molecules (Basel, Switzerland) Aug 2017A series of pyrimidine derivatives - were synthesized and evaluated for their binding affinities towards 5-HT receptors. With regard to designed molecules -, the...
A series of pyrimidine derivatives - were synthesized and evaluated for their binding affinities towards 5-HT receptors. With regard to designed molecules -, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT binding affinity and selectivity was studied. The most promising diasteromeric mixtures and were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols and , prepared by an enzymatic kinetic resolution. Pyrimidine analogue ()- displayed an excellent 5-HT binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes.
Topics: Animals; CHO Cells; Cricetulus; Models, Molecular; Molecular Structure; Pyrimidines; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Structure-Activity Relationship
PubMed: 28846591
DOI: 10.3390/molecules22091416