96258-53-6Relevant academic research and scientific papers
Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry
Cao, Jiangying,Ma, Chunhua,Zang, Jie,Gao, Shuai,Gao, Qianwen,Kong, Xiujie,Yan, Yugang,Liang, Xuewu,Ding, Qin'ge,Zhao, Chunlong,Wang, Binghe,Xu, Wenfang,Zhang, Yingjie
, p. 3145 - 3157 (2018/06/01)
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia
Fushimi, Nobuhiko,Fujikura, Hideki,Shiohara, Hiroaki,Teranishi, Hirotaka,Shimizu, Kazuo,Yonekubo, Shigeru,Ohno, Kohsuke,Miyagi, Takashi,Itoh, Fumiaki,Shibazaki, Toshihide,Tomae, Masaki,Ishikawa-Takemura, Yukiko,Nakabayashi, Takeshi,Kamada, Noboru,Ozawa, Tomonaga,Isaji, Masayuki,Kobayashi, Susumu
, p. 6598 - 6612,15 (2012/12/12)
Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyran
Synthesis and antiparasitic and antitumor activity of 2,4-diamino-6- (arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of piritrexim
Rosowsky, Andre,Papoulis, Andrew T.,Forsch, Ronald A.,Queener, Sherry F.
, p. 1007 - 1017 (2007/10/03)
Nineteen previously undescribed 2,4-diamino-6-(arylmethyl)-5,6,7,8- tetrahydroquinazolines (5a-m, 10-12) were synthesized as part of a larger effort to assess the therapeutic potential of lipophilic dihydrofolate reductase (DHFR) inhibitors against opportunistic infections of AIDS. Condensation of appropriately substituted (arylmethyl)triphenylphosphoranes with 4,4-ethylenedioxycyclohexanone, followed by hydrogenation (H2/Pd-C) and acidolysis, yielded the corresponding 4-(arylmethyl)cyclohexanones, which were then condensed with cyanoguanidine to form the tetrahydroquinazolines. Three simple 2,4-diamino-6-alkyl-5,6,7,8-tetrahydroquinazoline model compounds (9a-c) were also prepared in one step from commercially available 4-alkylcyclohexanones by this method. Enzyme inhibition assays against rat liver DHFR, Pneumocystis carinii DHFR, and the bifunctional DHFR-TS enzyme from Toxoplasma gondii were carried out, and the selectivity ratios IC50(rat)/IC50(P. carinii) and IC50(rat)/IC50(T. gondii) were compared. The three most potent inhibitors of P. carinii DHFR were the 2,5- dimethoxybenzyl (5j), 3,4-dimethoxybenzyl (5k), and 3,4,5-trimethoxybenzyl (51) analogues, with IC50 values of 0.057, 0.10, and 0.091 μM, respectively. The remaining compounds generally had IC50 values in the 0.1- 1.0 μM range. However all the compounds were more potent against the rat liver enzyme than the P. carinii enzyme and thus were nonselective. The T. gondii enzyme was always more sensitive than the P. carinii enzyme, with most of the analogues giving IC50 values of 0.01-0.1 μM. Moderate 5-10-fold selectivity for T. gondii versus rat liver DHFR was observed with five compounds, the best combination of potency and selectivity being achieved with the 2-methoxybenzyl analogue 5d, which had an IC50 of 0.014 μM and a selectivity ratio of 8.6. One compound (51) was tested for antiproliferative activity against P. carinii trophozoites in culture at a concentration of 10 μg/mL and was found to completely suppress growth over 7 days. The suppressive effect of 51 was the same as that of trimethoprim (10 μg/mL) + sulfamethoxazole (250 μg/mL), a standard clinical combination for the treatment of P. carinii pneumonia in AIDS patients. Four compounds (5a,h,k,l) were tested against T. gondii tachyzoites in culture and were found to have a potency (IC50 = 0.1-0.5 μM) similar to that of pyrimethamine (IC50 = 0.69 μM), a standard clinical agent for the treatment of cerebral toxoplasmosis in AIDS patients. Compound 5h was also active against T. gondii infection in mice when given qdx8 by peritoneal injection at doses ranging from 62.5 (initial dose) to 25 mg/kg. Survival was prolonged to the same degree as with 25 mg/kg clindamycin, another widely used drug against toxoplasmosis. Three compounds (5j-l) were tested for antiproliferative activity against human tumor cells in culture. Among the 25 cell lines in the National Cancer Institute panel for which data were confirmed in two independent experiments, the IC50 for at least two of these compounds was 50 of 50 was 0.01 μM.
Stabilization Demands of Diethyl Phosphonate Substituted Carbocations as Revealed by Substituent Effects
Creary, Xavier,Underiner, Ted L.
, p. 2165 - 2170 (2007/10/02)
Trifluoroethanolyses of a series of mesylate derivatives of diethyl (1-aryl-1-hydroxymethyl)phosphonates, 9, gave a Hammett ρ value of -10.1 in the electron donor substituent region.This value was slightly less than the value of -11.6 seen in the corresponding benzyl mesylates, ArCH2OMs, 12, in hexafluoroisopropyl alcohol.These data suggest that the demand for aryl group stabilization in the intermediate phosphoryl-substituted cation 10 does not surpass that of the α-H analogues, the benzyl cations.Some other factor must therefore account for the relative ease of formation of cations 10, which have the electronegative diethyl phosphonate group attached directly to the cationic center.The likely factor is an offsetting cation stabilizing feature associated with the diethyl phosphonate group.The Hammett plots for both mesylates 9 and 12 show a break, with decreased ρ values (-6.1 and -5.1, respectively) being observed in the electron-withdrawing region of the plot.Solvent effect studies on 9-m-F suggested that a change to "borderline behavior" is the origin of the break in the Hammett plot.A mechanistic change to the kδ process could be ruled out.The triflate derivative of diethyl (1-hydroxyethyl)phosphonate, 14, gave mixtures of substitution and elimination products on solvolysis.Solvent effect studies indicated a largely nucleophilic mechanism, while isotope effect studies were in line with some cationic character in the transition state in the highly ionizing, nonnucleophilic hexafluoroisopropyl alcohol solvent.Ion pair formation or the SN2 (intermediate) mechanism could rationalize the behavior of 14 in more highly ionizing solvents.
