Bioorganic and Medicinal Chemistry Letters This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Identification of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffolds as potent Lck inhibitors as anti-cancer agents
In this study, we found that compound 12a exerted significant inhibitory potency against Lck with an IC50 value of 10.6 nM. In addition, 12a demonstrated high efficacy in various colon cancer cell lines as indicated by GI50 values ranging from 0.24-1.26 μM. Notably, 12a inhibited the phosphorylation of Lck in Colo201 cells. Overall, the anti-proliferative effects of 12a on diverse cancer cell lines highlights its potential application for the treatment of various cancer types.PMID:38316368 | DOI:10.1016/j.bmcl.2024.129645 (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2024 Category: Chemistry Authors: Su Hyun Ji Han Byeol Kim Yeonju Song Hwan Won Chung Duck-Hyung Lee Cheulhee Jung Yeonjin Ko Seo-Jung Han Source Type: research

Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors
Bioorg Med Chem Lett. 2024 Feb 3;100:129643. doi: 10.1016/j.bmcl.2024.129643. Online ahead of print.ABSTRACTReceptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2024 Category: Chemistry Authors: J ózsef Levente Petró Gyula B ényei P éter Bana Nikolett Linke Ferenc Horti Judit Eszter Szab ó Krisztina Katalin Szalai G ábor Hornyánszky Istv án Greiner J ános Éles Source Type: research

Glycosidase-activated H 2 S donorsto enhance chemotherapy efficacy
Bioorg Med Chem Lett. 2024 Feb 3;100:129644. doi: 10.1016/j.bmcl.2024.129644. Online ahead of print.ABSTRACTHydrogen sulfide (H2S) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (H2S) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, H2S was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67 %. H2S release was also detected by H2S probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of ...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2024 Category: Chemistry Authors: Zizhen Ye Jixiang Li Jiarui Shi Yuguang Song Yangping Liu Jingli Hou Source Type: research

Exploring 2-methyl-substituted vitamin K 3 derivatives with potent inhibitory activity against the 3CL protease of SARS-CoV-2
Bioorg Med Chem Lett. 2024 Feb 2;100:129642. doi: 10.1016/j.bmcl.2024.129642. Online ahead of print.ABSTRACTSince the outbreak of the pandemic, various anti-SARS-CoV-2 drugs have been developed. In particular, 3CL protease (3C-like protease, 3CLpro) is an attractive drug target because it is an essential enzyme for viral multiplication and is present only in viruses, not in humans. To date, 3CLpro inhibitors against SARS-CoV-2 such as nirmatrelvir and ensitrelvir have been launched as oral drugs in Japan, but there is still no potent drug against SARS-CoV-2, due to issues of in vivo absorption and stability. Recently, vita...
Source: Bioorganic and Medicinal Chemistry Letters - February 4, 2024 Category: Chemistry Authors: Ryohto Koharazawa Mayu Hayakawa Kazuki Takeda Kotone Miyazaki Chisato Tode Yoshihisa Hirota Yoshitomo Suhara Source Type: research

Discovery of a novel series of selective macrocyclic PKCTheta inhibitors
Bioorg Med Chem Lett. 2024 Feb 1;100:129630. doi: 10.1016/j.bmcl.2024.129630. Online ahead of print.ABSTRACTA series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing...
Source: Bioorganic and Medicinal Chemistry Letters - February 2, 2024 Category: Chemistry Authors: Stefano Crosignani Sebastien Campos Claire Bouix-Peter Craig Harris Eric Talbot Haiyang Hu Shun Wang John Maclean Ugo Zanelli Simon Taylor Kevin Foote Feriel Hacini-Rachinel Edwige Nicodeme Valerie Julia Source Type: research

Identification of (4-chlorophenyl)(5-hydroxynaphtho[1,2-b]furan-3-yl)methanone as novel COX-2 inhibitor with analgesic profile
Bioorg Med Chem Lett. 2024 Feb 1;100:129631. doi: 10.1016/j.bmcl.2024.129631. Online ahead of print.ABSTRACTChronic pain is a serious problem that affects billions of people worldwide, but current analgesic drugs limit their use in chronic pain management due to their respective side effects. As a first-line clinical drug for chronic pain, COX-2 selective inhibitors can relieve mild to moderate pain, but they also have some problems. The most prominent one is that their analgesic intensity is not enough, and they cannot well meet the treatment needs of chronic pain. Therefore, there is an urgent need to develop COX-2 inhib...
Source: Bioorganic and Medicinal Chemistry Letters - February 2, 2024 Category: Chemistry Authors: Shilong Hu Wencheng Liu Yu Gan Xi Yang Yanfang Wang Xing Wei Meiyuan Chen Di Zhang Bowen Ke Source Type: research

Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist
Bioorg Med Chem Lett. 2024 Jan 30;100:129629. doi: 10.1016/j.bmcl.2024.129629. Online ahead of print.ABSTRACTModulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery of CVN766, a potent orexin 1 receptor antagonist that has greater than 1000-fold selectivity for the orexin 1 receptor over the orexin 2 receptor and demonstrates low off target hits in a diversity screen. In agreement with its in vitro ADME data, CVN766 demonstrated moderate in vivo clearance in rodents and displayed good brain p...
Source: Bioorganic and Medicinal Chemistry Letters - January 31, 2024 Category: Chemistry Authors: Angela Glen Roland W B ürli David Livermore William Buffham Stephanie Merison Anna E Rowland Robert Newman Charlotte Fieldhouse David J Miller Lee A Dawson Kim Matthews Mark B Carlton Nicola L Brice Source Type: research

Novel xanthone derivatives as potent sirtuin 2 inhibitors
Bioorg Med Chem Lett. 2024 Jan 26;100:129620. doi: 10.1016/j.bmcl.2024.129620. Online ahead of print.ABSTRACTSix amino derivatives of xanthone were obtained via chemical synthesis. Biochemical studies revealed their SIRT2 inhibitory activity ranging from 48.5 % (compound 4, 5-chloro-2-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-9H-xanthen-9-one hydrochloride) to 93.2 % (compound 3, 5-chloro-2-(((2-methoxyphenethyl)amino)methyl)-9H-xanthen-9-one hydrochloride). The structure-activity analysis showed favourable properties of secondary amines relative to tertiary piperazine derivatives. The tested compounds do not possess add...
Source: Bioorganic and Medicinal Chemistry Letters - January 27, 2024 Category: Chemistry Authors: Gabriela Mazur Katarzyna Pa ńczyk-Straszak Karolina Krysi ńska Karolina Niemiec Anna Waszkielewicz Source Type: research

Cytotoxic effects of kinetin riboside and its selected analogues on cancer cell lines
Bioorg Med Chem Lett. 2024 Jan 25;100:129628. doi: 10.1016/j.bmcl.2024.129628. Online ahead of print.ABSTRACTN6-[(Furan-2-yl)methyl]adenosine (kinetin riboside) and its seven synthesized analogues were examined for the ability to inhibit the growth of five human carcinoma cell lines and for comparison of normal human lung fibroblast cell line (MRC-5). Out of the compounds evaluated, 8-azakinetin riboside was shown to exhibit significant cytotoxic activity for 72 h treatment against ovarian OVCAR-3 and pancreatic MIA PaCa-2 cancer cells (IC50 = 1.1 μM) with an observed weaker effect against MRC-5 cells (IC50 = 4.6 μM). Ki...
Source: Bioorganic and Medicinal Chemistry Letters - January 27, 2024 Category: Chemistry Authors: Ewa Toto ń Natalia Lisiak Aleksandra Romaniuk-Drapa ła Grzegorz Framski Eliza Wyszko Tomasz Ostrowski Source Type: research

Further structural optimization and SAR study of sungsanpin derivatives as cell-invasion inhibitors
Bioorg Med Chem Lett. 2024 Feb 1;99:129627. doi: 10.1016/j.bmcl.2024.129627. Epub 2024 Jan 23.ABSTRACTMetastasis is one of the major causes of death in patients with cancer, and cell invasion plays a fundamental part in this process. Because of the absence of efficacious treatments, caring for these patients is challenging. Recently, we optimized the structure of the naturally occurring lasso peptide sungsanpin. We identified two peptides, octapeptide S3 and cyclic peptide S4, which inhibited invasion into A549 cells effectively. We undertook an alanine scan of S3 to explore the structure-activity relationship. The linear ...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2024 Category: Chemistry Authors: Shuai Chen Kai Zhang Jihua Zou Zhou Yu Conghao Gai Xiaoyun Chai Qingjie Zhao Yan Zou Source Type: research

Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines
Bioorg Med Chem Lett. 2024 Feb 1;99:129624. doi: 10.1016/j.bmcl.2024.129624. Epub 2024 Jan 23.ABSTRACTA structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyace...
Source: Bioorganic and Medicinal Chemistry Letters - January 25, 2024 Category: Chemistry Authors: Wentian Wang Alok Ranjan Wei Zhang Qiren Liang Karen S MacMillan Karen Chapman Xiaoyu Wang Preethi Chandrasekaran Noelle S Williams Daniel M Rosenbaum Jef K De Brabander Source Type: research

Direct-to-biology platform: From synthesis to biological evaluation of SHP2 allosteric inhibitors
Bioorg Med Chem Lett. 2024 Jan 23;100:129626. doi: 10.1016/j.bmcl.2024.129626. Online ahead of print.ABSTRACTTyrosine phosphatase SHP2 is a proto-oncogenic protein involved in cell growth and differentiation via diverse intracellular signaling pathways. With the scope of identifying new SHP2 allosteric inhibitors, we report here the development and optimization of a high-throughput "Direct-to-Biology" (D2B) workflow including the synthesis and the biological evaluation of the reaction crude, thus eliminating the need for purification. During this labor-saving procedure, the structural diversity was introduced through a SNA...
Source: Bioorganic and Medicinal Chemistry Letters - January 24, 2024 Category: Chemistry Authors: Simona Ponzi Federica Ferrigno Monica Bisbocci Cristina Alli Jesus M Ontoria Alessia Petrocchi Carlo Toniatti Esther Torrente Source Type: research

Synthesis and biological evaluation of novel 18 F-labeled 2,4-diaminopyrimidine derivatives for detection of ghrelin receptor in the brain
In this study, we newly designed and synthesized diaminopyrimidine derivatives ([18F]BPP-1 and [18F]BPP-2) and evaluated their utility as novel PET probes targeting GHSR. In in vitro competitive binding assays, the binding affinity of BPP-2 for GHSR (Ki = 274 nM) was comparable to that of the diaminopyimidine lead compound Abb8a (Ki = 109 nM). In a biodistribution study using normal mice, [18F]BPP-2 displayed low uptake in the brain and moderate uptake in the pancreas, but high radioactivity accumulation in bone was observed due to its defluorination in vivo. Taken together, although further improvement of the pharmacokine...
Source: Bioorganic and Medicinal Chemistry Letters - January 22, 2024 Category: Chemistry Authors: Haruka Saito Hiroyuki Watanabe Masahiro Ono Source Type: research

Design, synthesis and bioactivity evaluation of the combination of evodiamine and erlotinib linked by indolequinone
Bioorg Med Chem Lett. 2024 Feb 1;99:129619. doi: 10.1016/j.bmcl.2024.129619. Epub 2024 Jan 18.ABSTRACTCompared with single-targeted therapy, the design and synthesis of heterozygous molecules is still a significant challenge for the discovery of antitumor drugs. Quinone oxidoreductase-1 (NQO1) is a potential target for selective cancer therapy due to its overexpression in many cancer cells and its unique bioredox properties. Based on the principle of combinatorial drug design, we successfully synthesized a new hybrid molecules 13 with an indolequinone structure. We found that the synthesized compounds exhibited much higher...
Source: Bioorganic and Medicinal Chemistry Letters - January 20, 2024 Category: Chemistry Authors: Binbin Wei Jingjing Ma Hui Guo Yuwei Wang Dongyan Guo Yuping Tang Source Type: research

Structure-based design and synthesis of sulfonylureas as novel NLRP3 inhibitors for Alzheimer's disease
Bioorg Med Chem Lett. 2024 Feb 1;99:129622. doi: 10.1016/j.bmcl.2024.129622. Epub 2024 Jan 19.ABSTRACTAlzheimer's disease (AD) remains an incurable neurodegenerative condition that poses a threat to humanity. Immune signaling in the brain, particularly the NLR family pyrin domain containing 3 (NLRP3), is currently targeted for AD treatment. Based on the crystal structure of the NACHT domain of NLRP3 and its renowned inhibitor MCC950, we designed and synthesized nineteen sulfonylurea compounds and evaluated their capacity to inhibit caspase-1 and interleukin-1β (IL-1β). Of these, nine were selected for measuring their IC5...
Source: Bioorganic and Medicinal Chemistry Letters - January 20, 2024 Category: Chemistry Authors: Eun Young Kim Jae Hong Im Jinhe Han Won-Jea Cho Source Type: research