Mammalian cells replicate ~ 3 × 109 base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint ...kinase ataxia‐telangiectasia‐and‐RAD3‐related (ATR). Proteolysis‐targeting‐chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non‐catalytic functions of enzymes. This work defines the first‐in‐class ATR PROTAC, Abd110/Ramotac‐1. It is derived from the ATR inhibitor VE‐821 and recruits the E3 ubiquitin‐ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti‐leukemic effects of the clinically used ribonucleotide reductase‐2 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE‐821 against human primary leukemic cells but spares normal primary immune cells. CRISPR‐Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild‐type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti‐leukemic effects of an ATR PROTAC.
Hydroxyurea depletes the cellular dNTP pools and causes DNA replication stress. The checkpoint kinase ATR protects cells from DNA replication catastrophe and apoptosis upon drug‐induced DNA replication stress. In leukemic cells from various origins, the PROTAC Abd110/Ramotac‐1, which is based on the ATR inhibitor VE‐821 and the E3 ubiquitin‐ligase component CRBN, exerts synergistically lethal effects with hydroxyurea.
A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity ...toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC50 = 56 nM) and 9n against MOLT-4 (IC50 = 80 nM), more potent than monastrol (IC50 = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
A series of dihydropyrimidines (DHPMs) bearing 1,3,4-oxadiazole moiety were designed and synthesized as monastrol analogues. Compound 9i, 9k, 9m and 9n possessed significant activity against HL-60(TB) and MOLT-4 compared to monastrol. Display omitted
•A series of DHPM derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues.•Thirteen compounds were subjected to in vitro NCI antitumor screening at a single dose of 10 μM concentration.•IC50 of the most potent compounds were evaluated against leukemia HL-60(TB) and MOLT-4 cancer cell lines.•Four compounds showed potent activity against HL-60(TB) and MOLT-4 compared to monastrol.
The Ataxia telangiectasia and RAD3-related (ATR) kinase is a key regulator of DNA replication stress responses and DNA-damage checkpoints. Several potent and selective ATR inhibitors are reported and ...four of them are currently in clinical trials in combination with radio- or chemotherapy. Based on the idea of degrading target proteins rather than inhibiting them, we designed, synthesized and biologically characterized a library of ATR-targeted proteolysis targeting chimera (PROTACs). Among the synthesized compounds, the lenalidomide-based PROTAC 42i was the most promising. In pancreatic and cervix cancer cells cancer cells, it reduced ATR to 40 % of the levels in untreated cells. 42i selectively degraded ATR through the proteasome, dependent on the E3 ubiquitin ligase component cereblon, and without affecting the associated kinases ATM and DNA-PKcs. 42i may be a promising candidate for further optimization and biological characterization in various cancer cells.
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•A library of ATR PROTACs was synthesized based on three selective ATR inhibitors.•Lenalidomide based PROTAC 42i (Abd110) showed degradation of ATR in pancreatic cancer cells MIA PaCa-2.•42i (Abd110) selectively decreases ATR and phospho-ATR without affecting related kinases ATM and DNA-PKcs.•Proteasome inhibitors and CRBN knock-down prevent 42i (Abd110) mediated depletion of ATR.
Tenoxicam (TX) is a non-steroidal anti-inflammatory agent that can be used to control pain in various ophthalmic lesions like cataracts, refractive surgery, and corneal abrasion. TX has a very ...slightly aqueous solubility of 0.072 mg/mL resulting in difficulty to be formulated in ophthalmic solutions. This study aims to improve TX solubility by converting it into its potassium salt to achieve a target of 10 mg/mL (1%w/v) concentration of TX in the desired aqueous medium for the formulation of aqueous ophthalmic solutions. The synthesized TX salt was characterized by different evaluation parameters such as solubility studies,
1
H NMR, IR, and elemental analyses. Different TX potassium solutions were formulated at concentrations of 0.5% and 1% w/v using different viscosity-imparting agents. The prepared solutions were characterized for their physicochemical properties including visual inspection, pH, rheological,
in vitro
release, and kinetic behavior. Also, the formulations were biologically evaluated
in vivo
using male albino rabbits. The obtained results showed the successful synthesis of TX salt, as indicated by IR and NMR, and elemental analysis. The solubility study showed that the solubility of TX was improved hugely to 18 mg/mL (250-fold). In addition, the results showed that the prepared formulations showed acceptable physicochemical properties. The highest release rate was obtained with formula F1, which contains no viscosity-imparting agents. While as, the lowest release rate was obtained in the case of formula F9, composed of Pluronic F127 (12% w/v). The
in vivo
results showed that TX optimized ophthalmic solutions F8 and F9 inhibited the redness and edema in an extended or sustained manner.
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•Pyrimidine-5-carbonitrile hybrids were designed and synthesized as COX-2 inhibitors.•All compounds were in vitro evaluated for their COX-1/COX-2 inhibitory activity.•Nine compounds ...were found to be the most potent and selective inhibitors of COX-2.•10c, 10j and 14e displayed superior in vivo anti-inflammatory activity than celecoxib.•GIT safety was also confirmed by ulcerogenic liability, and histopathological studies.
Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041–0.081 μM, SI 139.74–321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3–48.3, 1 h; 58.4–60.5, 2 h; 70.8–83.2, 3 h; 78.9–89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.
In the title molecule, C23H20Cl2N4O3S, the thiazole ring is planar while the pyrimidine unit fused to it adopts a screw-boat conformation. In the crystal, thick sheets parallel to the bc plane are ...formed by N—H...N, C—H...N and C—H...O hydrogen bonds together with π–π interactions between the formamido carbonyl groups and the thiazole rings. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (30.9%), Cl...H/H...Cl (20.7%), C...H/H...C (16.8%) and O...H/H...O (11.4%) interactions.
In the title compound, C24H23FN4O4S·0.25H2O, the dihydropyrimidine ring is distinctly non-planar, with the flap C atom deviating by 0.297 (2) Å from the least-squares plane. In the crystal, zigzag ...chains are formed by N—H...N hydrogen bonds parallel to 010 and are connected into layers parallel to (100) by O—H...O, O—H...F, C—H...O, C—H...F and C—H...N hydrogen bonds. Additional C—H...O hydrogen bonds connect the layers into a three-dimensional network. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from H...H (42.6%), O...H/H...O (16.8%) and C...H/H...C (15.5%) contacts.
•A new tetrahydroisoquinoline derivatives were synthesized.•X-ray diffraction, FT-IR, and NMR were applied to solve the molecular structure.•DFT calculations were performed to confirm experimental ...data.•NBO analysis explains the formation of H bonding interaction.•Both compounds exhibit considerable NLO character.
Efficient synthesis of biologically active molecules is one of the main objectives of organic and medicinal chemistry. In this context, thiazolopyrimidine derivatives were synthesized in good yield (average 84%). The molecular docking studies suggest that the two derivatives 3a and 3b of the thiazolopyrimidines have good binding affinity towards adenosine receptors (ARs) (Thermostabilised HUMAN A2a) complex. To probe intermolecular interactions DFT (NBO/NLO/QTAIM) calculations were performed. In addition, an ADMET analysis has been performed and discussed for both compounds. The results suggest that both compounds could exhibit a strong binding affinity for the thermostabilized human A2a receptor complex.
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In the title compound, C
24
H
23
FN
4
O
4
S·0.25H
2
O, the dihydropyrimidine ring is distinctly non-planar, with the flap C atom deviating by 0.297 (2) Å from the least-squares plane. In the crystal, ...zigzag chains are formed by N—H...N hydrogen bonds parallel to 010 and are connected into layers parallel to (100) by O—H...O, O—H...F, C—H...O, C—H...F and C—H...N hydrogen bonds. Additional C—H...O hydrogen bonds connect the layers into a three-dimensional network. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from H...H (42.6%), O...H/H...O (16.8%) and C...H/H...C (15.5%) contacts.
In the title compound, C24H23FN4O4S·0.25H2O, the di-hydro-pyrimidine ring is distinctly non-planar, with the flap C atom deviating by 0.297 (2) Å from the least-squares plane. In the crystal, zigzag ...chains are formed by N-H⋯N hydrogen bonds parallel to 010 and are connected into layers parallel to (100) by O-H⋯O, O-H⋯F, C-H⋯O, C-H⋯F and C-H⋯N hydrogen bonds. Additional C-H⋯O hydrogen bonds connect the layers into a three-dimensional network. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from H⋯H (42.6%), O⋯H/H⋯O (16.8%) and C⋯H/H⋯C (15.5%) contacts.In the title compound, C24H23FN4O4S·0.25H2O, the di-hydro-pyrimidine ring is distinctly non-planar, with the flap C atom deviating by 0.297 (2) Å from the least-squares plane. In the crystal, zigzag chains are formed by N-H⋯N hydrogen bonds parallel to 010 and are connected into layers parallel to (100) by O-H⋯O, O-H⋯F, C-H⋯O, C-H⋯F and C-H⋯N hydrogen bonds. Additional C-H⋯O hydrogen bonds connect the layers into a three-dimensional network. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from H⋯H (42.6%), O⋯H/H⋯O (16.8%) and C⋯H/H⋯C (15.5%) contacts.
