Chun-Lan Tang

4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTPs. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

Design and synthesis of paracaseolide A analogues as selective protein tyrosine phosphatase 1B inhibitors

A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects.

Well-width dependence of in-plane optical anisotropy in (001) GaAs/AlGaAs quantum wells induced by in-plane uniaxial strain and interface asymmetry

The well-width dependence of in-plane optical anisotropy (IPOA) in (001) GaAs/AlxGa1-xAs quantum wells induced by in-plane uniaxial strain and interface asymmetry has been studied comprehensively. Theoretical calculations show that the IPOA induced by in-plane uniaxial strain and interface asymmetry exhibits much different well-width dependence. The strain-induced IPOA is inversely proportional to the energy spacing between heavy- and light-hole subbands, so it increases with the well width. However, the interface-related IPOA is mainly determined by the probability that the heavy- and light-holes appear at the interfaces, so it decreases with the well width. Reflectance difference spectroscopy has been carried out to measure the IPOA of (001) GaAs/AlxGa1-xAs quantum wells with different well widths. Strain- and interface-induced IPOA have been distinguished by using a stress apparatus, and good agreement with the theoretical prediction is obtained. The anisotropic interface potential parameters are also determined. In addition, the energy shift between the interface- and strain-induced 1H1E reflectance difference (RD) structures, and the deviation of the 1L1E RD signal away from the prediction of the calculation model have been discussed.

Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.

A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).

Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC(50)=12.74 μM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP.

Strain-induced in-plane optical anisotropy in (001) GaAs∕AlGaAs superlattice studied by reflectance difference spectroscopy

In-plane optical anisotropy (IPOA) in (001) GaAs/AlGaAs superlattice induced by uniaxial strain has been investigated by reflectance difference spectroscopy (RDS). Uniaxial strain on the order of 10(-4) was introduced by bending a strip sample with a stress apparatus. The IPOA of all interband transitions shows a linear dependence on strain. The birefringence and dichroism spectra induced by strain are obtained by RDS on the basis of a three-phase model, which is in good agreement with the reported results. (c) 2006 American Institute of Physics.

PTP1B inhibitors from stems of Angelica keiskei (Ashitaba).

Three new chalcones, xanthoangelols K-M (1-3), together with 19 known compounds were isolated from the stems of Angelica keiskei Koidzumi, a well-known rejuvenated and anti-diabetic plant originated from Japan. The structures of compounds 1-3 were elucidated on the basis of spectroscopic data and Moshers method. All compounds were evaluated for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Among them, six chalcones, xanthoangelol K (1), xanthoangelol (4), xanthoangelol F (5), 4-hydroxyderricin (6), xanthoangelol D (7), xanthoangelol E (8), and a coumarin, methoxsalen (17), showed strong PTP1B inhibitory effect with IC50 values of 0.82, 1.97, 1.67, 2.47, 3.97, 1.43, and 2.53μg/mL, respectively. A kinetic study revealed that compound 1 inhibited PTP1B with characteristics typical of a competitive inhibitor. Molecular docking simulations elucidated that ring B of 1 may anchor in a pocket of PTP1B and the molecule is stabilized by hydrogen bonds with Arg47, Asp48, and π-π interaction with Phe182 of PTP1B.

Design, synthesis, and biological evaluation of novel 2-ethyl-5-phenylthiazole-4-carboxamide derivatives as protein tyrosine phosphatase 1B inhibitors with improved cellular efficacy.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin and leptin signal-transduction pathways. PTP1B inhibitors have emerged as attractive and potent pharmaceutical agents for the treatment of type 2 diabetes and obesity. We identified a series of 2-ethyl-5-phenylthiazole-4-carboxamide (PTA) derivatives, inspired from the ACT scaffold of Scleritodermin A, as a novel class of PTP1B inhibitors. Structure-activity relationship (SAR) analysis and docking studies revealed the molecular basis of PTP1B inhibition by these compounds. PTA derivative 18g was capable of inhibiting intracellular PTP1B and subsequently activating the insulin signaling pathway. Treatment of cells with 18g markedly increased the phosphorylation levels of IRβ and Akt as well as the rate of glucose uptake.

Synthesis and biological evaluation of novel bis-aromatic amides as novel PTP1B inhibitors.

A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them, compound 15 displayed an IC50 value of 2.34±0.08 μM with 5-fold preference over TCPTP. More importantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insulin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

The two- to three-dimensional growth transition of InAs/GaAs epitaxy layer studied by reflectance difference spectroscopy

In this work, we have adopted reflectance difference spectroscopy to study the evolution of InAs layer grown at different temperatures in GaAs matrix. Associated with the two- to three-dimensional growth transition of InAs layer, the transition energies and the in-plane optical anisotropy of InAs wetting layer exhibit abrupt changes. This provides a new way to decide the critical thickness h(c) for the growth transition. The obtained h(c)s are compared with those determined by atomic force microscope measurement, and discrepancy is found at high temperatures. The origin of the difference is clarified and the variations in hc with temperature are further discussed