Month: November 2022

Yan, Luping published the artcileStructure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer, Quality Control of 343338-28-3, the main research area is marine sintokamide androgen receptor antagonist prostate cancer antitumor preparation.

Synthetic analogs of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogs. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogs missing the nonchlorinated Me groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogs with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. The tetramic acid fragment and the Me ether on the tetramic acid fragment are essential for activity. The SAR optimized analog 76 is more selective, easier to synthesize, more potent, and presumed to be more resistant to proteolysis than the natural sintokamides.

Journal of Natural Products published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Quality Control of 343338-28-3.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Boskovic, Zarko V. published the artcileSynthesis of piperlogs and analysis of their effects on cells, Related Products of amides-buliding-blocks, the main research area is piperlog preparation antitumor structure activity; reactive oxygen species level piperlog; piperlongumine analog preparation antitumor structure activity; Michael acceptors; piperlongumine; reactive oxygen species; toxicity.

Piperlongumine (PL) (I) is a naturally occurring small mol. previously shown to induce cell death preferentially in cancer cells relative to non-cancer cells. An initial effort to synthesize analogs highlighted the reactivities of both of piperlongumine’s α,β-unsaturated imide functionalities as key features determining PL’s cellular effects. In this study, a second-generation of analogs, e.g., II, was synthesized and evaluated in cells to gain further insight into how the reactivity, number, and orientation of PL’s reactive olefins contribute to its ability to alter the physiol. of cells.

Tetrahedron published new progress about Antitumor agents. 10405-38-6 belongs to class amides-buliding-blocks, name is N,N’-(Butane-1,4-diyl)diacrylamide, and the molecular formula is C10H16N2O2, Related Products of amides-buliding-blocks.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Chand, Apramita published the artcileHydrogen bonding structure and dynamics of cis- and trans- conformers of N-methylformamide in water, DMSO and water-DMSO mixtures at varying compositions, Safety of N-Methylformamide, the main research area is methylformamide water DMSO mixture composition hydrogen bonding structure.

The local hydrogen bonding structure and dynamics of cis- and trans- N-methylformamide (NMF) in water, DMSO and in water-DMSO mixture is investigated by classical mol. dynamics simulations. We have considered five different concentrations of NMF in water as well as in DMSO at 298 K. In the case of NMF (XNMF = 0.20) in water-DMSO mixtures, we have considered six different concentrations, varying from NMF in pure water to DMSO. It is observed that the donating ability of amide-hydrogen of NMF to the oxygen of DMSO is higher compared to the oxygen of water. The variation of DMSO shows negligible effects on the HNMF…ODMSO radial distribution function (RDF), whereas the HNMF…OWAT decreases with the addition of water to the solution In the case of NMF in water-DMSO mixtures, the addition of DMSO strengthens the HNMF…ODMSO as well as HNMF…OWAT correlation, but it differently affects for cis- and trans- NMF in the solution DMSO prefers cis- conformer, whereas water prefers trans- NMF. In NMF-water-DMSO mixtures, the addition of DMSO strengthens HWAT…ONMF up to intermediate DMSO concentration, but at very high DMSO concentration, it decreases due to preferable HNMF…ODMSO interaction. The probability of hydrogen bonding between NMF-NMF is higher in NMF-DMSO solution compared to NMF-water. The dynamical slowdown is observed for all the species in water-NMF mixtures at intermediate concentration, whereas in the case of NMF-DMSO solution, faster dynamics are observed with the addition of DMSO. For NMF in water-DMSO mixtures, the dynamical slowdown is observed as DMSO is added to the NMF-water solution Our calculated hydrogen-bond lifetime suggested that the DMSO forms a stronger hydrogen bond with cis-NMF whereas water generally prefers trans-NMF.

Journal of Molecular Liquids published new progress about Antitumor agents. 123-39-7 belongs to class amides-buliding-blocks, name is N-Methylformamide, and the molecular formula is C2H5NO, Safety of N-Methylformamide.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Futaki, Kentaro published the artcileSynthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein-Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1-C9 Macrolactone Part and the C24-C34 Side Chain, Synthetic Route of 123-39-7, the main research area is aplyronine A analog preparation antitumor protein protein interaction inducer; structure activity aplyronine A analog protein protein interaction inducer.

Aplyronine A (ApA) is an antitumor marine macrolide that induces protein-protein interaction (PPI) between actin and tubulin. The C1-C9 macrolactone part including the C7 N,N,O-trimethylserine (TMSer) ester is important for its highly potent activities. To develop new antitumor PPI inducers, four aplyronine analogs were synthesized, which bear the C1-C9 macrolactone part with 0-2 TMSer ester(s) and the C24-C34 actin-binding side-chain. Despite exhibiting potent actin-depolymerizing activity comparable to that of ApA, these analogs did not show potent cytotoxicity or depolymerize microtubules. Mol. modeling studies suggested that the whole macrolactone moiety of aplyronines was important to fix the conformation of the C7 TMSer ester moiety, while the linear C1-C9 part was insufficient. Still, our study newly proposed that fixed conformations of the C7 or C9 TMSer esters in aplyronines that protrude from the actin surface are important for binding to tubulin and inhibit microtubule dynamics.

ACS Omega published new progress about Antitumor agents. 123-39-7 belongs to class amides-buliding-blocks, name is N-Methylformamide, and the molecular formula is C2H5NO, Synthetic Route of 123-39-7.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Farand, Julie published the artcileDiscovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation, Product Details of C2H3F2NO, the main research area is antitumor drug target MTH1 inhibitor preparation tetrahydro naphthyridine derivative.

We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncol. target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystn. of 5 with MTH1 revealed the ligand in a Φ-cis-N-(pyridin-2-yl)acetamide conformation enabling a key intramol. hydrogen bond and polar interactions with residues Gly34 and Asp120. Modification of literature compound TH287 with O- and N-linked aryl and alkyl aryl substituents led to the discovery of potent pyrimidine-2,4,6-triamine 25 (IC50 = 0.49 nM). Triazolopyridine 32 emerged as a highly selective lead compound with a suitable in vitro profile and desirable pharmacokinetic properties in rat. Elucidation of the DNA damage response, cell viability, and intracellular concentrations of oxo-NTPs (oxidized nucleoside triphosphates) as a function of MTH1 knockdown and/or small mol. inhibition was studied. Based on our findings, we were unable to provide evidence to further pursue MTH1 as an oncol. target.

ACS Medicinal Chemistry Letters published new progress about Antitumor agents. 359-38-6 belongs to class amides-buliding-blocks, name is 2,2-Difluoroacetamide, and the molecular formula is C2H3F2NO, Product Details of C2H3F2NO.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Heightman, Tom D. published the artcileDiscovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2, Product Details of C4H11NOS, the main research area is solid tumors ERK inhibitors ASTX029 clin metabolism physicochem pharmacokinetic.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clin. trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clin. candidate ASTX029 (15)(I) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chem. campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochem. properties. These efforts led to the identification of ASTX029, which showed the desired pharmacol. profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclin. pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clin. trial in patients with advanced solid tumors.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Product Details of C4H11NOS.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Shukla, Manojkumar R. published the artcileDiscovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models, Related Products of amides-buliding-blocks, the main research area is anticancer PI3K delta inhibitor DLBCL cell pharmacokinetic bioavailability iNHL.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a “”three-blade propeller”” shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel “”four-blade propeller”” shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 (I)has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Related Products of amides-buliding-blocks.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Blaszczyk, Roman published the artcileDiscovery and Pharmacokinetics of Sulfamides and Guanidines as Potent Human Arginase 1 Inhibitors, Synthetic Route of 343338-28-3, the main research area is arginase inhibitor pharmacokinetics sulfamide guanidine cancer immunotherapy.

We designed and synthesized a series of arginase inhibitors as derivatives of the well-known 2-(S)-amino-6-boronohexanoic acid (ABH) with basic and neutral side chains in the α-position relative to the amino acid group. In an effort to improve the pharmacokinetic profile of literature examples and retain potent enzymic activity, sulfamido moieties were introduced to generate hydrogen bond interaction with the aspartic acid residue in the arginase active site. The compounds with basic guanidine-containing side chains were even more potent arginase inhibitors. Both groups of compounds, as designed, demonstrated low clearance in their pharmacokinetic profile. The most active inhibitor 15aa showed high nanomolar potency with IC50 = 32 nM toward human arginase 1 and demonstrated low clearance (4.2 mL/min/kg), long t1/2, and moderate volume of distribution in rat pharmacokinetic studies.

ACS Medicinal Chemistry Letters published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Synthetic Route of 343338-28-3.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Karim, Rezaul Md published the artcileDiscovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain, Application In Synthesis of 343338-28-3, the main research area is AZD6738 pyrrolopyridine synthesis anticancer SAR ATR kinase bromodomain TAF1.

Bromodomains regulate chromatin remodeling and gene transcription through recognition of acetylated lysines on histones and other proteins. Bromodomain-containing protein TAF1, a subunit of general transcription factor TFIID, initiates preinitiation complex formation and cellular transcription. TAF1 serves as a cofactor for certain oncogenic transcription factors and is implicated in regulating the p53 tumor suppressor. Therefore, TAF1 is a potential target to develop small mol. therapeutics for diseases arising from dysregulated transcription, such as cancer. Here, we report the ATR kinase inhibitor AZD6738 (Ceralasertib) and analogs thereof as bona fide inhibitors of TAF1. Crystallog. and small-angle X-ray scattering studies established that newly identified and previously reported inhibitors stabilize distinct structural states of the TAF1 tandem bromodomain through “”open-closed”” transitions and dimerization. Combined with functional studies on p53 signaling in cancer cell lines, the data provide new insights into the feasibility and challenges of TAF1 inhibitors as chem. probes and therapeutics.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Application In Synthesis of 343338-28-3.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics

Cao, Hengyi published the artcileDiscovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration, Formula: C4H11NOS, the main research area is glioblastoma antitumor pharmacokinetics isocitrate dehydrogenase 1 blood brain barrier; Acute myeloid leukemia; Blood-brain barrier; Cancer therapy; Glioblastoma; Isocitrate dehydrogenase 1; Small molecule inhibitors.

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5, (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(7-(trifluoromethyl)4,5-dihydroimidazo[1,5-a]quinolin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one [2379528-08-0], exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclin. candidate to treat IDH1-mutant brain tumors.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 343338-28-3 belongs to class amides-buliding-blocks, name is (S)-2-Methylpropane-2-sulfinamide, and the molecular formula is C4H11NOS, Formula: C4H11NOS.

Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics