Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity
We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.PMID:35447555 | DOI:10.1016/j.ejmech.2022.114369 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - April 21, 2022 Category: Chemistry Authors: Wael Zeinyeh Yannick J Esvan B éatrice Josselin Mathilde Defois Blandine Baratte Stefan Knapp Apirat Chaikuad Fabrice Anizon Francis Giraud Sandrine Ruchaud Pascale Moreau Source Type: research

Convenient PET-tracer production via SuFEx < sup > 18 < /sup > F-fluorination of nanomolar precursor amounts
Eur J Med Chem. 2022 Apr 14;237:114383. doi: 10.1016/j.ejmech.2022.114383. Online ahead of print.ABSTRACTRecently, a protocol for radiolabeling of aryl fluorosulfates ("SuFEx click radiolabeling") using ultrafast 18F/19F isotopic exchange has been reported. Although promising, the original procedure turned out to be rather inefficient. However, systematic optimization of the reaction parameters allowed for development of a robust method for SuFEx radiolabeling which obviates the need for azeotropic drying, base addition and HPLC purification. The developed protocol enabled efficient 18F-fluorination of low nanomolar amount...
Source: European Journal of Medicinal Chemistry - April 21, 2022 Category: Chemistry Authors: Nils Walter Jan Bertram Birte Drewes Victor Bahutski Marco Timmer Markus B Sch ütz Felicia Kr ämer Felix Neumaier Heike Endepols Bernd Neumaier Boris D Zlatopolskiy Source Type: research

Design, synthesis, and biological evaluation of novel diphenylamine derivatives as tubulin polymerization inhibitors targeting the colchicine binding site
Eur J Med Chem. 2022 Apr 16;237:114372. doi: 10.1016/j.ejmech.2022.114372. Online ahead of print.ABSTRACTA novel series of diphenylamine derivatives were designed and synthesized, and their biological activities were evaluated. The anti-proliferative activities of the derivatives were tested against five human cancer cell lines (MCF-7, MDA-MB-231, A549, HeLa and HT29). Among them, compound 5f exhibited the promising anti-proliferative activity against HT29 cell lines with the IC50 value of 23 nM. Further biological studies depicted that compound 5f inhibited cancer cell migration, colony formation and angiogenesis. Besides...
Source: European Journal of Medicinal Chemistry - April 21, 2022 Category: Chemistry Authors: Xiang-Yu Yan Jia-Fu Leng Ting-Ting Chen Yong-Jun Zhao Ling-Yi Kong Yong Yin Source Type: research

Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment
In this study, we identified a potent and oral EGFRL858R/T790M/C797S tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFRL858R/T790M/C797S mutant with IC50 value as 0.010 μM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFRL858R/T790M/C797S and induced tumor cell cycle arrest and cell apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharma...
Source: European Journal of Medicinal Chemistry - April 21, 2022 Category: Chemistry Authors: Cheng Wang Xin Wang Zhi Huang Tianqi Wang Yongwei Nie Shengyong Yang Rong Xiang Yan Fan Source Type: research

New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold
Eur J Med Chem. 2022 Apr 13;237:114366. doi: 10.1016/j.ejmech.2022.114366. Online ahead of print.ABSTRACTThe aldo-keto reductase 1C3 (AKR1C3) enzyme is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) because of its role in the biosynthesis of androgens. Flufenamic acid, a non-selective AKR1C3 inhibitor, has previously been subjected to bioisosteric modulation to give rise to a series of compounds with the hydroxytriazole core. In this work, the hit compound of the previous series has been modulated further, and new, more potent, and selective derivatives have been obtained. The poor solubilit...
Source: European Journal of Medicinal Chemistry - April 21, 2022 Category: Chemistry Authors: Agnese Chiara Pippione Z ühal Kilic-Kurt Sandra Kovachka Stefano Sainas Barbara Rolando Enrica Denasio Klaus Pors Salvatore Adinolfi Daniele Zonari Renzo Bagnati Marco Lucio Lolli Francesca Spyrakis Simonetta Oliaro-Bosso Donatella Boschi Source Type: research

Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity
We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.PMID:35447555 | DOI:10.1016/j.ejmech.2022.114369 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - April 21, 2022 Category: Chemistry Authors: Wael Zeinyeh Yannick J Esvan B éatrice Josselin Mathilde Defois Blandine Baratte Stefan Knapp Apirat Chaikuad Fabrice Anizon Francis Giraud Sandrine Ruchaud Pascale Moreau Source Type: research

The role of the maleimide ring system on the structure-activity relationship of showdomycin
Eur J Med Chem. 2022 Apr 11;237:114342. doi: 10.1016/j.ejmech.2022.114342. Online ahead of print.ABSTRACTShowdomycin produced by Streptomyces showdoensis ATCC 15227 is a C-nucleoside microbial natural product with antimicrobial and cytotoxic properties. The unique feature of showdomycin in comparison to other nucleosides is its maleimide base moiety, which has the distinct ability to alkylate nucleophilic thiol groups by a Michael addition reaction. In order to understand structure-activity relationships of showdomycin, we synthesized a series of derivatives with modifications in the maleimide ring at the site of alkylatio...
Source: European Journal of Medicinal Chemistry - April 19, 2022 Category: Chemistry Authors: Petja Rosenqvist Janne J M äkinen Kaisa Palmu Johanna Jokinen Ranjit K Prajapati Heidi J Korhonen Pasi Virta Georgiy A Belogurov Mikko Mets ä-Ketelä Source Type: research

The role of the maleimide ring system on the structure-activity relationship of showdomycin
Eur J Med Chem. 2022 Apr 11;237:114342. doi: 10.1016/j.ejmech.2022.114342. Online ahead of print.ABSTRACTShowdomycin produced by Streptomyces showdoensis ATCC 15227 is a C-nucleoside microbial natural product with antimicrobial and cytotoxic properties. The unique feature of showdomycin in comparison to other nucleosides is its maleimide base moiety, which has the distinct ability to alkylate nucleophilic thiol groups by a Michael addition reaction. In order to understand structure-activity relationships of showdomycin, we synthesized a series of derivatives with modifications in the maleimide ring at the site of alkylatio...
Source: European Journal of Medicinal Chemistry - April 19, 2022 Category: Chemistry Authors: Petja Rosenqvist Janne J M äkinen Kaisa Palmu Johanna Jokinen Ranjit K Prajapati Heidi J Korhonen Pasi Virta Georgiy A Belogurov Mikko Mets ä-Ketelä Source Type: research

Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes
Eur J Med Chem. 2022 Apr 4;237:114338. doi: 10.1016/j.ejmech.2022.114338. Online ahead of print.ABSTRACTThe NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a key cytosolic pattern recognition receptor that senses diverse pathogen- and host-originated threat signals. Aberrant activation of NLRP3 inflammasomes is closely associated with the pathogenesis of various complex inflammatory diseases. Nevertheless, the detailed regulation mechanism of NLRP3 inflammasome and its pathogenic roles in the inflammation progression remain to be fully elucidated. Fluorescent imaging with small molecule probe can prov...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Jiannan Zhao Yongling Li Jing Ma Jingting Liu Ruoxuan Xiao Linlin Wang Peng Li Yinyan He Feng Qian Ao Zhang Zhen-Liang Sun Chunyong Ding Source Type: research

The azulene scaffold from a medicinal chemist's perspective: Physicochemical and in  vitro parameters relevant for drug discovery
Eur J Med Chem. 2022 Apr 12;237:114374. doi: 10.1016/j.ejmech.2022.114374. Online ahead of print.ABSTRACTAzulene is a bicyclic scaffold rarely applied in medicinal chemistry. Here we report physicochemical and in vitro parameters relevant for drug discovery for a series of diversely substituted azulenes. We synthesized and characterized several scaffold hopping series of analogously substituted azulenes, indoles and naphthalenes. This enabled a comparison of azulene with the more common scaffolds indole and naphthalene. Our data indicates that undesirably low photostability of azulenes is restricted to certain substitution...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Teppo O Leino Peter Sieger Jari Yli-Kauhaluoma Erik A A Wall én J örg T Kley Source Type: research

Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors
Eur J Med Chem. 2022 Mar 25;236:114307. doi: 10.1016/j.ejmech.2022.114307. Online ahead of print.ABSTRACTAiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives 10ã10k. Based on ATX enzymatic assay, we further changed the substituents within benzyl carbamate moiety and tuned the carbamate linker to urea group. Delightfully, compound 10c bearing a N-hydroxyethyl piperazinyl group was identifi...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Hongrui Lei Xinyu Wang Guolong Zhao Tong Li Youbao Cui Huinan Wu Jing Yang Nan Jiang Xin Zhai Source Type: research

Design, synthesis and preclinical evaluation of bio-conjugated amylinomimetic peptides as long-acting amylin receptor agonists
Eur J Med Chem. 2022 Apr 4;236:114330. doi: 10.1016/j.ejmech.2022.114330. Online ahead of print.ABSTRACTPramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic th...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Raymond J Patch Rui Zhang Suzanne Edavettal Mark J Macielag Annette J Eckardt Jiali Li Marie-Laure Rives Wilson Edwards Simon A Hinke Xi Qiu Wenying Jian Ondrej Libiger Songmao Zheng Jey Jeyaseelan Yin Liang Shamina M Rangwala James N Leonard Pamela Hornb Source Type: research

Overview of SIRT5 as a potential therapeutic target: Structure, function and inhibitors
Eur J Med Chem. 2022 Apr 8;236:114363. doi: 10.1016/j.ejmech.2022.114363. Online ahead of print.ABSTRACTSirtuin belongs to a family of coenzyme nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, which could be classified as seven isoforms (SIRT1-SIRT7). Recently, SIRT5 has drawn extensive attention due to its specific catalytic activity for low deacetylation activity but significant desuccinylation, demalonylation and deglutarylation activities. SIRT5 is thought to be closely related to some diseases such as cancer and neurodegenerative diseases. Herein, we present an overview of the structure and bio...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Yingying Wang Hui Chen Xiaoming Zha Source Type: research

Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes
Eur J Med Chem. 2022 Apr 4;237:114338. doi: 10.1016/j.ejmech.2022.114338. Online ahead of print.ABSTRACTThe NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a key cytosolic pattern recognition receptor that senses diverse pathogen- and host-originated threat signals. Aberrant activation of NLRP3 inflammasomes is closely associated with the pathogenesis of various complex inflammatory diseases. Nevertheless, the detailed regulation mechanism of NLRP3 inflammasome and its pathogenic roles in the inflammation progression remain to be fully elucidated. Fluorescent imaging with small molecule probe can prov...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Jiannan Zhao Yongling Li Jing Ma Jingting Liu Ruoxuan Xiao Linlin Wang Peng Li Yinyan He Feng Qian Ao Zhang Zhen-Liang Sun Chunyong Ding Source Type: research

The azulene scaffold from a medicinal chemist's perspective: Physicochemical and in  vitro parameters relevant for drug discovery
Eur J Med Chem. 2022 Apr 12;237:114374. doi: 10.1016/j.ejmech.2022.114374. Online ahead of print.ABSTRACTAzulene is a bicyclic scaffold rarely applied in medicinal chemistry. Here we report physicochemical and in vitro parameters relevant for drug discovery for a series of diversely substituted azulenes. We synthesized and characterized several scaffold hopping series of analogously substituted azulenes, indoles and naphthalenes. This enabled a comparison of azulene with the more common scaffolds indole and naphthalene. Our data indicates that undesirably low photostability of azulenes is restricted to certain substitution...
Source: European Journal of Medicinal Chemistry - April 18, 2022 Category: Chemistry Authors: Teppo O Leino Peter Sieger Jari Yli-Kauhaluoma Erik A A Wall én J örg T Kley Source Type: research