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.

2-Phenylcyclopropylmethylamine (PCPMA) as a privileged scaffold for central nervous system drug design
Bioorg Med Chem Lett. 2024 Feb 13:129654. doi: 10.1016/j.bmcl.2024.129654. Online ahead of print.ABSTRACTThe use of privileged scaffolds in medicinal chemistry is an effective way to accelerate the drug discovery process, especially at the hit/lead optimization stage. 2-Phenylcyclopropylmethylamine (PCPMA) is a less commonly used chemical scaffold in medicinal chemistry, but many PCPMA-containing compounds exert therapeutic effects for various diseases, in particular central nervous system (CNS) diseases such as depression, schizophrenia, sleep disorder, and Parkinson's disease. The backbone of the PCPMA scaffold enables a...
Source: Bioorganic and Medicinal Chemistry Letters - February 15, 2024 Category: Chemistry Authors: Huiqiong Li Jianjun Cheng Source Type: research

PSMA-targeted SMART molecules outfitted with SN38
Bioorg Med Chem Lett. 2024 Feb 14;101:129657. doi: 10.1016/j.bmcl.2024.129657. Online ahead of print.ABSTRACTHerein, we report the modular synthesis and evaluation of a prostate-specific membrane antigen (PSMA) targeted small molecule drug conjugate (SMDC) carrying the chemotherapeutic agent, SN38. Due to the fluorogenic properties of SN38, payload release kinetics from the platform was observed in buffers representing the pH conditions of systemic circulation and cellular internalization. It was found that this platform is stable with minimal payload release at physiological pH with most rapid payload release observed at ...
Source: Bioorganic and Medicinal Chemistry Letters - February 15, 2024 Category: Chemistry Authors: Emily A Savoy Feyisola P Olatunji Nooshin Mesbahi Ryanne K Ballard Christine L Lovingier Aaron T Hendricksen Melody D Fulton Clifford E Berkman Source Type: research

A Gene-encoded Aldehyde Tag Repurposed from RiPP Cyclophane-forming Pathway
Bioorg Med Chem Lett. 2024 Feb 13:129653. doi: 10.1016/j.bmcl.2024.129653. Online ahead of print.ABSTRACTGene-encoded aldehyde tag technology has been widely utilized in protein bioorthogonal chemistry and biotechnological application. Herein, we report utilization of the promiscuous rSAM cyclophane synthase SjiB involved in triceptide biosynthesis as a dedicated and highly efficient formylglycine synthase. The new aldehyde tag sequence in this system, YQSSI, is biosynthetically orthogonal to the known aldehyde tag (C/S)x(P/A)xR. The potential use of SjiB/YQSSI aldehyde tag system was further validated in fluorescent label...
Source: Bioorganic and Medicinal Chemistry Letters - February 15, 2024 Category: Chemistry Authors: Suze Ma Heng Chen Shuxun Liu Xuedong Huang Tianlu Mo Wanqiu Liu Wei Zhang Wei Ding Qi Zhang Source Type: research

PSMA-targeted SMART molecules outfitted with SN38
Bioorg Med Chem Lett. 2024 Feb 13:129657. doi: 10.1016/j.bmcl.2024.129657. Online ahead of print.ABSTRACTHerein, we report the modular synthesis and evaluation of a prostate-specific membrane antigen (PSMA) targeted small molecule drug conjugate (SMDC) carrying the chemotherapeutic agent, SN38. Due to the fluorogenic properties of SN38, payload release kinetics from the platform was observed in buffers representing the pH conditions of systemic circulation and cellular internalization. It was found that this platform is stable with minimal payload release at physiological pH with most rapid payload release observed at pH v...
Source: Bioorganic and Medicinal Chemistry Letters - February 15, 2024 Category: Chemistry Authors: Emily A Savoy Feyisola P Olatunji Nooshin Mesbahi Ryanne K Ballard Christine L Lovingier Aaron T Hendricksen Melody D Fulton Clifford E Berkman Source Type: research

Discovery of N-(1-(2-hydroxyethyl)quinolin-2-one)-N'-(1-phenyl-1H-pyrazol-5-yl)methyl) urea as Mode-Selective TRPV1 antagonist
Bioorg Med Chem Lett. 2024 Feb 12:129656. doi: 10.1016/j.bmcl.2024.129656. Online ahead of print.ABSTRACTTo discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A- and C-regions. The structure activity relationship was investigated systematically by modifying the A-region by incorporating a polar side chain on the pyridone and then by changing the C-region with a variety of substituted pyridine and pyrazole moieties. The 3-t-butyl and 3-(1-methylcyclopropyl) pyrazole C-region analogs provided high potency as well ...
Source: Bioorganic and Medicinal Chemistry Letters - February 14, 2024 Category: Chemistry Authors: Dongxu Zuo Mannkyu Hong Aeran Jung Sunho Lee Nayeon Do Sungwon Jung Yubum Jeon Ji Won Jeong Guocheng Huang Li-Xuan Li Peter M Blumberg Hongryul Yoon Yoonji Lee Jihyae Ann Jeewoo Lee Source Type: research

Discovery of a novel series of pyridone amides as Na < sub > V < /sub > 1.8 inhibitors
Bioorg Med Chem Lett. 2024 Feb 11:129655. doi: 10.1016/j.bmcl.2024.129655. Online ahead of print.ABSTRACTThe NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity aga...
Source: Bioorganic and Medicinal Chemistry Letters - February 13, 2024 Category: Chemistry Authors: Yanfang Wang Shilong Hu Yuhao Chen Meiyuan Chen Di Zhang Wencheng Liu Chunxia Chen Yu Gan Menglan Luo Bowen Ke Source Type: research

Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors
Bioorg Med Chem Lett. 2024 Feb 10:129652. doi: 10.1016/j.bmcl.2024.129652. Online ahead of print.ABSTRACTMixed-lineage protein kinase 3 (MLK3) is implicated in several human cancers and neurodegenerative diseases. A series of 3H-imidazo[4,5-b]pyridine derivatives were designed, synthesized and evaluated as novel MLK3 inhibitors. A homology model of MLK3 was developed and all designed compounds were docked to assess their binding pattern and affinity toward the MLK3 active site. Based on this knowledge, we synthesized and experimentally evaluated the designed compounds. Majority of the compounds showed significant inhibitio...
Source: Bioorganic and Medicinal Chemistry Letters - February 12, 2024 Category: Chemistry Authors: Hye Ree Yoon Anand Balupuri Jinwoo Lee Chaeeun Lee Dong-Hyun Son Re Gin Jeoung Kyung Ah Kim Sungwook Choi Nam Sook Kang Source Type: research

Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants
Bioorg Med Chem Lett. 2024 Feb 9:129651. doi: 10.1016/j.bmcl.2024.129651. Online ahead of print.ABSTRACTA novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of...
Source: Bioorganic and Medicinal Chemistry Letters - February 11, 2024 Category: Chemistry Authors: Sihan Meng Yu Gao Guowei Qiang Zhiwei Hu Qi Shan Juxian Wang Yucheng Wang Jie Mou Source Type: research

Cytotoxic leuconoxine-type diazaspiroindole alkaloids isolated from Cryptolepis dubia
Bioorg Med Chem Lett. 2024 Feb 8:129650. doi: 10.1016/j.bmcl.2024.129650. Online ahead of print.ABSTRACTTwo leuconoxine-type diazaspiroindole alkaloids, the known compound, (+)-melodinine E (1), and its new analogue, (+)-11-chloromelodinine E (2), were isolated from the stems of Cryptolepis dubia (Burm.f.) M.R. Almeida (Apocynaceae), collected in Laos. The chemical structures of these compounds were determined by analysis of their spectroscopic data and by comparison these data with literature values, of which the molecular structure of 1 has been determined previously by analysis of its single-crystal X-ray diffraction da...
Source: Bioorganic and Medicinal Chemistry Letters - February 10, 2024 Category: Chemistry Authors: Yulin Ren Elizabeth N Kaweesa Joshua M Henkin Kongmany Sydara Mouachanh Xayvue Pankaj Pandey Amar Gopal Chittiboyina Zulfiqar Ali Daneel Ferreira Djaja D Soejarto Joanna E Burdette A Douglas Kinghorn Source Type: research

Lipid bilayer membrane permeability mechanism of the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 elucidated by molecular dynamics simulations
In this study, we aim to clarify the mechanism by molecular dynamics (MD) simulations. Initially, we simulated the molecular conformations of KS-58 in water (a polar solvent) and in chloroform (a non-polar solvent). The identified stable conformations were significantly different in each solvent. KS-58 behaves as a chameleon-like molecule as it alters its polar surface area (PSA) depending on the solvent environment. It was also discovered that orientation of Asp's side chain is a critical energy barrier for KS-58 altering its conformation from hydrophilic to lipophilic. Taking these properties into consideration, we simul...
Source: Bioorganic and Medicinal Chemistry Letters - February 10, 2024 Category: Chemistry Authors: Kotaro Sakamoto Takatsugu Hirokawa Source Type: research

Potential of several triazene derivatives against DENGUE viruses
In conclusion, these new triazenes could serve as a lead to develop and optimize drugs against DENV.PMID:38331225 | DOI:10.1016/j.bmcl.2024.129646 (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - February 8, 2024 Category: Chemistry Authors: Seynabou Sokhna Natacha M érindol Marc Presset Insa Seck Marie-Pierre Girard Seydou Ka Samba Fama Ndoye Lalla A ïcha Ba Issa Samb Lionel Berthoux Erwan Le Gall Isabel Desgagn é-Penix Matar Seck Source Type: research

Design, synthesis and biological evaluation of 2-phenylaminopyrimidine derivatives as EGFR inhibitors
Bioorg Med Chem Lett. 2024 Feb 6:129648. doi: 10.1016/j.bmcl.2024.129648. Online ahead of print.ABSTRACTIn the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance is a major factor that affects the efficacy of third-generation epidermal growth factor receptor (EGFR) inhibitors like Osimertinib. To overcome the L858R/T790M/C797S mutation, taking the Brigatinib as the positive control, two classes of 20 target compounds were designed and synthesized with 2-phenylaminopyrimidine as the core structure on the basis of summarizing the structure-activity relationship (SAR), following the basic principles of ...
Source: Bioorganic and Medicinal Chemistry Letters - February 8, 2024 Category: Chemistry Authors: Chunlei Tang Jie Wang Dong Wang Huabing Wang Shengkai Cui Tianxin Xiao Weizheng Fan Yan Zhang Source Type: research

Identification of novel benzothiazole derivatives as inhibitors of NEDDylation pathway to inhibit the progression of gastric cancer
In this study, we designed and synthesized a series of novel neddylation inhibitors bearing benzothiazole scaffolds by molecular hybridization strategy and all compounds were evaluated for antiproliferative activity against MGC-803, MCF-7, A549 and KYSE-30 cell lines. In vitro anti-tumor studies showed that the most promising compound X-10, effectively suppressed MGC-803 cells growth and migration, induced apoptosis and arrested cell cycle at G2/M phase. Importantly, by directly interacting with NAE1, X-10 blocked NAE1 activity, specifically preventing neddylation of Cullin 3 and Cullin 1, and produced a dose-response decl...
Source: Bioorganic and Medicinal Chemistry Letters - February 6, 2024 Category: Chemistry Authors: Xuan Wang Mei Zhao Yuanyuan Chang Sumeng Guan Mengyu Li Hua Yang Moran Sun Source Type: research