Day: December 5, 2022

Wang, Ziqian published the artcileBcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics, COA of Formula: C16H12N2O2, the publication is Journal of Medicinal Chemistry (2016), 59(7), 3152-3162, database is CAplus and MEDLINE.

No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, the authors extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, the authors constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, compound I that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.

Journal of Medicinal Chemistry published new progress about 13599-22-9. 13599-22-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Carboxylic acid,Benzene, name is 1,5-Diphenyl-1H-pyrazole-3-carboxylic acid, and the molecular formula is C15H12O8, COA of Formula: C16H12N2O2.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Chen, Dizhong published the artcileDesign, Synthesis, and Preclinical Evaluation of Fused Pyrimidine-Based Hydroxamates for the Treatment of Hepatocellular Carcinoma, Safety of 1H-Pyrazole-4-boronic acid, the publication is Journal of Medicinal Chemistry (2018), 61(4), 1552-1575, database is CAplus and MEDLINE.

Class I histone deacetylases (HDACs) are highly expressed and/or upregulated in hepatocellular carcinoma (HCC) and are associated with aggressiveness, spread, and increased mortality of HCC. Activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway was involved in the development of HCC and acquired resistance to sorafenib. A series of purine or 5H-pyrrolo[3,2-d]pyrimidine based hydroxamates were designed and developed as multitarget drugs to modulate both HDACs and the PI3K/Akt/mTOR pathway. Among 39 cell lines screened, the mols. (e.g., I, II, and III) were the most selective against leukemia, lymphoma, and HCC cells; they also demonstrated target modulation in cancer cell lines and in mice bearing MV4-11 and HepG2 tumors. Compound II in particular showed significant single agent oral efficacy in hypervascular liver cancer models (e.g., HepG2, HuH-7, and Hep3B) and was well-tolerated. These encouraging results, along with its favorable target profile and tissue distribution, warrant further development of II.

Journal of Medicinal Chemistry published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C3H5BN2O2, Safety of 1H-Pyrazole-4-boronic acid.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Chen, Zicong published the artcilePalladium-Phenylpyrazolylphosphine-Catalyzed Cross-Coupling of Alkenyl Pivalates, SDS of cas: 930-36-9, the publication is Asian Journal of Organic Chemistry (2021), 10(4), 776-779, database is CAplus.

A new type of easily accessible phenylpyrazole phosphine ligand was developed. The catalyst generated from Pd(OAc)₂ and PP-Phos was highly effective in the palladium-catalyzed cross-coupling of alkenyl pivalates with organomagnesium reagents. The reaction accommodated a broad scope of alkenyl carboxylates under mild conditions, providing an alternative but practical way to the synthesis of multi-substituted alkenes, e.g., I in value.

Asian Journal of Organic Chemistry published new progress about 930-36-9. 930-36-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole, name is 1-Methylpyrazole, and the molecular formula is C4H6N2, SDS of cas: 930-36-9.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Caffo, Lindy published the artcileSimvastatin and ML141 Decrease Intracellular Streptococcus pyogenes Infection, Synthetic Route of 71203-35-5, the publication is Current Pharmaceutical Biotechnology (2019), 20(9), 733-744, database is CAplus and MEDLINE.

To determine whether simvastatin, a therapeutic approved for use in the treatment of hypercholesterolemia, and ML141, a first-in-class small mol. inhibitor with specificity for human CDC42, limit host cell invasion by S. pyogenes. Assays to assess host cell invasion, bactericidal activity, host cell viability, actin depolymerization, and fibronectin binding were performed using the RAW 267.4 macrophage cell line and Human Umbilical Vein Endothelial Cells (HUVEC) infected with S. pyogenes (90-226) and treated with simvastatin, ML141, structural analogs of ML141, or vehicle control. Simvastatin and ML141 decreased intracellular infection by S. pyogenes in a dose-dependent manner. Inhibition by simvastatin persisted following 1 h washout whereas inhibition by ML141 was reversed. During S. pyogenes infection, actin stress fibers depolymerized in vehicle control treated cells, yet remained intact in simvastatin and in ML141 treated cells. Consistent with the previous characterization of ML141, simvastatin decreased host cell binding to fibronectin. Structural analogs of ML141, designated as the RSM series, decreased intracellular infection through non-cytotoxic, nonbactericidal mechanisms. Our findings demonstrate the potential of repurposing simvastatin and of developing CDC42-targeted therapeutics for eradicating intracellular S. pyogenes infection to break the cycle of recurrent infection through a host-directed approach.

Current Pharmaceutical Biotechnology published new progress about 71203-35-5. 71203-35-5 belongs to pyrazoles-derivatives, auxiliary class GPCR/G Protein,Ras, name is 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, and the molecular formula is C22H21N3O3S, Synthetic Route of 71203-35-5.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Britton, Luke published the artcileManganese-Catalyzed C(sp²)-H Borylation of Furan and Thiophene Derivatives, Category: pyrazoles-derivatives, the publication is ACS Catalysis (2021), 11(12), 6857-6864, database is CAplus.

Aryl boronic esters are bench-stable, platform building-blocks that can be accessed through metal-catalyzed aryl C(sp²)-H borylation reactions. C(sp²)-H bond functionalization reactions using rare- and precious-metal catalysts are well established, and while examples using Earth-abundant alternatives have emerged, Mn catalysis remains lacking. The Mn-catalyzed C-H borylation of furan and thiophene derivatives is reported alongside an in situ activation method providing facile access to the active Mn hydride species. Mechanistic studies showed that blue light irradiation directly affected catalysis by action at the metal center, that C(sp²)-H bond borylation occurs through a C-H metalation pathway, and that the reversible coordination of pinacolborane to the catalyst gave a Mn borohydride complex, which was as an off-cycle resting state.

ACS Catalysis published new progress about 930-36-9. 930-36-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole, name is 1-Methylpyrazole, and the molecular formula is C4H6N2, Category: pyrazoles-derivatives.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Gharbaoui, Tawfik published the artcileAgonist lead identification for the high affinity niacin receptor GPR109a, Safety of 3-Isopropyl-1H-pyrazole-5-carboxylic acid, the publication is Bioorganic & Medicinal Chemistry Letters (2007), 17(17), 4914-4919, database is CAplus and MEDLINE.

A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.

Bioorganic & Medicinal Chemistry Letters published new progress about 890590-91-7. 890590-91-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Carboxylic acid, name is 3-Isopropyl-1H-pyrazole-5-carboxylic acid, and the molecular formula is C7H10N2O2, Safety of 3-Isopropyl-1H-pyrazole-5-carboxylic acid.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Sagar, Satish published the artcileStructure activity relationship (SAR) study identifies a quinoxaline urea analog that modulates IKKβ phosphorylation for pancreatic cancer therapy, Application of 1-Methylpyrazole, the publication is European Journal of Medicinal Chemistry (2021), 113579, database is CAplus and MEDLINE.

Genetic models validated Inhibitor of nuclear factor (NF) kappa B kinase beta (IKKβ) as a therapeutic target for KRAS mutation associated pancreatic cancer. Phosphorylation of the activation loop serine residues (S177, S181) in IKKβ is a key event that drives tumor necrosis factor (TNF) α induced NF-κB mediated gene expression. Here we conducted structure activity relationship (SAR) study to improve potency and oral bioavailability of a quinoxaline analog 13-197 that was previously reported as a NFκB inhibitor for pancreatic cancer therapy. The SAR led to the identification of a novel quinoxaline urea analog 84 that reduced the levels of p-IKKβ in dose- and time-dependent studies. When compared to 13-197, analog 84 was âˆ?.5-fold more potent in TNFα-induced NFκB inhibition and âˆ?-fold more potent in inhibiting pancreatic cancer cell growth. Analog 84 exhibited âˆ?.3-fold greater exposure (AUC0-âˆ? resulting in âˆ?.7-fold increase in oral bioavailability (%F) when compared to 13-197. Importantly, oral administration of 84 by itself and in combination of gemcitabine reduced p-IKKβ levels and inhibited pancreatic tumor growth in a xenograft model.

European Journal of Medicinal Chemistry published new progress about 930-36-9. 930-36-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole, name is 1-Methylpyrazole, and the molecular formula is C4H6N2, Application of 1-Methylpyrazole.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Xu, Jing published the artcileMolecular Mechanisms of the Blockage of Glioblastoma Motility, Name: 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, the publication is Journal of Chemical Information and Modeling (2021), 61(6), 2967-2980, database is CAplus and MEDLINE.

Glioblastoma (GBM) is the most common and lethal brain tumor. GBM has a remarkable degree of motility and is able to infiltrate the healthy brain. In order to perform a rationale-based drug-repositioning study, we have used known inhibitors of two small Rho GTPases, Rac1 and Cdc42, which are upregulated in GBM and are involved in the signaling processes underlying the orchestration of the cytoskeleton and cellular motility. The selected inhibitors (R-ketorolac and ML141 for Cdc42 and R-ketorolac and EHT 1864 for Rac1) have been successfully employed to reduce the infiltration propensity of GBM in live cell imaging studies. Complementarily, all-atom simulations have elucidated the mol. basis of their inhibition mechanism, identifying the binding sites targeted by the inhibitors and dissecting their impact on the small Rho GTPases�function. Our results demonstrate the potential of targeting the Rac1 and Cdc42 proteins with small mols. to contrast GBM infiltration growth and supply precious information for future drug discovery studies aiming to fight GBM and other infiltrative cancer types.

Journal of Chemical Information and Modeling published new progress about 71203-35-5. 71203-35-5 belongs to pyrazoles-derivatives, auxiliary class GPCR/G Protein,Ras, name is 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide, and the molecular formula is C14H26O2, Name: 4-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Finar, I. L. published the artcileReaction between aroylacetones and arylhydrazines, Formula: C16H12N2O2, the publication is Journal of the Chemical Society (1958), 200-4, database is CAplus.

PhNHNH₂ and ο-, m-, and p-nitrobenzoylacetones react to form only 5-ο-, -m-, and -p-nitrophenyl-3-methyl-1-phenylpyrazoles (I), 3,1,-5-MePh(x-O₂NC₆H₄)C₃HN₂, whereas BzCH₂Ac and 2,4-(O₂N)₂C₆H₃NHNH₂ give both 1-(2,4-dinitrophenyl)-3-methyl-5-phenylpyrazole (II) and 1-(2,4-dinitrophenyl)-5-methyl-3-phenylpyrazole (III). The orientation of I (x = 3 or 4) (IIIa, IIIb) was established by reduction to the amine, diazotization, and treatment with H₃PO₂ to give 3-methyl-1,5-diphenylpyrazole (IV). Similar treatment of I (x = 2) (IVa) gave 3-methyl-1-phenyl-1H-pyrazolo[4,5-c]cinnoline (V) instead of the expected methyldiphenylpyrazole. To prevent the formation of V, IVa was converted into the 4-Br derivative Reduction to the amine, followed by diazotization and treatment of the diazonium salt (VI) with H₃PO₂ gave 4-bromo-3-methylpyrazolo[1,2-d]phenanthridine (VII). Oxidation of IV by boiling with KMnO₄ in dilute C₅H₅N gave authentic 1,5-diphenylpyrazole-3-carboxylic acid. PhNHNH₂ (1.3 g.) and 2.35 g. ο-O₂NC₆H₄COCH₂Ac heated 10 min. in alc. at 35-40° gave 3.17 g. yellow phenylhydrazone (IX), m. 156° (cf. Koenigs and Freund, C.A. 42, 1935h). Heating 10 g. diketone in alc. with 5.4 g. PhNHNH₂ in alc. on a steam bath 5 min. gave 6.4 g. of another form of the phenylhydrazone (IXa), m. 136°, together with 7.5 g. IVa. Colorless IXa boiled in alc. and the solution cooled quickly gave IX. Both IX and IXa heated in alc. on a steam bath or recrystallized from CHCl₃, AcOH, or C₆H₆ slowly formed IVa. PhNHNH₂ (1.2 g.) and 2.3 g. m-O₂NC₆H₄COCH₂Ac refluxed 3 hrs. in alc. yielded 93% IIIa, m. 102-3°. Condensation of p-O₂NC₆H₄COCl with AcCH₂CO₂Et in the presence of NaOMe in MeOH by an adaptation of the method of Bülow and Hailer [Ber. 35, 932(1902)], dilution of the mixture with ice H₂O, filtration, pouring the filtrate into cold AcOH, and extraction with Et₂O yielded 48% p-O₂NC₆H₄COCH₂CO₂Et, converted according to Knorr and Jödicke [Ber. 18, 2259(1885)] to 3-methyl-5-(p-nitrophenyl)-1-phenylpyrazole-4-carboxylic acid (X), m. 210°, and transformed by heating 3 hrs. at 240-50° to IIIb, m. 111-12°, also obtained in 36% yield by refluxing 2.0 g. p-O₂NC₆H₄COCH₂Ac and 1.1 g. PhNHNH₂ in alc. BzCH₂Ac (20 g.) in alc. and 16 g. 2,4-(O₂N)₂C₆H₃NHNH₂ in 32 ml. 98% H₂SO₄ and 350 ml. hot alc. heated 10 min. on a steam bath and the mixture decanted gave 15.3 g. II, m. 137° (alc. or AcOH). The decanted solution cooled and filtered yielded 2.1 g. III, m. 154° (alc. or AcOH). IVa, II, and III in AcOH treated with excess Br at room temperature and filtered, the precipitate taken up in CHCl₃, and the solution washed with aqueous Na₂CO₃ and H₂O gave 86, 93, and 91% of the corresponding 4-Br derivatives m. 141, 176, and 158°, resp. The nitro compounds IIIa, IIIb, and IVa (1 mole) in alc. heated 1 hr. on a steam bath with 8 moles SnCl₂ in concentrated HCl and the cooled solution made alk. with 30% NH₄OH, the amine extracted with Et₂O, and recrystallized (alc.) yielded the corresponding 5-aminophenyl-3-methyl-1-phenylpyrazoles (XI): m-amino (XIa), m. 161.5°; p-amino (XIb), m. 93°; ο-amino (XIc), m. 96°, also obtained as a better product, m. 99°, by heating 17.5 g. IVa in 10 ml. 60% N₂H₄.H₂O in alc. on a steam bath in the presence of 2 g. Pd-C. Similar reduction of 10 g. 4-Br derivative of IVa gave 5.1 g. 5-(ο-aminophenyl)-4-bromo-3-methyl-1-phenylpyrazole (XId), m. 135°. X was converted by the procedure of K. and J. (loc. cit.) to the corresponding 5-(p-aminophenyl)-3-methyl-1-phenylpyrazole-4-carboxylic acid (XIe), m. 261°. II (8 g.) in 500 ml. alc. and 15 ml. 30% NH₄OH saturated with H₂S heated 1 hr. on a steam bath and evaporated, the crystalline product (5.3 g.) taken up in concentrated HCl and filtered, the filtrate diluted with H₂O, and the precipitate crystallized gave 1-(4-amino-2-nitrophenyl)-3-methyl-5-phenylpyrazole (XII), m. 182° (alc.). III (1.4 g.) in 60 ml. alc. and 3 ml. 30% NH₄OH reduced with H₂S yielded 54% 1-(4-amino-2-nitrophenyl)-5-methyl-3-phenylpyrazole, m. 170° (alc. or ligroine). The aminophenylpyrazoles (0.6 g.) in 3 ml. concentrated HCl were diazotized 30 min. with 0.3 g. NaNO₂ in 0.5 ml. H₂O and the solution poured into 7 ml. 30% H₃PO₂. XIa and XIb both gave IV, characterized as its Br derivative m. 75°. XIe gave authentic 3-methyl-1,5-diphenyl-pyrazole-4-carboxylic acid, m. 205°. The product obtained by heating 4-chloroquinaldine with excess PhNHNH₂ in a sealed tube at 200° (K. and F., loc. cit.) was shown to be 3-(ο-aminophenyl)-5-methyl-1-phenylpyrazole (XIII) since it gave 5-methyl-1,3-diphenylpyrazole (picrate, m. 108°). XIc gave V, m. 216°, also obtained when the diazonium salt solution was heated with alc. and Gattermann Cu powder or with boiling 50% H₂SO₄, or was made alk. with NaOH solution XId was similarly converted through the diazonium salt VI to VII, m. 140°. XII gave red needles, m. 108°, by the above procedure but deaminating by addition of 1 g. XII, in 12 ml. AcOH to 0.3 g. NaNO₂ in 1.5 ml. concentrated H₂SO₄ at 5°, keeping the mixture 30 min. at 5°, heating 30 min. on a steam bath with 20 ml. alc., diluting with H₂O, and extracting with Et₂O gave authentic 3-methyl-1-(ο-nitrophenyl)-5-phenylpyrazole, m. 104°. Reduction of the aminophenylpyrazoles with Na and alc. and evaporation, solution in concentrated H₂SO₄, and addition of aqueous NaNO₂ according to the Knorr pyrazoline reaction procedure gave red color with XIa, XIb, XIc, and 1-(ο-aminophenyl)-3-methyl-5-phenylpyrazole (C.A. 51, 7357g), and a blue color with XIII.

Journal of the Chemical Society published new progress about 13599-22-9. 13599-22-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Carboxylic acid,Benzene, name is 1,5-Diphenyl-1H-pyrazole-3-carboxylic acid, and the molecular formula is C16H12N2O2, Formula: C16H12N2O2.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Lyalin, B. V. published the artcileOxidative transformation of N-substituted 3-aminopyrazoles to azopyrazoles using electrogenerated bromine as a mediator, Quality Control of 105675-85-2, the publication is Russian Chemical Bulletin (2018), 67(3), 510-516, database is CAplus.

The one-pot process of anodic transformation of N-alkyl-3-aminopyrazoles into azopyrazoles I [R¹ = H, Me, Et; R² = H, Me; R³ = Br, Me] under conditions of membraneless electrolysis in an aqueous solution of NaBr was studied for the first time. It was found that under these conditions the aminopyrazoles, which do not have a substituent at position 4, transform into the corresponding 4,4′-dibromoazopyrazoles. The corresponding yield was in the interval of 28-80%, depending on the structure of the products. The transformation of 4-substituted aminopyrazoles resulted in the formation of azopyrazoles in the yields lying within 62-86% when this process was implemented under conditions with the anodically generated Br₂ acting as a mediator. A convenient method of anodic synthesis of azopyrazoles in an aqueous medium without the use of additives of chem. oxidants was proposed. The process was environmentally sound and was characterized by a high atom efficiency (>85%).

Russian Chemical Bulletin published new progress about 105675-85-2. 105675-85-2 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Bromide,Amine, name is 4-Bromo-1-methyl-1H-pyrazol-5-amine, and the molecular formula is C4H6BrN3, Quality Control of 105675-85-2.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics