Search

Oxazolo[5,4‐d]pyrimidine derivatives have been reported to exhibit interesting biological activities. Herein, we described a solid‐phase synthetic method to produce N‐alkyl‐7‐alkylamino‐2‐aryloxazolo[5,4‐d]pyrimidine‐5‐carboxamide derivatives. The strategy consists of loading the template compounds (i.e., 2‐aryl‐6,7‐dihydrooxazolo[5,4‐d]pyrimidin‐7‐one‐5‐carboxylic acids) onto aminated acid‐sensitive methoxybenzaldehyde (AMEBA) resins, the subsequent benzotriazol‐1‐yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)‐mediated direct amination with primary/secondary amines, and the final cleavage from the solid support to afford the target compounds. The template 2‐aryl‐6,7‐dihydrooxazolo[5,4‐d]pyrimidin‐7‐one‐5‐carboxylic acids were prepared using a five‐step solution‐phase synthetic route from ethyl 2‐cyano‐2‐(hydroxyimino)acetate. BOP‐mediated direct amination conditions were optimized by a solution‐phase model study. The solid‐phase synthetic method provided the 17 target compounds in 16%–92% five‐step overall isolated yields from the Merrified resin for selected template compounds and primary/secondary amines. [ABSTRACT FROM AUTHOR]

For an analog‐based design of novel Wee1 inhibitors, we profiled in vitro ADMET and in vivo PK properties of adavosertib. Based on the properties of adavosertib, we aimed to improve its metabolic stability by designing a novel target compound 1a with an aminosulfonyl group instead of the 2‐hydroxypropan‐2‐yl moiety in adavosertib. Derivatives of target compound 1a were synthesized and evaluated for Wee1 enzyme inhibition and liver microsomal phase I stability. We identified compound 1a as a sub‐nanomolar Wee1 inhibitor and 10 additional compounds with one‐digit nanomolar Wee1 inhibitory activity, among which seven compounds including 1a exhibited improved metabolic stabilities compared with adavosertib. However, MDA‐MB‐231 cell growth inhibitory activities of all synthesized compounds and Wee1 substrate phosphorylation inhibitory activities of selected compounds were inferior to adavosertib overall. Moreover, the representative compound 1a exhibited low permeability, which may be the reason for the low cellular activities of compound 1a. [ABSTRACT FROM AUTHOR]

A central nervous system (CNS)‐oriented compound collection was screened to find hit compounds for human glioblastoma T98G cell growth inhibition. A series of quinoxaline‐based derivatives were identified as hit compounds having one‐ to two‐digit micromolar GI50 values. Anti‐glioblastoma activity was improved in structure–activity relationship studies varying the substituents on the quinoxaline ring system, resulting in the discovery of four compounds exhibiting sub‐micromolar GI50 values. The potentials of the four compounds to induce apoptosis were confirmed by annexin V staining assay. The development potential of the four compounds as CNS drug leads was evaluated by in vitro MDR‐MDCK cell permeability and in vivo brain disposition in mice. The mouse pharmacokinetic and kinome profiling studies for compound 10g, which showed high brain‐penetrating ability, revealed that the compound is orally bioavailable and inhibits the kinase activities of anaplastic lymphoma kinase (ALK) and Erb‐B2 receptor tyrosine kinase (ERBB3). [ABSTRACT FROM AUTHOR]

Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists. [ABSTRACT FROM AUTHOR]

Keywords: p53; MDM2; Protein-protein interaction; PPI inhibitor; 1,2-naphthoquinone In this study, we performed an inhibitor screen against our in-house chemical library to search for new p53-MDM2 inhibitors and identified 7-pentyloxy-4-phenyl-1,2-naphtalenedione as a hit compound with an IC SB 50 sb of 2.4 M. The substitutions at R SP 2 sp position were especially interesting since some of the compounds (compound B 13 b and B 14 b ) were found to be highly potent whose IC SB 50 sb values are nearly comparable to that of Nutlin-3, a previously well-known p53-MDM2 inhibitor.[7] P53, MDM2, Protein-protein interaction, PPI inhibitor, 1,2-naphthoquinone. [Extracted from the article]

This work describes the process by which a metabolically unstable TRT‐0002 compound exhibiting Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐sensitizing activity for Huh7 cells at a high working concentration (40 μM) is converted to more potent and metabolically improved analogues by modifying the 5‐amino group and the 1‐aryl moiety in the 1H‐indazole skeleton. The efforts enabled us to identify 5‐sulfonamido derivatives, TRT‐0029 and TRT‐0173 compounds, working at lower concentrations (10 and 20 μM, respectively) and with improved metabolic stabilities. As reported previously by us, co‐treating cultured Huh7 cells with either TRT‐0029 or TRT‐0173 and TRAIL resulted in TRAIL‐induced apoptosis due to the inhibition of the MKK7–TOR signaling pathway regulator‐like (TIPRL) interaction and subsequent phosphorylation of MKK7 and JNK. In addition, the injection of TRT‐0029 or TRT‐0173 compound suppressed tumor growth in combination with TRAIL in an in vivo hepatocellular carcinoma (HCC) mouse xenograft model. TRT‐0029 and TRT‐0173 compounds and the relevant structure–activity relationship can provide an insight into further study on optimization of potency and metabolic stability. [ABSTRACT FROM AUTHOR]

The coupling of 7-aryl-3,4-dihydro-4-oxothieno[3,2- d]pyrimidine-2-carboxylic acid with a primary alkylamine-loaded acid-sensitive methoxy benzaldehyde (AMEBA) resin, a benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate ( BOP)-mediated amination reaction, and cleavage from the solid support yielded N-alkyl-4-(alkylamino)-7-arylthieno[3,2- d]pyrimidine-2-carboxamide derivatives. The progress of the reactions on solid phase was monitored through attenuated total reflectance- FTIR spectroscopy and was compared with representative solution-phase surrogates. Additionally, N-acylation (acid chloride, InF3 , CH3CN, room temperature) and cyclization ( DBN, 1,4-dioxane, 80°C) of a 3-amino-4-(4- t-butoxycarbonylphenyl)thiophene-2-carboxamide intermediate under previously unreported conditions provided 2-substituted thieno[3,2- d]pyrimidin-4(3 H)-one derivatives, which were subsequently converted to 2-substituted 4-alkylamino-7-[4-(alkylaminocarbonyl)phenyl]thieno[3,2- d]pyrimidine derivatives through a reaction sequence consisting of a BOP-mediated amination reaction, t-butyl deprotection, and amide formation. [ABSTRACT FROM AUTHOR]

Tetrasubstituted thieno[3,2- b]pyridin-5(4 H)-one derivatives were selected as a highly functionalized heterocyclic scaffold for a multisite-specific tagging process utilizing a previously devised fluorous fluorescent tag system. A suitable synthetic method was established for the 7-alkoxy-2,4,6-trisubstituted-thieno[3,2- b]pyridin-5(4 H)-one derivatives, and incorporating t-butoxycarbonyl-functionalized building blocks into the reaction sequence produced precursors that could be used in the tagging process. Fluorous solid-phase extraction facilitated the purification of the tagged target compounds after a series of reactions, including t-Bu deprotection/ N-hydroxysuccinimidyl ester formation/amidation. [ABSTRACT FROM AUTHOR]

Utilizing polymer-bound anthranilic acid derivatives 1, we were able to obtain the 1,4-benzodiazepine-2,5-dione derivatives 3 (R 3= H, R 4= H, MeO, Cl) through an unprecedented reaction sequence, reductive alkylation-N-protected amino acid coupling-deprotective cyclization, in 28-71% five-step overall isolated yields and 95-99% purities from Wang resin 4. Applying the novel protocol to the resin 2, the 7-benzamido-1,4-benzodiazepine-2,5-dione derivatives 3 (R 1= Bn, R 4= 7-BzNH) could be obtained in 19-42% seven- or eight-step overall isolated yields and 92-98% purities from AMEBA resin 7. [ABSTRACT FROM AUTHOR]

Treatment of [(alkylamino and anilino)(cyano)methylene]-2,2-dimethyl-1,3-dioxane-4,6-diones with benzyl alcohol for 20 min at reflux gave 3-(alkylamino and anilino)-4-benzyloxycarbonylmaleimides. [Copyright &y& Elsevier]

A simple and efficient approach of controlling the side-chain density in the electron donating polymers has been demonstrated to tune their 3-D packing structure and HOMO level, which increases the hole mobility and Vocvalues, thus improving the solar cell performance. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers. We first identified the hit compound, TRT-0002, from a chemical library of 6,000 compounds using a previously developed high-throughput enzyme-linked immunosorbent assay (ELISA) screening system, which was based on the interaction of mitogen-activated protein kinase kinase 7 (MKK7) and TOR signaling pathway regulator-like (TIPRL) proteins and a cell viability assay. To increase the efficacy of this TRAIL sensitizer, we synthesized 280 analogs of TRT-0002 and finally identified two lead compounds (TRT-0029 and TRT-0173). Co-treating cultured Huh7 cells with either TRT-0029 or TRT-0173 and TRAIL resulted in TRAIL-induced apoptosis due to the inhibition of the MKK7-TIPRL interaction and subsequent phosphorylation of MKK7 and c-Jun N-terminal kinase (JNK). In vivo , injection of these compounds and TRAIL into HCC xenograft tumors resulted in tumor regression. Taken together, our results suggest that the identified lead compounds serve as TRAIL sensitizers and represent a novel strategy to overcome TRAIL resistance in HCC., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

A new solid-phase route for preparation of 1,3,6-trisubstituted-1H-thiazolo[4,5-c][1,2]thiazin-4(3H)one-2,2-dioxide derivatives is described. Our synthetic route is begun with a thiazole resin and relies on the sulfonamide formation, Mitsunobu-type N-alkylation, cyclization, and nucleophilic substitution methodology cleavage on a solid support. The strategy permits the incorporation of three points of diversity into the thiazolo[4,5-c][1,2]thiazine ring system in good overall yields.

Despite remarkable progress in the elucidation of energy balance and regulation, the development of new anti-obesity drugs is still at the stage of infancy. Herein we briefly reviewed several investigational anti-obesity agents currently under development, consisting of agents controlling appetite, modulating nutrient absorption and lipid metabolism, sensing and regulating nutrient status, stimulating energy expenditure, and reducing adiposity. In particular, two promising targets such as melanocortin-4 (MC-4) receptor and melanin concentrating hormone (MCH)-1 receptor will be highlighted in this review covering major medicinal chemistry efforts and biological aspects of the compounds synthesized. Considering the enthusiastic efforts to develop efficacious and safe anti-obesity drugs, a range of novel medications treating obesity more effectively than is currently managed by pharmacotherapy will be available in near future.

[reaction: see text] A library containing 1200 analogues of 2,6-difunctionalized 2-methyl-2H-1-benzopyran was constructed by using a solid-phase synthesis protocol. Polymer-bound 6-amido-, 6-sulfonamido-, and 6-uredo-functionalized 2-hydroxymethyl-2-methylbenzopyrans 10 were prepared as part of a first-generation diversification step by employing reactions of respective acid halides, sulfonyl chlorides, and isocyanates with the amine precursor 7. Transformations of the resin-bound intermediates 10 by reactions with alkyl and acid halides were then used to produce a diverse series of 2,6-difunctionalized 2-methyl-2H-1-benzopyran analogues 12 and 14.