Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

In this paper, we synthesized a series of proteolysis targeting chimeras(PROTACs) using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC₅₀ value of (18.6±1.3) nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC₅₀ value of (34.2±4.3) nmol/L and capable of inducing degradation of BRD4 protein at 0.4—0.6 µmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRD4 degrader.     

Studies on New Steroidal Saponins from Allii macrostemonis Bulbus and Their Antitumor Activities

Two new steroidal saponins(2, 3) and two known compounds(1, 4) were isolated from 75% ethanol extract of Allii macrostemonis bulbus by various spectral methods. The two new steroidal saponins were respectively elucidated as (25S)-26-O-β-D-glucopyranosyl-5α-furostanol-2α,3β,22,26-tetrol-3-O-β-D-glucopyranosyl(1→2)-[β-D- glucopyranosyl(1→3)]-β-D-glucopyranosyl(1→4)-β-D-galactopyranoside(2) and 26-O-β-D-glucopyranosyl-5α- furostanol-25(27)-ene-3β,22,26-tetrol-3-O-β-D-glucopyranosyl(1→2)-[β-D-glucopyranosyl(1→3)]-β-D-glucopyranosyl- (1→4)-β-D-galactopyranoside(3). Compound 4 was obtained from this medical plant for the first time. The activity experiments of proliferation inhibition on tumor cells were performed by cell counting kit-8(CCK-8) method for compound 2(25S-configuration) and its isomer(compound 1, 25R-configuration). The results show that compounds 1 and 2 have weak inhibition on lung cancer A549 cells, melanoma A375 cells and breast cancer MCF-7 cells as well as certain inhibitory effect on liver cancer HepG2 cells, and the inhibitory effect of compound 1 is stronger than that of compound 2.     

Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors

Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search.     

Convenient and Scalable Synthesis of 2,3-Dihydroquinazolin-4(1H)-one Derivatives and Their Anticancer Activities

An efficient and mild InBr₃-catalyzed approach to synthesize 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3aa) has been developed. Notably, all the products were isolated by recrystallization and the reaction is accessible on a gram scale. Moreover, the reactions only require 10–60 min. All the synthesized compounds were evaluated for their in vitro anticancer activity against four human cancer cell lines.     

1,3,4-(口恶)二唑硫醚酰胺为核心骨架的新型多杂环分子的合成及对Cdc25B与PTP1B的抑制活性

首先利用含有三嗪的芳香酰肼(3)构筑了1,3,4-噁二唑衍生物(5), 然后将化合物5与含有1,3,4-噻二唑的衍生物(6)拼合合成了18个目标分子. 利用红外光谱(IR)、 核磁共振波谱(NMR)和高分辨质谱(HRMS)等技术对其结构进行了表征. 考察了目标分子对细胞分裂周期25磷酸酯酶B(Cdc25B)和蛋白酪氨酸磷酸酯酶1B(PTP1B)的抑制活性. 结果表明, 有8个目标分子的抑制活性优于其阳性对照物, 有望成为潜在的Cdc25B抑制剂; 有12个目标分子的抑制活性优于其对照物, 有望成为潜在的PTP1B抑制剂.     

Synthesis and Characterization of a Novel Copoly(aryl ether ketone) Containing 4, 4''''-Biphenyl-bis[4-phthalazin-1(2H)-one] Moiety

Poly(aryl ether ketone)s are a category of high performance engineering thermoplastics characterized by high glass transition temperature and excellent thermooxidative stability. And they have important applications in electronic, electric, aircraft and aerospace industries1~3. Considerable efforts have been made towards the improvement of solubility or processability of poly(aryl ether ketone)s4,5. In our work, a novel bis(phthalazinone) monomer 1 4, 4-biphenyl-bis[4-phthalazin-1(2H)-one] …     

Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR)

As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.     

Design,Synthesis, Inhibiting HDACs Ability and Antitumor Activity of Pyrimidin-4(3H)-one Hydroxamate Derivatives

A series of novel pyrimidin-4(3H)-one hydroxamate derivatives was designed, synthesized and studied for their activities against histone deacetylases(HDACs). The results indicate that all the compounds show HDACs inhibitiory activity. The antiproliferative activities of the compounds against HeLa and A549 cells were also investigated. The pharmacological results show compound 9g has potent activity in the enzymatic inhibition assay and cell-based assay.     

Studies on Synthesis and Photochromism of a Novel Class of Fulgimide： （Z）-4-Oxazolylfulgimide

A novel class of fulgimide, (Z)-4-oxazolylfulgimide ((Z)-1-benzyl-4-isopropylidene-3-[1-(2-aryl-5-methyloxazolyl)ethylidene]tetrahydropyrrole-2,5-dione), was synthesized by the reaction of (Z)-4-oxazolyl fulgide (4-isopropylidene-3-[1-(2-aryl-5-methyloxazolyl) ethylidene]tetrahydrofuran-2,5-dione) with benzyl amine. Photochromic property of (Z)-4-oxazolylfulgimide was studied. Compared with (Z)-4-oxazolylfulgide, the absorption maximum of the colored form of (Z)-4-oxazolylfulgimide is bathochromic-shifted. Substituents on the aryl ring affect the absorption maximum of the open form and the colored form of (Z)-4-oxazolylfulgimide.     

4,4-(9-芴)二苯酚型聚碳酸酯的合成及其耐高温性能研究

以4,4-(9-芴)二苯酚(BHPF)和碳酸二苯酯(DPC)为原料,采用熔融酯交换法合成了4,4-(9-芴)二苯酚型聚碳酸酯(BHPF-PC).红外光谱、核磁共振碳谱及氢谱测试结果证实了所得聚合物的化学结构.采用了四苯基膦苯酚盐(C_(30)H_(25)OP)等2种季磷盐以及3种碱性无机盐催化剂作为合成聚碳酸酯的催化剂,结果四苯基膦苯酚盐的催化效果最好.分析了DPC/BHPF初始摩尔比对BHPF-PC的影响规律,随着DPC/BHPF初始摩尔比的增加,BHPF-PC的分子量呈现先增加后降低的趋势.进一步研究了聚合工艺包括缩聚时间和缩聚温度对BHPF-PC的影响,结果表明BHPF-PC分子量达到最大值所需要的时间随DPC/BHPF初始摩尔比的增加而增加.初始摩尔比为1.1∶1的DPC和BHPF,在1×10~(-5)mol/mol(BHPF)的四苯基膦苯酚盐催化作用下,于330℃缩聚150 min可以获得分子量最大的BHPF-PC.最后研究了BHPF-PC的耐高温性能和光学性能,其Tg达到了275℃,空气中失重率为5%时的分解温度T5%为440℃,同时透光率达到了88.1%,表明BHPFPC是一种具有优异耐高温性能的高光学透明材料.     

自然水体生物膜胞外蛋白质吸附铅和镉的研究

本文通过长春市南湖水中生物膜优势菌种胞外蛋白吸附Pb2+和Cd2+的实验, 研究了胞外蛋白吸附重金属的规律.     

Synthesis and properties of polyimides derived from 1,7-bis(4-aminophenoxy)naphthalene and aromatic tetracarboxylic dianhydrides

The novel diamine, 1,7-bis(4-aminophenoxy)naphthalene (1,7-BAPON), was synthesized and used to prepared polyimides. 1,7-BAPON was synthesized through the nucleophilic displacement of 1,7-dihydroxynaphthalene with p-fluoronitrobenzene in the presence of K₂CO₃ followed by catalytic-reduction. Polyimides were prepared from 1,7-BAPON and various aromatic tetracarboxylic dianhydrides by the usual two-step procedure that included ring-opening polyaddition to give poly(amic acid)s, followed by cyclodehydration to polyimides. The poly(amic acid)s had inherent viscosities of 0.74-2.48 dL/g. Most of the polyimides formed tough, creasible films. These polyimides had glass transition temperatures between 247–278°C and their 10% weight loss temperatures were recorded in the range of 515–575°C in nitrogen atmosphere. © 1995 John Wiley & Sons, Inc.     

Synthesis and Crystal Structure of a Novel Ethyl 5-(4-(2-Phenylacetamido)phenyl)-1H-pyrazole-3-carboxylate as an Acrosin Inhibitor

The title compound (ethyl5-(4-(2-phenylacetamido)phenyl)-1H-pyrazole-3-carboxy- late, C20H19N3O3) was synthesized by the reaction of Claisen condensation, cyclization, reduction and acylation. The structure was characterized by X-ray diffraction, MS, NMR and IR. It belongs to the monoclinic system, space group C2/c with a = 22.723(9), b = 9.324(4), c = 18.890(8) , β = 114.259(6)°, V = 3649(3) 3, Dc = 1.272 Mg·m-3, Z = 8, Mr = 349.38, μ = 0.087 mm-1, F(000) = 1472, the final R = 0.0615 and wR = 0.1643. The biological test shows that the title compound has a moderate acrosin inhibition activity.     

Synthesis and characterization of new cardo polyimides prepared from 5,5-Bis[4-(4-aminophenoxy)phenyl]-4,7-methanohexahydroindane

A new cardo diamine monomer, 5,5-bis[4-(4-aminophenoxy)phenyl]-4,7-methanohexahydroindane (II), was prepared in two steps with high yield. The monomer was reacted with six different aromatic tetracarboxylic dianhydrides in N,N-dimethylacetamide (DMAc) to obtain the corresponding cardo polyimides via the poly(amic acid) precursors and thermal or chemical imidization. All the poly(amic acid)s could be cast from their DMAc solutions and thermally converted into transparent, flexible, and tough polyimide films which were further characterized by x-ray and mechanical analysis. All of the polymers were amorphous and the polyimide films had a tensile strength range of 89–123 MPa, an elongation at break range of 6–10%, and a tensile modulus range of 1.9–2.5 GPa. Polymers V_c, V_e, and V_f exhibited good solubility in a variety of solvents such as N-methyl-2-pyrrolidinone (NMP), DMAc, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, γ-butyrolactone, and even in tetrahydrofuran and chloroform. These polyimides showed glass-transition temperatures between 274 and 299°C and decomposition temperatures at 10% mass loss temperatures ranging from 490 to 521°C and 499 to 532°C in nitrogen and air atmospheres, respectively. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 2815–2821, 1999     

Synthesis,Antitumor and Antibacterial Studies of New Shortened Analogues of (KLAKLAK)2-NH2 and Their Conjugates Containing Unnatural Amino Acids

(1) Background: (KLAKLAK)₂ is a representative of the antimicrobial peptide group which also shows good anticancer properties. (2) Methods: Herein, we report synthesis using SPPS and characterization by HPLC/MS of a series of shortened analogues of (KLAKLAK)₂. They contain single sequence KLAKLAK as C-terminal amides. In addition, substitution of some natural amino acids with unnatural β-Ala and nor-Leu is realized. In addition, these structures are conjugated with second pharmacophore with well proven anticancer properties 1,8-naphthalimide or caffeic acid. Cytotoxicity, antiproliferative effect and antimicrobial activity of newly synthesized structures were studied. (3) Results: The obtained experimental results reveal significant selective index for substances with common chemical structure KLβAKLβAK-NH₂. The antibacterial properties of newly synthesized analogues at two different concentrations 10 μM and 20 μM, were tested against Gram-negative microorganisms Escherichia coli K12 407. Only two of the studied compounds KLAKLAK-NH₂ and the one conjugated with second pharmacophore 1,8-naphthalimide and unnatural amino acid nor-Leu showed moderate activity against tested strains at concentration of 20 μM. (4) Conclusions: The obtained results reveal that the introducing of 1,8-naphthalimideGly- and Caf- increase the cytotoxicity and antiproliferative activity of the peptides but not their selectivity. Only two compounds KLAKLAK-NH₂ and 1,8-naphthalimideGKnLAKnLAK-NH₂ show moderate activity against Escherichia coli K12 at low concentration of 20 μM.     

1-(2-苯并噻唑)-3-(4-硝基苯)-三氮烯的合成及其与镉(Ⅱ)的显色反应研究

报道了１－（２－苯并噻唑）－３－（４－硝基苯）－三氮烯（ＢＴＮＰＴ）的合成及与镉（Ⅱ）的显色反应研究。在ＴｒｉｔｏｎＸ－１００的存在下,ｐＨ１１．６时,镉（Ⅱ）与ＢＴＮＰＴ形成摩尔比＝１∶２型黄色络合物,在４３５ｎｍ处有一最大正吸收,在５３０ｎｍ处有最大负吸收。以４３５ｎｍ为参比波长,５３０ｎｍ为测量波长进行双波长测定,表观摩尔吸光系数为２．５２×１０５Ｌ·ｍｏｌ－１·ｃｍ－１,线性范围为０～１０μｇ／２５ｍＬ。已用于测定地面水和人发中的镉含量。     

Studies on the Synthesis,Crystal Structure and Antitumor Activities of Mn(II) Complex Derived from the Desulfurization of N-(p-nitrophenyl)-N′-(methoxycarbonyl)thiourea and o-Phenanthroline

One new Mn(II) complex, 1, MnL₂(phen)₂ (L = p-nitrophenylcyanamido-N, phen = o-phenanthroline) has been synthesized and crystallographically characterized. Complex 1 was obtained from the desulfurization and hydrolysis of H₂pmt (H₂pmt = N-(p-nitrophenyl)-N′-(methoxycarbonyl)thiourea) in alkaline media. 1 crystallized in the triclinic space group P-1 with a = 11.0320(3), b = 11.7831(4), c = 12.9288(4) Å; α = 87.3590(10), β = 81.7500(10), γ= 84.0080(10)°. Preliminary pharmacological tests showed that complex 1 exhibited definite inhibition activities against human ovary tumor 3A0 and mice P388 in vitro.     

Synthesis,Crystal Structure and Characterization of a New Coordination Polymer from the Self-assembly of CoCl_2 Salt and Flexible Ligand 1,3-Bis（4-pyridyl）propane

A new 1D coordination polymer [Co(bpp)3Cl2(H2O)2]n 1 (bpp = 1,3-bis(4-pyridyl)-propane) was synthesized and characterized by elemental analysis,IR spectrum and single-crystal X-ray diffraction. The crystal belongs to the orthorhombic system,space group Ibca with a = 16.569(9),b = 17.240(10),c = 27.087(16) ,V = 7738(8) 3,Z = 8,Dc = 1.306 g/cm3,Mr = 760.65,λ(MoKa) = 0.71073 ,μ = 0.623 mm1,F(000) = 3192,the final R = 0.0678 and wR = 0.2011. The Co(II) atom is coordinated in a slightly distorted octahedral CoN4Cl2 geometry by two Cl atoms in the axial positions,four N atoms from the two bridging bpp ligands and two pendant bpp ligands. The CoN4Cl2 octahedra are connected by the bridging bpp ligands to form a 1D neutral coordination polymer chain. The chains are linked by face-to-face π-π interactions between adjacent pendant bpp ligands to give rise to a 3D supramolecular architecture. The photoluminescent investigation indicates that the emission of 1 is attributed to ligand-centered emission. The variable-temperature magnetic susceptibility measurement shows weak antiferromagnetic behavior in the complex.     

New poly(amide-imide) syntheses. XII. Preparation and properties of poly(amide-imide)s based on the diimide-diacid condensed from 9,9-bis[4-(4-aminophenoxy)phenyl] fluorene and trimellitic anhydride

A dicarboxylic acid ( I ) was prepared from the condensation of 9,9-bis[4-(4-aminophenoxy) phenyl] fluorene and trimellitic anhydride. A new family of poly(amide-imide)s having inherent viscosities of 0.75-1.04 dL/g was prepared by the triphenyl phosphite activated polycondensation from the diimide-diacid I with various aromatic diamines in a medium consisting of N-methyl-2-pyrrolidone (NMP), pyridine, and calcium chloride. Most of the resulting polymers showed an amorphous nature and were readily soluble in polar solvents such as NMP and N,N-dimethylacetamide. All the soluble poly(amide-imide)s afforded transparent, flexible, and tough films. The glass transition temperatures of these polymers were in the range of 262–325°C and the 10% weight loss temperatures were above 525°C in air. © 1994 John Wiley & Sons, Inc.     

Synthesis of New Phenolic Derivatives of Quinazolin-4(3H)-One as Potential Antioxidant Agents—In Vitro Evaluation and Quantum Studies

Considering the important damage caused by the reactive oxygen (ROS) and nitrogen (RNS) species in the human organism, the need for new therapeutic agents, with superior efficacy to the known natural and synthetic antioxidants, is crucial. Quinazolin-4-ones are known for their wide range of biological activities, and phenolic compounds display an important antioxidant effect. Linking the two active pharmacophores may lead to an increase of the antioxidant activity. Therefore, we synthesized four series of new hybrid molecules bearing the quinazolin-4-one and phenol scaffolds. Their antioxidant potential was evaluated in vitro, considering different possible mechanisms of action: hydrogen atom transfer, ability to donate electrons and metal ions chelation. Theoretical quantum and thermodynamical calculations were also performed. Some compounds, especially the ortho diphenolic ones, exerted a stronger antioxidant effect than ascorbic acid and Trolox.