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Bioorganic & Medicinal Chemistry

Ramit Singla, Kunj Bihari Gupta, Shishir Upadhyay, Monisha Dhiman, Vikas Jaitak
Ground breaking clinical therapeutic advances in the treatment of breast cancer (BC) is the introduction of selective estrogen receptor modulators (SERMs). We have expeditiously designed and synthesized indole-xanthendione hybrids by coalescing the indole nucleus with xanthendione. All the compounds were first screened for anti-proliferative activity, cytotoxicity and ER-α binding affinity by utilizing ER-α dominant T47D BC cell lines, PBMCs and ER-α competitor assay kit. From this study, two representative compounds 6e and 6f showing most promising activity were advanced for gene expression studies for targeting ER-α...
November 30, 2017: Bioorganic & Medicinal Chemistry
Yuichiro Kawamoto, Ryushi Seo, Nobuhito Murai, Hideki Hiyama, Hiromasa Oka
Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities...
November 26, 2017: Bioorganic & Medicinal Chemistry
Linxiao Wang, Shan Xu, Xiuying Chen, Xiaobo Liu, Yongli Duan, Dejia Kong, Dandan Zhao, Pengwu Zheng, Qidong Tang, Wufu Zhu
Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0...
November 26, 2017: Bioorganic & Medicinal Chemistry
Akihiro Kinoshita, Masato Higashino, Koji Yoshida, Yoshiyuki Aratani, Akito Kakuuchi, Keisuke Hanada, Hiroyuki Takeda, Atsushi Naganawa, Hidekazu Matsuya, Kazuyuki Ohmoto
A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold)...
November 24, 2017: Bioorganic & Medicinal Chemistry
Seul Ki Yeon, Ji Won Choi, Jong-Hyun Park, Ye Rim Lee, Hyeon Jeong Kim, Su Jeong Shin, Bo Ko Jang, Siwon Kim, Yong-Sun Bahn, Gyoonhee Han, Yong Sup Lee, Ae Nim Pae, Ki Duk Park
Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor...
November 24, 2017: Bioorganic & Medicinal Chemistry
Huailei Jiang, Aditya Bansal, Ribu Goyal, Kah-Whye Peng, Stephen J Russell, Timothy R DeGrado
Noninvasive imaging of iodide uptake via the sodium/iodide symporter (NIS) has received great interest for evaluation of thyroid cancer and reporter imaging of NIS-expressing viral therapies. In this study, we investigate 18F-labeled hexafluorophosphate (HFP or PF6-) as a high-affinity iodide analog for NIS imaging. 18F-HFP was synthesized by radiofluorination of phosphorus pentafluoride·N-methylpyrrolidine complex and evaluated in human NIS (hNIS)-expressing C6 glioma cells and a C6 glioma xenograft mouse model...
November 23, 2017: Bioorganic & Medicinal Chemistry
Mateusz Kozarski, Dorota Kubacka, Blazej A Wojtczak, Renata Kasprzyk, Marek R Baranowski, Joanna Kowalska
The hydrolysis of nucleoside 5'-monophosphates to the corresponding nucleosides and inorganic phosphate is catalysed by 5'-nucleotidases, thereby contributing to the control of endogenous nucleotide turnover and affecting the fate of exogenously delivered nucleotide- and nucleoside-derived therapeutics in cells. A recently identified nucleotidase cNIIIB shows preference towards 7-methylguanosine monophosphate (m7GMP) as a substrate, which suggests its potential involvement in mRNA degradation. However, the extent of biological functions and the significance of cNIIIB remains to be elucidated...
November 22, 2017: Bioorganic & Medicinal Chemistry
Poonam Piplani, Ankit Jain, Dhiksha Devi, Anjali, Anuradha Sharma, Pragati Silakari
The present study reports the effect of indanone derivatives on scopolamine induced deficit cholinergic neurotransmission serving as promising leads for the therapeutics of cognitive dysfunction. Eleven compounds 54-64 have been designed, synthesised and evaluated against behavioural alterations using step down passive avoidance protocol at a dose of 0.5 mg/kg with Donepezil (1) as the reference standard. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme...
November 22, 2017: Bioorganic & Medicinal Chemistry
Muhammad Taha, Hayat Ullah, Laode Muhammad Ramadhan Al Muqarrabun, Muhammad Naseem Khan, Fazal Rahim, Norizan Ahmat, Muhammad Tariq Javid, Muhammad Ali, Khalid Mohammed Khan
Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease...
November 21, 2017: Bioorganic & Medicinal Chemistry
Hend A A Abd El-Wahab, Mauro Accietto, Leonardo B Marino, Kirsty J McLean, Colin W Levy, Hamdy M Abdel-Rahman, Mahmoud A El-Gendy, Andrew W Munro, Ahmed S Aboraia, Claire Simons
Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1...
November 21, 2017: Bioorganic & Medicinal Chemistry
Miłosz Regulski, Hanna Piotrowska-Kempisty, Wiesław Prukała, Zbigniew Dutkiewicz, Katarzyna Regulska, Beata Stanisz, Marek Murias
25 new trans-stilbene and trans-stilbazole derivatives were investigated using in vitro and in silico techniques. The selectivity and potency of the compounds were assessed using commercial ELISA test. The obtained results were incorporated into 2D QSAR assay. The most promising compound 4-nitro-3',4',5'-trihydroxy-trans-stilbene (N1) was synthetized and its potency and selectivity were confirmed. N1 was classified as preferential COX-2 inhibitor. Its ability to inhibit COX-2 in MCF-7 cell line was established and its cytotoxicity by MTT test was assessed...
November 20, 2017: Bioorganic & Medicinal Chemistry
Guido V Janssen, Joyce A C van den Heuvel, Rik P Megens, Jorg C J Benningshof, Huib Ovaa
Large, diverse compound libraries are an essential requisite in target-based drug development. In this work, a robust microwave-assisted synthesis for the diastereoselective generation of 3-saccharinyl-trans-β-lactams is reported. The method is optimised for combinatorial library synthesis in which decoration of the scaffold is varied on both the β-lactam and the saccharine moiety. Within the European Lead Factory (ELF) consortium, a library of 263 compounds was efficiently produced using the developed methodology...
November 16, 2017: Bioorganic & Medicinal Chemistry
Fabien Hammerer, Florent Poyer, Laura Fourmois, Su Chen, Guillaume Garcia, Marie-Paule Teulade-Fichou, Philippe Maillard, Florence Mahuteau-Betzer
The proof of concept for two-photon activated photodynamic therapy has already been achieved for cancer treatment but the efficiency of this approach still heavily relies on the availability of photosensitizers combining high two-photon absorption and biocompatibility. In this line we recently reported on a series of porphyrin-triphenylamine hybrids which exhibit high singlet oxygen production quantum yield as well as high two-photon absorption cross-sections but with a very poor cellular internalization. We present herein new photosensitizers of the same porphyrin-triphenylamine hybrid series but bearing cationic charges which led to strongly enhanced water solubility and thus cellular penetration...
November 15, 2017: Bioorganic & Medicinal Chemistry
Yuxing Lin, Yuqi Gao, Zhao Ma, Tianyu Jiang, Xin Zhou, Zhenzhen Li, Xiaojun Qin, Yun Huang, Lupei Du, Minyong Li
To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.
November 14, 2017: Bioorganic & Medicinal Chemistry
Xiaoxia Qiu, Yiyou Huang, Deyan Wu, Fei Mao, Jin Zhu, Wenzhong Yan, Hai-Bin Luo, Jian Li
Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0...
November 14, 2017: Bioorganic & Medicinal Chemistry
Qiang Zhou, Jinjin Zhu, Jinglei Chen, Peng Ji, Chunhua Qiao
Signal transducer and activator of transcription (STAT3) is a proposed therapeutic target for the development of anti-cancer agents. In this report, a series of N-arylsulfonylsubstituted-1H indole derivatives were designed and synthesized as STAT3 inhibitors, their anti-proliferative activities were evaluated against a number of tumor cells, some potent compounds exhibited IC50 values less than 10 μM. The most potent compound 4a was further confirmed to inhibit STAT3 phosphorylation at Tyr705. It was further revealed that 4a arrested the cell cycle at the G2/M phase and inhibited tubulin polymerization...
November 13, 2017: Bioorganic & Medicinal Chemistry
Yuan Zhou, Shasha Zhang, Hongwu He, Wen Jiang, Leifeng Hou, Dan Xie, Meng Cai, Hao Peng, Lingling Feng
In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking...
November 13, 2017: Bioorganic & Medicinal Chemistry
Tiannan Hu, Scott R Suter, Madeline M Mumbleau, Peter A Beal
Toll-like receptor 8 (TLR8) is an important component of the human innate immune system that recognizes single stranded RNA (ssRNA). Recent X-ray crystal structures of TLR8 bound to ssRNA revealed a previously unrecognized binding site for a 5'-UpG-3' dinucleotide. Here we use an atomic mutagenesis strategy coupled with a cellular TLR8 activation assay to probe the importance of specific functional groups present on the guanine base in RNA-mediated receptor agonism and antagonism. Results from RNA analogs containing 7-deazaguanosine, 2-aminopurine and inosine confirm the importance of guanine N7, O6 and N2, respectively, in TLR8 activation...
November 11, 2017: Bioorganic & Medicinal Chemistry
Jieun Kwon, Tina Mistry, Jinhong Ren, Michael E Johnson, Shahila Mehboob
S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S...
November 11, 2017: Bioorganic & Medicinal Chemistry
Silvia Dei, Maria Novella Romanelli, Dina Manetti, Niccolò Chiaramonte, Marcella Coronnello, Milena Salerno, Elisabetta Teodori
In this study, a new series of heterodimers was synthesized. These derivatives are N,N-bis(alkanol)amine aryl esters or N,N-bis(ethoxyethanol)amine aryl esters carrying a methoxylated aryl residue combined with a flavone or chromone moiety. The new compounds were studied to evaluate their P-gp modulating activity on a multidrug-resistant leukemia cell line. Some of the new compounds show a good MDR reversing activity; interestingly this new series of compounds does not comply with the structure-activity relationships (SAR) outlined by previously synthesized analogs carrying different aromatic moieties...
November 10, 2017: Bioorganic & Medicinal Chemistry
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