244052-68-4

Upstream product

• 104-94-9 4-methoxy-aniline 
• 127099-85-8 N-Cyanoguanidine 
• 67-64-1 acetone 
• 4053-50-3 6-methoxy-2,2,4-trimethyl-1,2-dihydro-quinoline 
• 127099-85-8 dicyandiamide 
• 4153-89-3 1,2-dihydro-2,2,4-trimethyl-6-methoxyquinoline hydrochloride 

Relevant academic research and scientific papers

Quinazolin-2-ylamino-quinazolin-4-ols as novel non-nucleoside inhibitors of bacterial DNA polymerase III

High throughput screening led to the discovery of a novel series of quinazolin-2-ylamino-quinazolin-4-ols as a new class of DNA polymerase III inhibitors. The inhibition of chromosomal DNA replication results in bacterial cell death. The synthesis, struct

Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors

We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A2B receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2′-amino-4′-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding Ki value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with Ki values in the micromolar range. Since no enhancement of A2B receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched.

Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization

The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

COMPOUNDS TARGETING DUAL G-QUADRUPLEX DNA AND STAT3

The present invention relates to novel quinazoline compounds having the formula (I) or (II): (I) (II). The compounds are active both as stabilizers of G-quadruplex DNA structures and as inhibitors of STAT3 phosphorylation. The disclosed compounds are useful in medical treatment, such as the treatment of cancer.

New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2)

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes resistance to TOP2-targeted cancer therapy. Inhibiting TDP2 could sensitize cancer cells toward TOP2 inhibitors. However, potent TDP2 inhibitors with favorable physicochemical properties are not yet reported. Therefore, there is a need to search for novel molecular scaffolds capable of inhibiting TDP2. We report herein a new simple, robust, homogenous mix-and-read fluorescence biochemical assay based using humanized zebrafish TDP2 (14M_zTDP2), which provides biochemical and molecular structure basis for TDP2 inhibitor discovery. The assay was validated by screening a preselected library of 1600 compounds (Z′ ≥ 0.72) in a 384-well format, and by running in parallel gel-based assays with fluorescent DNA substrates. This library was curated via virtual high throughput screening (vHTS) of 460,000 compounds from Chembridge Library, using the crystal structure of the novel surrogate protein 14M_zTDP2. From this primary screening, we selected the best 32 compounds (2% of the library) to further assess their TDP2 inhibition potential, leading to the IC50 determination of 10 compounds. Based on the dose-response curve profile, pan-assay interference compounds (PAINS) structure identification, physicochemical properties and efficiency parameters, two hit compounds, 11a and 19a, were tested using a novel secondary fluorescence gel-based assay. Preliminary structure-activity relationship (SAR) studies identified guanidine derivative 12a as an improved hit with a 6.4-fold increase in potency over the original HTS hit 11a. This study highlights the importance of the development of combination approaches (biochemistry, crystallography and high throughput screening) for the discovery of TDP2 inhibitors.

BIS-QUINAZOLINE COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS

Bis-quinazoline compounds based on the compound (3,4-Dihydro-quinazolin-2-yl)-quinazolin-2-yl-amine, and methods of use of the compounds as inhibitors of bacterial DNA polymerase holoenzymes and in the treatment of bacterial infections are described.

Compounds for the treatment of pain

This invention provides methods of treating pain, urinary incontinence and other abnormalities mediated by a NPFF receptor, which comprises administering to a subject a therapeutically effective amount of a chemical compound which acts at the NPFF1 receptor, the NPFF2 receptor, or at both the NPFF1 and NPFF2 receptors.

Guanidines which are agonist/antagonist ligands for neuropeptide FF (NPFF) receptors

This invention provides compounds having the structure: wherein X=CH, C(CH3) or N; each of R1, R2, R3, R4 and R5 is independently H, C1-C10 straight chained or branched alkyl, C2-C10 straight chained or branched alkenyl, C2-C10 straight chained or branched alkynyl, C3-C10 cycloalkyl, substituted or unsubstituted aryl, hydroxy, halogenated ether, nitro, amino, halogen, —CN, —C(═Z)R6, —C(═Z)OR6, —C(═Z)N(R6)2, —N(R6)—C(═Z)R6, —N(R6)—C(═Z)N(R6)2, —OC(═Z)R6, —C(═Z)OR6—OR6 or —SR6; wherein Z is O or S; and wherein R6 is C1-C10 straight chained or branched alkyl, aryl, (CH2)nQ, C2-C10 alkenyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, wherein Q is OR7, SR7, N(R7)2 or aryl, wherein R7 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, wherein R2 and R3 and the carbons to which they are attached form a fused aryl, heteroaryl, C5-C10 cyclic alkyl or heterocyclic alkyl ring; or wherein R3 and R4 and the carbons to which they are attached form a fused aryl, heteroaryl, cyclic alkyl or heterocyclic alkyl ring; and wherein each alkyl, alkenyl, alkynyl and alkoxy group is optionally substituted with a substituent independently selected from Ra, where Ra is 1) hydroxy, 2) C1-C10 alkoxy, 3) halogen, 4) nitro, 5) amino, 6) CF3, or 7) carboxy, and each cycloalkyl group is optionally substituted with a substituent independently selected from Rb, where Rb is 1) a group selected from Ra, 2) C1-C7 alkyl, 3) C2-C7 alkenyl, 4) C2-C7 alkynyl or 5) cyclic C1-C10 alkyl, and each aryl is optionally substituted with R1. This invention also provides methods of treating pain, urge incontinence; as well as methods of preparing the compounds.