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Chemical Biology & Drug Design

Liangyu Zhang, Zelong Fu, Xia Li, Haitao Tang, Jiesi Luo, Dehui Zhang, Yongzhi Zhang, Zhiyang Han, Mingzhu Yin
Breast cancer is one for the most invasive cancer type in female population. The functional activity of transformation growth factor-activated factor 1 (TAK1) in breast cancer progression increasingly attracts attention since it provides a potential target for anti-breast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells...
February 21, 2017: Chemical Biology & Drug Design
Hua-Li Qin, Jing Leng, Bahaa G M Youssif, Muhammad Wahab Amjad, Maria Abdul Ghafoor Raja, Muhammad Ajaz Hussain, Zahid Hussain, Syeda Naveed Kazmi, Syed Nasir Abbas Bukhari
The incidence of cancer can be decreased by chemoprevention using either natural or synthetic agents. Apart from synthetic compounds, numerous natural products have exhibited promising potential to inhibit carcinogenesis in vivo. In this study, α, β-unsaturated carbonyl based anticancer compounds were used as starting materials to synthesize new oxime analogs. The findings from the antiproliferative assay using seven different human cancer cell lines provided a clear picture of structure-activity relationship...
February 10, 2017: Chemical Biology & Drug Design
Mahmoud S Ahmed, Fardous El-Senduny, Jessica Taylor, Fathi T Halaweish
Assembly of Cucurbitacin inspired estrone analogs have been previously synthesized and screened against melanoma cell lines. Further synthetic optimization was executed via installation of Azide polar functional moiety across 23, 24 α, β-unsaturated ketone side chain using Michael addition reaction. This was followed by biological screening against melanoma cell lines employing MTT assay, in-cell based ELISA assay, and western blot analysis to monitor the potential of the synthesized analogs to inhibit the phosphorylated ERK levels...
February 7, 2017: Chemical Biology & Drug Design
Sanaz Ebrahimi Samani, Zahra Seraj, Hossein Naderimanesh, Khosro Khajeh, Ahmad Reza Esmaeili Rastaghi, Taher Droudi, Peirhosein Kolivand, Hadi Kazemi, S Mohsen Asghari
Whereas several anticancer peptides are in different stages of clinical development, their administration is limited by fast elimination from the systemic circulation. Peptide loading on nano-carriers can pave the way for their future application. We have recently indicated that a disulfide loop rather than a Zn-binding loop improves the antiangiogenic and antitumor activities of the N-terminal fragment of endostatin. In this study, chitosan nanoparticles (CS NPs) are used for the controlled release of the engineered peptide...
February 6, 2017: Chemical Biology & Drug Design
Adriane F Brito, James O Fajemiroye, Hiasmin F S Neri, Dayane M Silva, Daiany P B Silva, Germán Sanz, Boniek G Vaz, Flávio S de Carvalho, Paulo C Ghedini, Luciano M Lião, Ricardo Menegatti, Elson A Costa
In this study we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening refered to as Irwin test, prior to sodium pentobarbital-induced sleep, open field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light-dark box tests. In addition, the mnemonic activity was evaluated through step-down test...
February 3, 2017: Chemical Biology & Drug Design
Albert H Chan, Sung Wook Yi, Ethan M Weiner, Brendan R Amer, Christopher K Sue, Jeff Wereszczynski, Carly A Dillen, Silvia Senese, Jorge Z Torres, J Andrew McCammon, Lloyd S Miller, Michael E Jung, Robert T Clubb
Staphylococcus aureus is a leading cause of hospital-acquired infections in the United States and is a major health concern as methicillin-resistant S. aureus (MRSA) and other antibiotic resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches...
February 3, 2017: Chemical Biology & Drug Design
Muhammad Usman Akbar, Tanveer Hussain Bokhari, Muhammad Khalid, Muhammad Razeen Ahmad, Samina Roohi, Saira Hina, Sajid Mehmood, Muhammad Sohaib, Tania Jabbar
Kanamycin is an antibiotic, isolated from Streptomyces kanamyceticus, which is used to treat serious bacterial infections. The fact that the present radioligand (99m) Tc-kanamycin used for diagnosis is short-lived, raised a need to label and study kanamycin with one of the most important beta (β) radiation emitting isotope (177) Lu. Labeling yield of (177) Lu-kanamycin was confirmed by different chromatography techniques such as paper chromatography, TLC, HPLC. Several experiments were performed to optimize labeling with changing reaction conditions such as pH, temperature, amount of ligand, and reaction time etc...
February 2, 2017: Chemical Biology & Drug Design
Balmukund S Thakkar, Marte Albrigtsen, John-Sigurd M Svendsen, Jeanette H Andersen, Richard A Engh
Drug discovery strategies include from broad random screening to focussed target-based approaches. Structure and substrate information greatly enable target-based design, but this is limited to relatively few targets; cell-based screening can identify new targets but often suffers from low hit rates and difficult hit optimization. Thus, newer approaches are needed that can improve the efficiency of screening and hit optimization. Here we describe an efficient approach for hit-generation, which may be called "biofocussed chemoprospecting"...
January 31, 2017: Chemical Biology & Drug Design
Kathrin Faber, Giovanni K Zorzi, Nathaly T Brazil, Marilise B Rott, Helder F Teixeira
: Current treatments for Acanthamoeba keratitis are unspecific. Due to the presence of the resilient cyst form of the parasite, the infection is persistent. Silencing the key protein of cyst formation, glycogen phosphorylase, has shown potential for reducing encystment processes of the Acanthamoeba trophozoite. However a suitable carrier to protect and deliver siRNA sequences is still needed. DOTAP: DOPE:DSPE-PEG liposomes were prepared by three different techniques and used to associate a therapeutic siRNA sequence...
January 30, 2017: Chemical Biology & Drug Design
G B Dharma Rao, Subhrajyoti Bhandary, Deepak Chopra, Katharigatta N Venugopala, Raquel M Gleiser, Kabange Kasumbwe, Bharti Odhav
The new-fangled bis(4-substituted benzyl) 4-(4-substitued phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate derivatives were synthesized by the union of substituted aryl aldehyde, tert-butyl acetoacetate, ammonium carbonate with 4-substituted benzyl alcohol via Hantzsch ester synthesis in aqueous medium under catalyst-free conditions. The newly synthesized compounds were characterized by spectroscopic techniques such as IR, NMR ((1) H & (13) C), ESI mass, elemental analysis and single crystal X-ray diffraction...
January 30, 2017: Chemical Biology & Drug Design
Chia-Jen Hsu, Wen-Chi Hsu, Der-Jay Lee, An-Lun Liu, Chia-Ming Chang, Huei-Jhen Shih, Wun-Han Huang, Guey-Jen Lee-Chen, Hsiu Mei Hsieh-Li, Guan-Chiun Lee, Ying-Chieh Sun
GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)-molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and 5 compounds that were analogous to a known inhibitor with an available crystal structure. TI-MD simulations of the first two compounds (analogs 1 and 2) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results...
January 27, 2017: Chemical Biology & Drug Design
Yan Liu, Tingting Wang, Yong Ling, Na Bao, Wei Shi, Li Chen, Jianbo Sun
Twenty-six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan-based derivatives (8a, 8b, 8c, 8d, 8e, 9e, and 9f) exhibited desirable cytotoxic activities, while NONOate-based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 (8a, IC50 = 0...
January 25, 2017: Chemical Biology & Drug Design
Beata Żołnowska, Jarosław Sławiński, Aneta Pogorzelska, Krzysztof Szafrański, Anna Kawiak, Grzegorz Stasiłojć, Mariusz Belka, Joanna Zielińska, Tomasz Bączek
A series of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives 12-46 have been synthesized by the reaction of aminoguanidines with an appropriate alpha-oxo-acids hydrates in glacial acetic acid. All the synthesized compounds were evaluated for their anticancer activity against HeLa, HCT-116 and MCF-7 human tumor cell lines. Two compounds 33 and 34 displayed outstanding cytotoxic effect selectively toward HeLa cancer cells (IC50 = 19 μM) and did not exhibit toxicity to the non-cancerous HaCaT cells...
January 25, 2017: Chemical Biology & Drug Design
Huan Hu, Songlin Yang, Jianghong Zhang, Guangyu Mao
The intermolecular recognition and interaction between human transforming growth factor β-1 (TGF-β1) and its cognate receptor TβRII have been implicated in the pathological condition of hypertrophic scarring (HS). Here, we attempted to rationally derive peptide inhibitors from the complex interface of TGF-β1 with TβRII to disrupt such interaction for the suppression of fibroblast activation involved in HS. A synthetic strategy that integrated computational design and fluorescence-based assay was described to examine the structural basis and energetic property of TGF-β1-TβRII crystal structure, from which a small peptide segment in the complex binding site was stripped artificially...
January 25, 2017: Chemical Biology & Drug Design
Fateme Haghiralsadat, Ghasem Amoabediny, Mohammad Hasan Sheikhha, Behrouz Zandieh-Doulabi, Samira Naderinezhad, Marco N Helder, Tymour Forouzanfar
A novel approach was developed for the preparation of stealth controlled-release liposomal doxorubicin. Various liposomal formulations were prepared by employing both thin film and pH gradient hydration techniques. The optimum formulation contained phospholipid and cholesterol in 1:0.43 molar ratios in the presence of 3% DSPE-mPEG (2000). The liposomal formulation was evaluated by determining mean size of vesicle, encapsulation efficiency, polydispersity index, zeta potentials, carrier's functionalization and surface morphology...
January 25, 2017: Chemical Biology & Drug Design
Diogo Rodrigo Magalhaes Moreira, Dourivaldo Silva Santos, Renan Fernandes do Espírito Santo, Flávia Evangelista Dos Santos, Gevanio Bezerra de Oliveira Filho, Ana Cristina Lima Leite, Milena Botelho Pereira Soares, Cristiane Flora Villarreal
Chemotherapy-induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy-induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potencial analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond...
January 23, 2017: Chemical Biology & Drug Design
Vishnupriya Kanakaveti, R Sakthivel, S K Rayala, M Michael Gromiha
Evasion of apoptosis owing to aberrant expression of Bcl-2 (B-cell lymphoma-2) anti-apoptotic proteins is a promising hallmark of cancer. These proteins are associated with resistance to chemotherapy and radiation. Currently available QSAR models are limited to a set of inhibitors corresponding to a particular chemical scaffold, and unified models are required to identify the differential specificity of diverse compounds towards inhibiting these targets. In this study, we predicted the factors driving differential activity and specificity implementing multiplexed QSAR analysis for a data set of 1649 reported inhibitors of Bcl-2 (B-cell lymphoma-2) and Bcl-xL (B-cell lymphoma-extra large)...
January 23, 2017: Chemical Biology & Drug Design
Paola Santos, Fabian López-Vallejo, Carlos-Y Soto
Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed...
January 22, 2017: Chemical Biology & Drug Design
Wei Shi, Miaobo Pan, Hao Qiang, Qianqian Qiu, Wenlong Huang, Haiyan Lin, Hai Qian, Liang Ge
A novel mitochondria targeting fluorescent probe compound S-N3 as the monitor of Hydrogen Sulfide (H2 S) in living cells has been designed and synthesized in this paper. This article contained the chemosynthesis and some studies on bioactivity of the target compound in living cells. Compound S-N3 is easy to synthesize and can remain stable under the effect of pH, system and photo. In additional, it shows low cytotoxicity in cell imaging. And it can react with H2 S highly selective in PBS or FBS solution, which would cause the obvious increase of fluorescence intensity...
January 21, 2017: Chemical Biology & Drug Design
Md Ataul Islam, Tahir S Pillay
In the current study, we searched for potential DNA GyrB inhibitors using pharmacophore-based virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors were collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptor and hydrophobicity were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature...
January 21, 2017: Chemical Biology & Drug Design
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