MMP-13 selective isonipecotamide α-sulfone hydroxamates

A series of N-aryl isonipecotamide α-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13.     

MMP-13 selective α-sulfone hydroxamates: a survey of P1' heterocyclic amide isosteres

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.^1a Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.     

Identification of the first potent,selective and bioavailable PPARα antagonist

The discovery and SAR of a novel series of potent and selective PPARα antagonists are herein described. Exploration of replacements for the labile acyl sulfonamide linker led to a biaryl sulfonamide series of which compound 33 proved to be suitable for further profiling in vivo. Compound 33 demonstrated excellent potency, selectivity against other nuclear hormone receptors, and good pharmacokinetics in mouse.     

Orally available and efficacious α4β1/α4β7 integrin inhibitors

A series of potent α4β1/α4β7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn’s disease.     

Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor α/γ dual agonists

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as β-oxidation products of arachidonic-acid-derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other hand, C18 polyunsaturated fatty acids (PUFAs), such as γ-linolenic acid (GLA), have various biological activities, and dinor-PGs are speculated to be biosynthesized from GLA. Here, we synthesized dinor-PGs that may possibly be derived from GLA and examined their activities towards peroxisome proliferator-activated receptors (PPARs). Dinor-PGD₁ (1) and its epimer 13-epi-dinor-PGD₁ (epi-1) were found to be dual agonists for PPARα/γ, whereas PGD₂ derived from arachidonic acid is selective for PPARγ. Thus, GLA-derived dinor-PGs may have unique biological roles.     

Synthesis of α-allylated α,β-unsaturated carbonyl compounds using vanadium/palladium contemporaneous dual catalysis

This protocol describes a new approach for the preparation of α-allylated α,β-unsaturated carbonyl compound by chemoselective cross-coupling of propargyl alcohols with allyl carbonates using an unprecedented vanadium/palladium contemporaneous dual catalysis. This process involves 1,3-transposition of propargyl alcohols by an oxyvanadium catalyst to generate vanadium allenoates and the activation of allyl carbonates by a palladium catalyst to generate π-allylpalladium species. These two active intermediates trap each other more rapidly to afford the observed product, rather than being intercepted by the large excess of starting propargyl alcohol. One example for the preparation of this type of α-allylated α,β-unsaturated carbonyl compound is included in the text. It takes ~20 h to complete the protocol: 1.0 h to set up the reaction, 16 h for the reaction and 2.0 h for isolation and purification. This chemistry has been applied to obtain a wide range of α-allylated α,β-unsaturated ketones, esters and amides, which are highly valuable building blocks in organic synthesis.     

A novel structural framework for α(1A/D)-adrenoceptor selective antagonists identified using subtype selective pharmacophores

In this study four and five-feature pharmacophores for selective antagonists at each of the three α(1)-adrenoceptor (AR) subtypes were used to identify novel α(1)-AR subtype selective compounds in the National Cancer Institute and Tripos LeadQuest databases. 12 compounds were selected, based on diversity of structure, predicted high affinity and selectivity at the α(1D)- subtype compared to α(1A)- and α(1B)-ARs. 9 out of 12 of the tested compounds displayed affinity at the α(1A) and α(1D) -AR subtypes and 6 displayed affinity at all three α(1)-AR subtypes, no α(1B)-AR selective compounds were identified. 8 of the 9 compounds with α(1)-AR affinity were antagonists and one compound displayed partial agonist characteristics. This virtual screening has successfully identified an α(1A/D)-AR selective antagonist, with low μM affinity with a novel structural scaffold of a an isoquinoline fused three-ring system and good lead-like qualities ideal for further drug development.     

Design and synthesis of selective CYP1B1 inhibitor via dearomatization of α-naphthoflavone

Selective cytochrome P450 (CYP) 1B1 inhibition has potential as an anticancer strategy that is unrepresented in the current clinical arena. For development of a selective inhibitor, we focused on the complexity caused by sp³-hybridized carbons and synthesized a series of benzo[h]chromone derivatives linked to a non-aromatic B-ring using α-naphthoflavone (ANF) as the lead compound. Ring structure comparison suggested compound 37 as a suitable cyclohexyl-core with improved solubility. Structural evolution of 37 produced the azide-containing cis-49a, which had good properties in three important respects: (1) selectivity for CYP1B1 over CYP1A1 and CYP1A2 (120-times and 150-times, respectively), (2) greater inhibitory potency of >2 times that of ANF, and (3) improved solubility. The corresponding aromatic B-ring compound 59a showed low selectivity and poor solubility. To elucidate the binding mode, we performed X-ray crystal structure analysis, which revealed the interaction mode and explained the subtype selectivity of cis-49a.     

慢性睡眠限制状态下大鼠髁突软骨MMP-1,MMP-13表达的变化

目的:探讨MMP-1,MMP-13在慢性睡眠限制引起大鼠髁突软骨结构变化中的表达变化及作用。方法:180只雄性Wistar大鼠随机分为3组(n=60):慢性睡眠限制组(CSR)、大平台组(LC)、笼养组(CON)。每组根据试验时间不同分别分为3个亚组(n=20):7天(7D)、14天(14D)、21天(21D)组。参考改良多平台法(MMPM)建立大鼠的慢性睡眠限制模型。通过HE染色观察大鼠髁突软骨的结构变化。通过免疫组化和实时定量PCR分别检测MMP-1和MMP-13的蛋白水平及m RNA水平的表达变化。结果:HE染色和扫描电镜结果显示,CSR组的大鼠髁突软骨出现了病理性的改变。与CON和LC组比较,CSR组MMP-1和MMP-13的m RNA转录和蛋白表达水平明显升高(P0.05)。结论:慢性睡眠限制能够引起大鼠颞下颌关节髁突软骨的病理性变化。MMP-1和MMP-13的表达水平的变化可能在大鼠髁突软骨病理性改变中起关键作用。     

Chiral analogues of (+)-cyclazosin as potent α1B-adrenoceptor selective antagonist

(+)-Cyclazosin [(+)-1] is one of most selective antagonists of the α_1B-adrenoceptor subtype (selectivity ratios, α_1B/α_1A?=?13, α_1B/α_1D?=?38–39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against α₁-adrenoceptors of several homochiral analogues of (+)-cyclazosin featuring different substituents on the carbonyl or amine groups, namely (?)-2, (+)-3, (?)-4–(?)-8, (+)-9. Moreover, we studied the activity of some their opposite enantiomers, namely (?)-1, (?)-3, (+)-6, and (?)-9, to evaluate the influence of stereochemistry on selectivity. The benzyloxycarbonyl and methyl (4aS,8aR) analogues (+)-3 and (?)-6 improved in a significant way the α_1B selectivity of the progenitor compound: 4 and 14 time vs. the α_1D subtype and 35 and 77 times vs. the α_1A subtype, respectively. The study confirmed the importance of the hydrophobic cis-octahydroquinoxaline moiety of these molecules for the establishment of interactions with the α₁-adrenoceptors as well that of their (4aS,8aR) stereochemistry to grant selectivity for the α_1B subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3.     

Fluoroalkyl α side chain containing 3,4-diamino-cyclobutenediones as potent and orally bioavailable CXCR2–CXCR1 dual antagonists

A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various fluoroalkyl groups as α side chain were prepared and found to show significant improvements in the binding affinities towards both CXCR2 and CXCR1 receptors.     

DKK-1和MMP-14在口腔鳞癌中的表达及其意义

目的:研究DKK-1蛋白和MMP-14蛋白在口腔鳞状细胞癌组织中的表达和临床意义。方法:选择口腔鳞癌石蜡标本62例作为实验组,25例正常口腔黏膜组织作为对照组。应用免疫组织化学法检测其DKK-1和MMP-14蛋白的表达,并分析二者与口腔鳞癌患者临床病理特征之间的关系及二者表达的相关性。结果:实验组DKK-1的阳性表达率为40.32%,明显低于对照组中(68%),而MMP-14的阳性表达率(72.58%)明显高于对照组(24%)(P0.05)。DKK-1和MMP-14的表达水平与口腔鳞癌的分期、淋巴结转移及分化程度有显著相关(P0.05)。口腔鳞癌组织中DKK-1和MMP-14蛋白的表达呈显著负相关(r=-0.600,P0.05)。结论:口腔鳞状细胞癌组织中DKK-1的表达下调,MMP-14的表达上调,二者可能参与了OSCC的发生和发展过程,并有望用于口腔鳞状细胞癌的病情和预后评估。     

Suppression of 12-O-Tetradecanoylphorbol-13-Acetate-Induced MCF-7 Breast Adenocarcinoma Cells Invasion/Migration by α-Tomatine Through Activating PKCα/ERK/NF-κB-Dependent MMP-2/MMP-9 Expressions

α-Tomatine, isolated from Lycopersicon esculentum Linn., is a naturally occurring glycoalkaloids in immature green tomatoes. Some reports demonstrated that α-tomatine had various anti-carcinogenic properties. First, the result demonstrated α-tomatine could inhibit TPA-induced the abilities of the adhesion, morphology/actin cytoskeleton arrangement, invasion, and migration by cell–matrix adhesion assay, immunofluorescence stain assay, Boyden chamber invasion assay, and wound-healing assay. Data also showed α-tomatine could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and protein kinase C-α (PKCα) involved in the downregulation of the enzyme activities and messenger RNA levels of matrix metalloproteinase-2/9 (MMP-2/MMP-9) induced by TPA. Next, α-tomatine also strongly inhibited TPA-induced the activation of nuclear factor kappa B (NF-κB) and phospho-inhibitor of kappa Bα (phospho-IκBα). In addition, TPA-induced translocation of PKC-α from cytosol to membranes, and suppression of TPA elicited the expression of PKC-α by adding the PKC-α inhibitors, GF-109203X and Gö-6983. The treatment of specific inhibitor for ERK (U0126) to MCF-7 cells could inhibit TPA-induced MMP-2/MMP-9 and phospho-ERK along with an inhibition on cell invasion and migration. Application of α-tomatine to prevent the invasion/migration of MCF-7 cells through blocking PKCα/ERK/NF-κB activation is first demonstrated herein.     

Design,synthesis and structure–activity relationships of azole acids as novel,potent dual PPAR α/γ agonists

The design, synthesis and structure–activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARα/γ agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.     

MQ-HCN-based pulse sequences for the measurement of 13C1′-1H1′, 13C1′-15N, 1H1′-15N, 13C1′-13C2′, 1H1′-13C2′, 13C6/8-1H6/8, 13C6/8-15N, 1H6/8-15N, 13C6-13C5, 1H6-13C5 dipolar couplings in 13C, 15N-labeled DNA (and RNA)

A suite of multiple quantum (MQ) HCN-based pulse sequences has been developed for the purpose of collecting dipolar coupling data in labeled nucleic acids. All the pulse sequences are based on the robust MQ-HCN experiment which has been utilized for assignment purposes in labeled nucleic acids for a number of years and provides much-needed resolution for the dipolar coupling measurements. We have attempted to collect multiple couplings centered on the 13C1' and 13C6/8 positions. Six pulse sequences are described, one each for measurement of one-bond 13C1'-1H1' and 13C6/8-1H6/8 couplings, one for measurement of one-bond 13C1'-15N and two-bond 1H1'-15N couplings, one for measurement of one-bond 13C6/8-15N and two-bond 1H6/8-15N couplings, one for measurement of one-bond 13C1'- 13C2' and two-bond 1H1'-13C2' couplings, and one for measurement of one-bond 13C6-13C5 and two-bond 1H6-13C5 couplings in the bases of C and T. These sequences are demonstrated for a labeled 18 bp DNA duplex in a 47 kDa ternary complex of DNA, CBFbeta, and the CBFalpha Runt domain, thus clearly demonstrating the robustness of the pulse sequences even for a very large complex.     

Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase

A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC₅₀: 1.79–10.71 nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC₅₀ = 0.14, 0.09 and 0.25 µM, respectively) were obvious higher than that of miglitol (IC₅₀ = 2.43 µM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFR^wt tyrosine kinase (IC₅₀ = 1.79 nM), also to α-glucosidase (IC₅₀ = 0.39 µM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase.     

A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold

Dual inhibition of microsomal prostaglandin E₂ synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of α-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC₅₀ mPGES-1 = 0.94 μM; IC₅₀ 5-LO = 0.1 μM) showing the most favorable in vitro pharmacological profile.