Tag: M.W=150-200

Spratt, Thomas E.; De los Santos, Hannah published the artcile< Reaction of O6-alkylguanine-DNA alkyltransferase with O6-methylguanine analogs: evidence that the oxygen of O6-methylguanine is protonated by the protein to effect methyl transfer>, Application In Synthesis of 84955-32-8, the main research area is alkylguanine DNA alkyltransferase methylguanine analog.

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) repairs the promutagenic O6-methylguanine lesion by transferring the Me group to a cysteine residue on the protein. A mechanism in which AGT activates the guanyl moiety as a leaving group by protonation of a heteroatom on guanine was probed by reacting AGT with analogs of O6-methylguanine in which the heteroatoms were changed. The initial rates of reaction were measured at various substrate concentrations in 50 mM Hepes, 1 mM EDTA, 1 mM DTT, and 10% glycerol, pH 7.8 at 37). The kinact (h-1) and Kin (mM) were determined for O6-methylguanine (1.66, 1.51) 0.32), 6-methoxypurine (1.07, 10.6), S6-methyl-6-thioguanine (0.63, 1.17), 6-methylthiopurine (no reaction), Se6-methyl-6-selenoguanine (1.76, 10.6), 6-methylselenopurine (2.51, 15.7), O6-methyl-1-deazaguanine (1.71, 14.8), O6-methyl-3-deazaguanine (1.90, 2.54), and O6-methyl-7-deazaguanine (1.97, 2.56). These results indicate that replacement of the nitrogens does not affect the kinact parameter but the Kin is increased upon removal of the exocyclic amino group and the nitrogen at the 1-position. Replacement of the oxygen with sulfur decreases the kinact, and replacement with selenium increases the Kin. The results are consistent with a mechanism in which O6-methylguanine binds to the active site of AGT with hydrogen bonds to the oxygen, the exocyclic amino group, and the nitrogen at the 1-position of the substrate. The Me group is then displaced from the guanine as a proton is transferred to the oxygen, neutralizing the charge on the leaving group.

Biochemistry published new progress about 84955-32-8. 84955-32-8 belongs to class pyrimidines, and the molecular formula is C7H8N4O, Application In Synthesis of 84955-32-8.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Watterson, Scott H.; Xiao, Zili; Dodd, Dharmpal S.; Tortolani, David R.; Vaccaro, Wayne; Potin, Dominique; Launay, Michele; Stetsko, Dawn K.; Skala, Stacey; Davis, Patric M.; Lee, Deborah; Yang, Xiaoxia; McIntyre, Kim W.; Balimane, Praveen; Patel, Karishma; Yang, Zheng; Marathe, Punit; Kadiyala, Pathanjali; Tebben, Andrew J.; Sheriff, Steven; Chang, Chieh Ying Y.; Ziemba, Theresa; Zhang, Huiping; Chen, Bang-Chi; DelMonte, Albert J.; Aranibar, Nelly; McKinnon, Murray; Barrish, Joel C.; Suchard, Suzanne J.; Murali Dhar, T. G. published the artcile< Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure-Activity Relationships Leading to the Identification of 6-((5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic Acid (BMS-688521)>, Safety of Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is spirocyclic hydantoin derivative preparation LFA1 antagonist SAR.

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or αLβ2, belongs to the β2 integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion mols. 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclin. animal studies and clin. data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunol. target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clin. compound (1, I), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clin. trials.

Journal of Medicinal Chemistry published new progress about Homo sapiens. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Safety of Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Chen, Junwei; Cao, Xin; An, Quanlin; Zhang, Yao; Li, Ke; Yao, Wenting; Shi, Fuchun; Pan, Yanfang; Jia, Qiong; Zhou, Wenwen; Yang, Fang; Wei, Fuxiang; Wang, Ning; Yu, Biao published the artcile< Inhibition of cancer stem cell like cells by a synthetic retinoid>, Quality Control of 89793-12-4, the main research area is cancer stem cell synthetic retinoid WYC209 anticancer.

Developing novel drugs that can abrogate the growth and metastasis of malignant tumors is a major challenge for cancer researchers. Here we describe a novel synthetic retinoid, namely WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs), known to resist conventional drug treatment, with an IC50 of 0.19 μM in a dose-dependent manner. WYC-209 also inhibits proliferation of TRCs of human melanoma, lung cancer, ovarian cancer, and breast cancer in culture. Interestingly, the treated TRCs fail to resume growth even after the drug washout. Importantly, the mol. abrogates 87.5% of lung metastases of melanoma TRCs in immune-competent wild-type C57BL/6 mice at 0.22 mg kg-1 without showing apparent toxicity. Pretreating the melanoma TRCs with retinoic acid receptor (RAR) antagonists or with RAR siRNAs blocks or reduces the inhibitory effect of the mol., suggesting that the target of the mol. is RAR. WYC-209 induces TRC apoptosis and pretreating the TRCs with caspase 3 inhibitor or depleting caspase 3 with siRNAs substantially rescues growth of TRCs from WYC-209 inhibition, suggesting that WYC-209 induces TRCs apoptosis primarily via the caspase 3 pathway. Our findings demonstrate the promise of the new retinoid WYC-209 in treating malignant melanoma tumors with high efficacy and little toxicity.

Nature Communications published new progress about Antiproliferative agents. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Quality Control of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhao, Chao; Choi, You Hee; Khadka, Daulat Bikram; Jin, Yifeng; Lee, Kwang-Youl; Cho, Won-Jea published the artcile< Design and synthesis of novel androgen receptor antagonists via molecular modeling>, SDS of cas: 89793-12-4, the main research area is androgen receptor antagonist preparation cancer; AR antagonist; Bioisostere; Molecular modeling; Nicotinamide; Pyrazinamide; Pyrimidinamide.

Several androgen receptor (AR) antagonists are clin. prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50 = 0.35 μM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biol. results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied mol. modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chem. modifications.

Bioorganic & Medicinal Chemistry published new progress about Androgen receptor antagonists. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, SDS of cas: 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Sanchez-Arias, Juan A.; Rabal, Obdulia; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Ugarte, Ana; Saez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease>, Computed Properties of 89793-12-4, the main research area is histone deacetylase phosphodiesterase 5 inhibitor preparation Alzheimer treatment; Alzheimer’s disease; HDACs; PDE5; dual inhibitor; tadalafil; vardenafil.

A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer’s disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead mol. CM-414 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, the authors have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead mol. bearing a different chemotype for in vivo testing.

ACS Chemical Neuroscience published new progress about Alzheimer disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Computed Properties of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Nitta, Yoshihiro; Okui, Kiyoshi; Ito, Kiyohiko published the artcile< Pyrimidine derivatives. I. Synthesis of a new series of sulfanilamides having dialkylamino groups in the pyrimidine nucleus>, Name: 6-Chloro-2-methoxypyrimidin-4-amine, the main research area is .

A solution of 7.1 g. Na in 300 mL. ROH was added dropwise to 50 g. 4-amino-2,6-dichloropyrimidine (I) in 3 l. of ROH during 6 h. at 50-60°. After 20 h. ROH was removed, mixture washed with H2O and crystallized to give II (R1 = Cl) (R, m.p., % yield, crystallization solvent given): MeO, 127-8°, 72, H2O; EtO, 128-9°, 75, MeOH-H2O; PrO, 114-15°, 78, MeOH-H2O; iso-Pr, 134-5°, 72, MeOH-H2O. The Cl compounds heated at 120° for 4-6 h. in a sealed tube with 20% Me2NH/MeOH gave II (R1 = NMe2) (R, m.p., % yield, crystn solvent given): MeO, 158-9°, 85, H2O; EtO, 136-7°, 95, C6H6; PrO, 96-7°, 87, ligroine; iso-Pr, 105-6°, 82, ligroine. II (R = Cl, R1 = MeO) (IIa) (16 g.) heated on the steam bath 2 h. in 200 mL. 10% NaOH and acidified with AcOH (pH 6) gave 12 g. 4-amino-6-chloro-2(1H)-pyrimidone (III), m. >300° (H2O). IIa treated with Me2NH as above and treated with NaOH gave 4-amino-6-dimethylamino-2(1H)-pyrimidone (IV), m. >300° (H2O). III and Me2N also gave IV. I (60 g.) in 300 mL. of 20% R3R2NH/MeOH became clear after stirring sometimes with heat for 4 h. Concentration and crystallization gave II (R = Cl) (R1, m.p., % yield, crystallization solvent given): Me2N, 152-3°, 73, H2O; Et2N, 124-5°, 75, C6H6; (CH2)4N, 184-5°, 90, MeOH-H2O; morpho-linoe, 153-4°, 84, MeOH-H2O; (H2C:CHCH2)2N, 91-3° (acetyl derivative), –, ligroine. Na(7.1 g.)in 3 mL. MeOH added to 50 g. I in 2.5 l. MeOH during 6 h. at 50-60°, the solution concentrated after 20 h. to 300 mL. and diluted with 700 mL. hot H2O gave IIa. The filtrate chilled to -10° gave a mixture which washed with MeOH and crystallized from MeOH gave II (R = MeO, R1 = Cl) (IIb), 3.5 g., m. 187-8°. IIb (0.01 mol) in 100 mL. 1% NH3/MeOH hydrogenated over 0.2 g. 10% Pd/C gave II (R = MeO, R1 = H), m. 155-6° (C6H6). Prepared similarly were II (R1 = H) (R, m.p., % yield given): EtO, 151-2°, 86; PrO, 132-3°, 90; iso-PrO, 93-4°, 92; BuO, 126-7°, 85; iso-BuO, 132-4°, 75; tert-BuO, 66-7°, 75. Similarly, from the 2-alkoxy-4-amino-6-chloropyrimidines were prepared II (R = H) (R1, m.p., % yield, crystallization solvent given): MeO, 168-9°, 75, H2O; EtO, 83-6°, 86, ligroine; PrO, 77-8°, 86, ligroine; iso-PrO, 75-6°, 85, ligroine. II (R and R1 = alkoxy) were obtained from II (R = XO, R1 = Cl) with NaOH and an alc. (R, R1, m.p., % yield, all crystallized from MeOH-H2O): MeO, MeO, 150-1°, 96; MeO, EtO, 144-5°, 94; MeO, iso-PrO, 98-9°, 91; EtO, MeO, 112-13°, 95. II (R = XO, R1 = Cl) and NaSR in the corresponding alcs. heated 3 h. on the steam bath, diluted with H2O and the product crystallized from dilute MeOH gave II (R, R1, m.p., % yield given): MeO, MeS, 143-4°, 94; MeO, EtS, 116-17°, 83; MeO, PrS, 99-100°, 80; MeO, iso-PrS, 116-17°, 86; EtO, MeS, 92-3°, 93; EtO, iso-PrS, 74-5°, 95. II (R = XO, R1 = Cl) (0.01 mol) in 200 mL. 10% Me2NH/MeOH heated at 100° 5 h. in a sealed tube gave II (R, R1, m.p., % yield, crystallization solvent given): MeO, Me2N, 93-4°, 95, ligroine; EtO, Me2N, 86-7°, 87, MeOH-H2O; H, Me2N, 153-5°, 90, C6H6. I (30 g.) in 200 mL. 20% Me2NH/MeOH heated at 120-130° for 6 h. in a sealed tube, concentrated, and diluted with 100 mL. of 10% NaOH gave 25 g. II (R = R1 = NMe2), m. 116-17° (H2O). Acetyl derivatives of the following II were prepared and crystallized from MeOH or dilute MeOH (R, R1, m.p., yield % given): Cl, MeO, 195-6°, 94; Cl, EtO, 194-6°, 94; MeO, Cl, 216-17°, 93; EtO, Cl, 215-16°, 90; MeO, H, 138-9°, 94; EtO, H, 130-1°, 95; PrO, H, 135-6°, 74; iso-PrO, H, 105-6°, 70; BuO, H, 95-6°, 63; MeO, Me2N, 187-8°, 90; EtO, Me2N, 166-7°, 92; PrO, Me2N, 165-7°, 84; iso-PrO, Me2N, 156-7°, 87; EtS, Me2N, 155-6°, 83; PrS, Me2N, 165-7°, 94; iso-PrS, Me2N, 186-7°, 90. The 4-aminopyrimidines and p-MeCONHC6H4SO2Cl in C5H5N (1 mL./g. chloride) at room temperature 12 h. were diluted with H2O and the crude products (V) (R2 = Ac) hydrolyzed in 10 volumes of 10% NaOH at 100° for 1 h. and neutralized with AcOH to give V (R2 = H). V (R2 = Ac) (R, R1, m.p., % yield, crystallization solvent given): Me2N, MeO, 218-20°, 82, MeOH; Me2N, EtO, 220-4°, 74, MeOH; Me2N, PrO, 215-16°, 70, MeOH; Me2N, iso-PrO, 166-7°, 74, MeOH; MeO, Me2N, 251-3°, 69, MeOH; EtO, Me2N, 223-4°, 75, MeOH; PrO, Me2N, 161-2°, 73, MeOH; EtS, Me2N, 226-7°, 81, MeOH-H2O; PrS, Me2N, 203-5°, 75, MeOH-H2O; iso-PrS, Me2N, 180-2°, 86, MeOH-H2O; Cl, Me2N, 261-2°, 70, MeOH; Cl, Et2N, 194-5°, 50, MeOH; Cl, (C3H6)2N, 178-9°, 29, MeOH-H2O; Cl, (CH2)4N, 234-5°, 81, MeOH-H2O; Cl, morpholino, 273-4°, 75, Me2CO; Me2N, H, 296-7°, 72, MeOH; Me2N, Me2N, 210-15° (crude), 32, –; Me2N, MeS, 230-5° (crude), 85, –. V (R2 = H, given as above): Me2N, MeO, 207-8°, 95, MeOH; Me2N, EtO, 228-30°, 87, MeOH-H2O; Me2N, PrO, 182-3°, 92, MeOH-H2O; Me2N, iso-PrO, –, 92, MeOH-H2O; MeO, Me2N, 218-20°, 90, MeOH-H2O; EtO, Me2N, 185-6°, 90, MeOH-H2O; PrO, Me2N, 90-1°, 65, Me2CO-C6H6; EtS, Me2N, 139-40°, 87, MeOH-H2O; PrS, Me2N, 165-7°, 70, MeOH-H2O; iso-PrS, Me2N, 170-1°, 76, MeOH-H2O; Cl, Me2N, 203-4°, 92, Me2CO-H2O; Cl, Et2N, 178-80°, 93, MeOH-H2O; Cl, (C3H5)2N, 170-2°, 98, MeOH-H2O; Cl, (CH2)4N, 234-5°, 84, Me2CO-H2O; Cl, morpholino, 280-2°, 89, Me2CO-H2O; Me2N, H, 276-7°, 64, MeOH; Me2N, Me2N, 221-3°, 56, MeOH; Me2N, MeS, 242-3°, 68, MeOH-H2O. V (R = R2 = H, R1 = Me2N), m. 146-7° (MeOH-H2O), was prepared in 82% yield from V (R = Cl, R1 = Me2N, R2 = H). V (R = MeO, R1 = Et2N, R2 = H), m. 186-8° (MeOH-H2O), was prepared in 85% yield from V (R = Cl, R1 = Et2N, R2 = H). V (R = Cl, R1 = NR3R4, R2 = H) showed good antibacterial properties.

Chemical & Pharmaceutical Bulletin published new progress about 3286-55-3. 3286-55-3 belongs to class pyrimidines, and the molecular formula is C5H6ClN3O, Name: 6-Chloro-2-methoxypyrimidin-4-amine.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Tsuno, Naoki; Yukimasa, Akira; Yoshida, Osamu; Suzuki, Shinji; Nakai, Hiromi; Ogawa, Tomoyuki; Fujiu, Motohiro; Takaya, Kenji; Nozu, Azusa; Yamaguchi, Hiroki; Matsuda, Hidetoshi; Funaki, Satoko; Yamanada, Natsue; Tanimura, Miki; Nagamatsu, Daiki; Asaki, Toshiyuki; Horita, Narumi; Yamamoto, Miyuki; Hinata, Mikie; Soga, Masahiko; Imai, Masayuki; Morioka, Yasuhide; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Iso, Yasuyoshi published the artcile< Pharmacological evaluation of novel (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives as TRPV4 antagonists for the treatment of pain>, Application In Synthesis of 89793-12-4, the main research area is TRPV4 antagonist analgesic pain; Ion channel; Pain; TRPV4 antagonist; Transient receptor potential vanilloid 4; Vanilloid receptor.

A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund’s Complete Adjuvant (FCA) induced mech. hyperalgesia model in guinea pig and rat. Modification of right part based on the compound I which was disclosed in the previous communication led to the identification of compound II as a flagship compound In this paper, the authors described the details about design, synthesis and structure-activity relationship (SAR) anal.

Bioorganic & Medicinal Chemistry published new progress about Analgesics. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Application In Synthesis of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia