Linker Moiety Research Articles

Dimeric C34 Derivatives Linked through Disulfide Bridges as New HIV-1 Fusion Inhibitors.

C34, a 34-mer fragment peptide, is contained in the HIV-1 envelope protein gp41. A dimeric derivative of C34 linked through a disulfide bridge at its C terminus was synthesized and found to display potent anti-HIV activity, comparable with that of a previously reported PEGylated dimer of C34REG. The reduction in the size of the linker moiety for dimerization was thus successful, and this result might shed some light on the mechanism of the suppression of six-helix bundle formation by these C34 dimeric derivatives. Addition of a Gly-Cys(CH2 CONH2 )-Gly-Gly motif at the N-terminal position of a C34 monomeric derivative significantly increased the anti-HIV-1 activity. This moiety functions as a new pharmacophore, and this might provide a useful insight into the design of potent HIV-1 fusion inhibitors.

An Indacenodithieno[3,2-b]thiophene-Based Organic Dye for Solid-State p-Type Dye-Sensitized Solar Cells.

An indacenodithieno[3,2-b]thiophene (IDTT) unit is used as a linker moiety to design a new p-type dye-TIP-for solid-state p-type dye-sensitized solar cells. Solar cells based on the TIP dye offered an efficiency of 0.18 % with an open-circuit photovoltage of 550 mV and a short-circuit photocurrent density of 0.86 mA cm-2 , which is better than those of two reference dyes, PB6 and BH4. Charge lifetime experiments reveal that the IDTT linker-based TIP dye significantly suppresses charge recombination losses in the devices.

P‐192: Development of New Linker Moiety for TADF Materials: Elucidation of Material Properties by Substitution Position Effect

Two thermally activated delayed fluorescent(TADF) materials, 23TrzCz and 32TrzCz, were successfully designed and synthesized using an aromatic linker moiety for green organic light emitting diodes(OLEDs). The donor moiety was 3,3‐bicarbazole and the acceptor moiety was diphenyltriazine. The synthesized materials were used as an emitter in OLED device and the 23TrzCz showed highly efficient device performance with a power efficiency of 31.0 lm/W and an external quantum efficiency of 18.3%. In addition, the 23TrzCz showed emission of CIE x,y (0.30, 0.56) suitable for green devices.

Structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi-QSAR modeling study

Histone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disease conditions such as tumorigenesis, cell proliferation, cancer, viral infections, neuronal disorders and other epigenetic diseases. Therefore, inhibition of HDAC8 is a primary method to combat these diseases. In this article, a multi-QSAR modeling study on tetrahydroisoquinoline derivatives was conducted to identify important contributions of the structural features of these compounds toward HDAC8 inhibition. All these QSAR modeling techniques were individually validated and justified the observations of each other. The results implied that the tetrahydroisoquinoline moiety may be effective as a cap group than as a linker moiety for HDAC8 inhibition. Different substitutions at the tetrahydroisoquinoline scaffold were also found to be crucial in modulating HDAC8 inhibition.Communicated by Ramaswamy H. Sarma

Thermal, soluble, and hydrophobic properties of polyimides derived from 4-(4-diethylamino)phenyl-2,6-bis(4-(4-aminophenoxy)phenyl)pyridine

A novel aromatic diamine monomer, 4-(4-diethylamino)phenyl-2,6-bis(4-(4-aminophenoxy)phenyl)pyridine (EPAPP), containing pyridine ring units, ether linkage moieties and diethylaminophenyl pendent groups, has been designed and synthesized through three-step methods, and then used to prepare for a series of polyimides with commercial aromatic dianhydrides via two-step solution polycondensation. The resulting polyimides showed good solubility in common polar solvents, such as NMP, DMF, DMSO. They exhibited high thermal stability with the glass transition temperature (Tgs) more than 254 °C, and the temperature of 10% weight loss over 544 °C with more than 64% residue at 800 °C under nitrogen. They presented excellent hydrophobic properties with the contact angle in the range of 81.9–91.9°. In addition, the results of Wide-angle X-ray Diffraction (WAXD) indicated that these polymers revealed an amorphous structure.

The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons

In this paper, we designed, synthesized and tested a small set of three new derivatives potentially targeting the D3R-nAChR heteromer, a receptor complex recently identified and characterized as the molecular entity that, in dopaminergic neurons, mediates the neurotrophic effects of nicotine. By means of a partially rigidified spacer of variable length, we incorporated in the new compounds (1a–c) the pharmacophoric substructure of a known β2-subunit-containing nAChR agonist (A-84543) and that of the D2/D3R agonist drug ropinirole. All the compounds retained the ability to bind with high affinity both β2-subunit-containing nAChR and D3R. Compound 1a, renamed HyNDA-1, which is characterized by the shortest linker moiety, was the most interesting ligand. We found, in fact, that HyNDA-1 significantly modulated structural plasticity on both mice and human dopaminergic neurons, an effect strongly prevented by co-incubating this ligand with either nAChR or D3R antagonists. Moreover, the neurotrophic effects of HyNDA-1 were specifically lost by disrupting the complex with specific interfering peptides. Interestingly, by using the Bioluminescence Resonance Energy Transfer 2 (BRET2) assay in HEK-293 transfected cells, we also found that HyNDA-1 has the ability to increase the affinity of interaction between nAChR and D3R. Overall, our results indicate that the neurotrophic effects of HyNDA-1 are mediated by activation of the D3R-nAChR heteromeric complex specifically expressed on dopaminergic neurons.

Flexible vs. rigid bis(2-benzimidazolyl) ligands in Cu(II) complexes: Impact on redox chemistry and oxidative DNA cleavage activity

Cu(II) complexes of bis(2-benzimidazolyl) ligands connected by different linker moieties (disulfide, ethylene, ortho-phenylene) were applied in DNA cleavage reactions. Hydroxyl radicals and hydrogen peroxide were proven as reactive oxygen species (ROS) in a DNA quenching experiment. Thus, an oxidative DNA cleavage mechanism is suggested. The binding affinity of the Cu(II) complexes to DNA was studied by UV–VIS (DNA melting), fluorescence (ethidium bromide displacement assay) and circular dichroism (CD) spectroscopy indicating a correlation between DNA binding and DNA cleavage efficiency. The most important finding was that oxidative nuclease activity correlated with flexibility of the linker between the benzimidazole moieties. A more flexible linker allowed for an easier switch between square planar (Cu(II)) and tetrahedral geometry (Cu(I)) for the complex, and thus resulted in an enhanced ROS generation. EPR spectroscopy and cyclic voltammetry were applied to investigate such changes in geometry and redox state.

Theoretical study of 5,10-diphenylindeno[2,1-a]indene (DPI) dyes for dye sensitized solar cells (DSSC)

Six D-DPI-A (D-π-A) dyes combining various arylamine electron donors (diphenylamine and triphenylamine moieties) with a fixed π-linker (DPI) and a fixed electron acceptor (cyanoacrylic acid) were designed to determine their electronic, photophysical and photovoltaic properties. It was found that electron-donating ability correlates positively with the energy of the highest occupied molecular orbital (EHOMO) of the electron donor moiety. Optimized structures and electronic properties (highest occupied molecular orbital energy (EHOMO), lowest unoccupied molecular orbital (ELUMO), and energy difference (Eg) between HOMO and LUMO) were calculated by the density functional theory (DFT/B3LYP/6-31G(d)) method. Photovoltaic properties [electron injection driving force (ΔGinj)] and photophysical properties [oscillator strengths (f), selected absorption wavelengths ( $$\lambda_{\text{abs}}^{\text{calc}}$$ ) and light harvesting efficiency related to longest absorption wavelength ( $${\text{LHE}}_{{\lambda_{\text{longest}} }}$$ )] were calculated by the time-dependent density functional theory TD/BHandHLYP/6-31G(d) method. Both ΔGinj and longest absorption wavelength (λlongest) can be enhanced by increasing the electron-donating ability of the electron donor in these dyes. According to photophysical property analysis, λlongest is the intra-molecular charge transfer band which can be regarded as the HOMO to LUMO transition. The electron density of HOMO is localized at the electron donor and the π-conjugated linker (DPI) moiety. The electron density of LUMO is trapped at the π-linker (DPI) and the electron-acceptor moiety. It is concluded that the electron-donating ability of the electron donor strongly influences the photophysical properties of the DSSC.

Lipopolysaccharide Structural Differences between Western and Asian Helicobacter pylori Strains.

Recent structural analysis of the lipopolysaccharide (LPS) isolated from Helicobacter pylori G27 wild-type and O-antigen ligase mutant resulted in the redefinition of the core-oligosaccharide and O-antigen domains. The short core-oligosaccharide (Glc–Gal–Hep-III–Hep-II–Hep-I–KDO) and its attached trisaccharide (Trio, GlcNAc–Fuc–Hep) appear to be highly conserved structures among H. pylori strains. The G27 LPS contains a linear glucan–heptan linker between the core-Trio and distal Lewis antigens. This linker domain was commonly identified in Western strains. In contrast, out of 12 partial LPS structures of Asian strains, none displayed the heptan moiety, despite the presence of Lewis antigens. This raises the question of how Lewis antigens are attached to the Trio, and whether the LPS structure of Asian strains contain another linker. Of note, a riban was identified as a linker in LPS of the mouse-adapted SS1 strain, suggesting that alternative linker structures can occur. In summary, additional full structural analyses of LPS in Asian strains are required to assess the presence or absence of an alternative linker in these strains. It will also be interesting to study the glucan-heptan linker moieties in pathogenesis as H. pylori infections in Asia are usually more symptomatic than the ones presented in the Western world.

Development of new HO-1 inhibitors by a thorough scaffold-hopping analysis

HO-1 inhibition is considered a valuable anticancer approach. In fact, up-regulation of HO-1 had been repeatedly reported in many types of human malignancies, and in these clinical cases, poor outcomes are reported. To identify novel HO-1 inhibitors suitable for drug development, a scaffold-hopping strategy calculation was utilized to design novel derivatives. Different parts of the selected molecule were analyzed and the different series of novel compounds were virtually evaluated. The calculation for the linker moiety of the classical HO-1 inhibitors structure led us to compounds 5 and 6. A synthetic pathway for the two molecules was designed and the compounds were synthesized. The biological activity revealed an HO-1 inhibition of 0.9 and 54 μM for molecules 5 and 6 respectively. This study suggested that our scaffold-hopping approach was successful and these results are ongoing for further development.

Glutamic acid\u2013valine\u2013citrulline linkers ensure stability and efficacy of antibody\u2013drug conjugates in mice

Valine–citrulline linkers are commonly used as enzymatically cleavable linkers for antibody–drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody–drug conjugate with glutamic acid–valine–citrulline linkers is responsive to enzymatic drug release but undergoes almost no premature cleavage in mice. We demonstrate that this construct exhibits greater treatment efficacy in mouse tumor models than does a valine–citrulline-based variant. Notably, our antibody–drug conjugate contains long spacers facilitating the protease access to the linker moiety, indicating that our linker assures high in vivo stability despite a high degree of exposure. This technology could add flexibility to antibody–drug conjugate design and help minimize failure rates in pre-clinical studies caused by linker instability.

Development of biotin-retinoid conjugates as chemical probes for analysis of retinoid function

Herein, we report the rational design, synthesis and biological evaluation of conjugates consisting of the synthetic retinoid Am580 and biotin connected via a linker moiety. We found that the linking substructure between the retinoid part and the biotin part is critical for retaining the biological activity. Conjugate 4 with a shorter linker showed similar potency to endogenous retinoid ATRA (1) and the parent compound Am580 (2) for neural differentiation of mouse embryotic carcinoma P19 cells, and showed the same pattern of induction of gene expression. It is expected to be useful as a probe for investigations of retinoid function. The design rationale and structure-activity relationship of the linker moiety are expected to be helpful for developing biotin conjugates of other nuclear receptor ligands.

Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety

Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1 μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.

Biophysical Properties and Heating-Induced Aggregation of Lysine-Conjugated Antibody-Drug Conjugates

The commercially available antibody-drug conjugate (ADC) product, Kadcyla® is synthesized using a 2-step reaction, wherein the linker is conjugated to native lysines on the mAb in step 1, followed by drug conjugation to the linker-modified antibody in step 2. In our study, we synthesized a lysine-conjugated ADC (Syn-ADC) on the same trastuzumab scaffold as Kadcyla® using a 1-step reaction. Mass spectrometry of both products revealed a subpopulation of Kadcyla® containing free linkers conjugated to the mAb, but not conjugated to the drug, which were absent in the 1-step reaction ADC product. Differential scanning calorimetry thermograms showed that the drug and linker conjugation significantly reduced the thermal stability and energies of activation for the denaturation of the CH2 domain of the ADCs. The heating induced aggregation events started as early as ∼57°C and ∼45°C for Kadcyla® and Syn-ADC, respectively, compared with 71°C for Herceptin®. The colloidal stability measurements clearly showed that the hydrophobic drug payload on ADCs significantly reduced the repulsive interprotein interactions when compared to the unconjugated antibody under formulation buffer conditions (pH 6.0). Attaching hydrophobic drug and linker moieties onto the antibody lowered the thermal and colloidal stabilities and increased the aggregation propensity of the ADCs.

Computational Investigation of the Influence of π‐Bridge Conjugation Order of Thiophene and Thiazole Units in Triphenylamine Based Dyes in Dye‐Sensitized Solar Cells

AbstractIn this study, ten triphenylamine based dyes were investigated by varying the π‐bridge size with a different order of thiophene and thiazole units to understand their potential use in dye‐sensitized solar cells (DSSCs). Geometry optimization, the energy levels and electron density of the highest occupied molecular orbital and the lowest unoccupied molecular orbital, and UV‐visible absorption spectra were calculated using density functional theory (DFT) and time‐dependent DFT (TD‐DFT) methods. The electron injection driving force, dye regeneration driving force, natural bond orbital (NBO) analysis of dye‐(TiO2)8 cluster and dye reorganization energy were calculated to predict the most suitable dyes for DSSC application. Dye 4 ((Z)‐2‐cyano‐3‐(2′‐((E)‐4‐(diphenylamino)styryl)‐[2, 5′‐bithiazol]‐4‐yl)acrylic acid) followed by Dye 6 ((Z)‐2‐cyano‐3‐(5‐(2‐((E)‐4‐(diphenylamino)styryl)thiazol‐5‐yl)thiophen‐3‐yl)acrylic acid) having two linker moieties were identified as the potential candidates.

Synthesis and properties of a biodegradable polymer-drug conjugate: Methotrexate-poly(glycerol adipate)

Polymer-drug conjugates have been actively developed as potential anticancer drug delivery systems. In this study, we report the first polymer-anticancer drug conjugate with poly(glycerol adipate) (PGA) through the successful conjugation of methotrexate (MTX). MTX-PGA conjugates were controllably and simply fabricated by carbodiimide-mediated coupling reaction with various high molar ratios of MTX. The MTX-PGA conjugate self-assembled into nanoparticles with size dependent on the amount of conjugated MTX and the pH of medium. Change in particle size was attributed to steric hindrance and bulkiness inside the nanoparticle core and dissociation of free functional groups of the drug. The MTX-PGA nanoparticles were physically stable in media with pH range of 5-9 and ionic strength of up to 0.15 M NaCl and further chemically stable against hydrolysis in pH 7.4 medium over 30 days but enzymatically degradable to release unchanged free drug. Although 30%MTX-PGA nanoparticles exhibited only slightly less potency than free MTX in 791T cells in contrast to previously reported human serum albumin-MTX conjugates which had >300 times lower potency than free MTX. However, the MTX nanoparticles showed 7 times higher toxicity to Saos-2 cells than MTX. Together with the enzymic degradation experiments, these results suggest that with a suitable biodegradable polymer a linker moiety is not a necessary component. These easily synthesised PGA drug conjugates lacking a linker moiety could therefore be an effective new pathway for development of polymer drug conjugates.

STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.

Discovery of carbazole carboxamides as novel RORγt inverse agonists

A novel series of carbazole carboxamides was discovered as potent RORγt inverse agonists using a scaffold hybridization strategy. Structure-activity relationship exploration on the amide linker, carbazole ring and arylsulfone moiety of the hybrid amide 3a led to identification of potent RORγt inverse agonists. Compound 6c was found to have a good RORγt activity with an IC50 of 58.5 nM in FRET assay, and reasonable inhibitory activity in mouse Th17 cell differentiation assay (58.8% inhibition at 0.3 μM). The binding mode of carbazole carboxamides in RORγt ligand binding domain was discussed.

Dianionic Phase-Transfer Catalyst for Asymmetric Fluoro-cyclization

Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro-cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro-carbocation intermediate.

Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery.

The pan-histone deacetylase (HDAC) inhibitors comprise a fish-like structural orientation where hydrophobic aryl- and zinc-binding groups act as head and tail, respectively of a fish. The linker moiety correlates the body of the fish linking head and tail groups. Despite these pan-HDAC inhibitors, selective HDAC-8 inhibitors are still in demand as a safe remedy. HDAC-8 is involved in invasion and metastasis in cancer. This review deals with the rationale behind HDAC-8 inhibitory activity and selectivity along with detailed structure-activity relationships of diverse hydroxamate-based HDAC-8 inhibitors. HDAC-8 inhibitory potency may be increased by modifying the fish-like pharmacophoric features of such type of pan-HDAC inhibitors. This review may provide a preliminary basis to design and optimize new lead molecules with higher HDAC-8 inhibitory activity. This work may surely enlighten in providing useful information in the field of target-specific anticancer therapy.