Article
Chemistry, Medicinal
Junkang Ren, Xu Quan, Ying Liu, Jiani Li, Xiaoyu Zhang, Zhiyu Li, Xiaomeng Zhang
Summary: Inhibition of PARP has been successful in clinical treatment of homologous recombination-deficient malignancy. Recent study shows that both PARP-1 inhibition and DNA trapping contribute to the efficacy in BRCA mutant tumors, and toxicities result from poor selectivity of PARP-1 over PARP-2. A series of compounds were synthesized and compound 8m was identified as a highly potent and selective inhibitor and DNA trapper of PARP-1.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Nisha Pillay, Laura Mariotti, Mariola Zaleska, Oviya Inian, Matthew Jessop, Sam Hibbs, Ambroise Desfosses, Paul C. R. Hopkins, Catherine M. Templeton, Fabienne Beuron, Edward P. Morris, Sebastian Guettler
Summary: This research reveals the structure of the active unit filament of tankyrase and shows how its catalytic and non-catalytic functions are controlled by polymerization. The cryo-electron microscopy reconstruction provides detailed insights into the interactions between the SAM domain and the catalytic domain, as well as the role of head-to-head and tail-to-tail interactions at the active site.
Article
Chemistry, Multidisciplinary
Chrysoula Mikra, Zoi Melissari, Maroula G. Kokotou, Panagiotis Gritzapis, Konstantina C. Fylaktakidou
Summary: A series of quinazolinone derivatives were synthesized using a microwave-assisted one-pot four-component or two-step reaction protocol. The reaction conditions and yield were evaluated, and the molecules were found to have potential applications in organic, medicinal, and material chemistry.
SUSTAINABLE CHEMISTRY AND PHARMACY
(2022)
Article
Chemistry, Organic
Natalia B. Kilimciler, Nicolas M. Palavecino, Nadia Gruber, Daniel R. Vega, Liliana R. Orelli, Jimena E. Diaz
Summary: A novel method utilizing trimethylsilyl polyphosphate (PPSE) has been developed to synthesize quinazolin4(3H)-imines (QIs) by reacting 2-aminobenzonitrile with secondary amides. This general reaction allows for the synthesis of N3-aryl and N3-alkyl QIs with varying 2-substituents, resulting in high yields. The procedure can also be applied to derivatives containing additional functional groups. The simplicity of the method, along with readily available starting materials and a mild dehydrating agent, makes it suitable for scalability. Based on literature data and experimental observations, a possible reaction path involving an intermediate nitrilium ion is proposed.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Sumit Kumar, Kishor Padala, Barnali Maiti
Summary: A quinazolin-4(3H)-one ring system is a privileged heterocyclic moiety with distinct biological properties. This study presents an efficient strategy for the synthesis of quinazolin-4(3H)-one using substituted 2-amino benzamide with dimethyl sulfoxide as a carbon source and hydrogen peroxide as an oxidant.
Article
Chemistry, Organic
Erina Niijima, Tomomi Imai, Hayate Suzuki, Yuuki Fujimoto, Osamu Kitagawa
Summary: Various optically pure N-C axially chiral quinazolin-4-one derivatives reacted with Lawesson's reagent without significant decrease in optical purity, producing optically active quinazoline-4-thione derivatives with high rotational barriers in good yields (93-99% ee).
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Tebyan O. Mirgany, Ashraf N. Abdalla, Md Arifuzzaman, A. F. M. Motiur Rahman, Huda S. Al-Salem
Summary: A series of quinazolin-4(3H)-one derivatives showed potent cytotoxicity against human breast adenocarcinoma and ovarian carcinoma cell lines, with some compounds exhibiting inhibitory activity against key enzymes like CDK2, HER2, EGFR, and VEGFR2. Docking analysis revealed that compounds 2i and 3i act as inhibitors against specific kinases, showing superior interactions compared to known inhibitors. Additionally, the drug likeness properties of the derivatives demonstrated better ADME values than the positive control lapatinib.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Osamu Sano, Masahiro Ito, Masayo Saito, Akinori Toita, Toshio Tanaka, Hironobu Maezaki, Shinsuke Araki, Hidehisa Iwata
Summary: Phenotypic screening has identified a new modality of compounds called molecular glues, which induce the degradation of target proteins through ternary complexes of E3 ligases. In this study, a novel Cyclin K degrader, T4, was identified using global proteomic analysis, originally discovered through phenotypic screening for alternative poly-adenylation regulation. Further analysis revealed that T4 induces Cyclin K degradation and regulates alternative polyadenylation. Additionally, a more potent Cyclin K degrader, TR-213, was generated through a structure-activity relationship study of T4, providing novel chemical tools for studying Cyclin K degradation and alternative polyadenylation regulation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Sumit Kumar, Kishor Padala, Barnali Maiti
Summary: The synthesis of quinazolin-4(3H)-one has always been a challenge in synthetic chemistry. In this report, we propose an efficient protocol using substituted 2-amino benzamide with dimethyl sulfoxide (DMSO) as a carbon source and H2O2 as an oxidant.
Article
Chemistry, Medicinal
Ling Lv, Mireguli Maimaitiming, Yan Huang, Jichen Yang, Shuxia Chen, Yanfeng Sun, Xuetao Zhang, Xin Li, Changhu Xue, Pingyuan Wang, Chang-Yun Wang, Zhiqing Liu
Summary: A series of quinazolin-4(3H)-one derivatives with cholinesterase inhibition and anti-inflammatory activities were designed and synthesized. The compound MR2938 showed promising inhibitory activity against acetylcholinesterase and suppressed NO production. It also decreased the levels of pro-inflammatory cytokines and suppressed neuroinflammation through blocking certain signaling pathways. These results suggest that MR2938 could be developed as a potential lead compound for anti-AD drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Priyanka Bhandu, Himanshu Verma, Manmeet Singh, Manoj Kumar, Gera Narendra, Shalki Choudhary, Pankaj Kumar Singh, Om Silakari
Summary: The withdrawal of Zenarestat from clinical trials due to renal toxicity was a setback in the development of ALR2-targeted agents for diabetic complications. However, by making structural modifications and using scaffold hopping, a library of optimized analogues was obtained, and some of them showed potential as ALR2 inhibitors. The synthesized quinazolin-4(3H)-one derivatives, particularly compounds Q2, Q3, and Q10, exhibited potent inhibitory activity against ALR2.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Chemistry, Medicinal
Xin Wen, Minmin Zhang, Zhiqiang Duan, Yanrui Suo, Weiwei Lu, Rui Jin, Baiyang Mu, Kaige Li, Xu Zhang, Linghua Meng, Yu Hong, Xingyu Wang, Hangchen Hu, Jian Zhu, Weixiao Song, Aijun Shen, Xiaojie Lu
Summary: The study presents a new DNA-encoded library (DEL) containing a privileged scaffold quinazolin-4(3H)-one, generated through a robust DNA-compatible multicomponent reaction. Affinity-mediated DEL selection identifies a series of novel glutathione S-transferase (GST) inhibitors, with compound 16 showing inhibitory potency against SjGST and hGSTM2. The co-crystal structure of compound 16 with SjGST reveals a distinct binding mode compared to known GSH-like compounds, suggesting its potential as a different type of probe for discovering more potent GST inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Eric P. Gillis, Kyle Parcella, Michael Bowsher, James H. Cook, Christiana Iwuagwu, B. Narasimhulu Naidu, Manoj Patel, Kevin Peese, Haichang Huang, Lourdes Valera, Chunfu Wang, Kasia Kieltyka, Dawn D. Parker, Jean Simmermacher, Eric Arnoult, Robert T. Nolte, Liping Wang, John A. Bender, David B. Frennesson, Mark Saulnier, Alan Xiangdong Wang, Nicholas A. Meanwell, Makonen Belema, Umesh Hanumegowda, Susan Jenkins, Mark Krystal, John F. Kadow, Mark Cockett, Robert Fridell
Summary: Long-acting HIV-1 antiretroviral therapy offers advantages over daily oral therapy, but the criteria for compounds entering clinical development are high. This study reports the discovery of capsid inhibitors with a quinazolinone core that maintain potent activity against HIV-1 infection while tolerating structural modifications. The characterization of a prototypical compound, GSK878, including X-ray co-crystal structure and pharmacokinetic data in animals, is presented.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Haiping Yao, Yanyan Wang, Jiangwen Mo, Yan Peng, Zhu Wang
Summary: In this study, twelve new derivatives of isoquinolin-1(2H)-one were designed and synthesized as tankyrase (TNKS) inhibitors, among which compound 11c showed the highest potency with low IC50 values against TNKS1 and TNKS2. Molecular docking analysis revealed that compound 11c occupied a unique subpocket and formed a hydrogen bond with Glu1138 of TNKS2, suggesting a novel binding mode for TNKS inhibitors. Further research is warranted to explore the potential of compound 11c as a promising TNKS inhibitor.
Article
Chemistry, Medicinal
Shangde Liu, Duo Yuan, Shanshan Li, Roujie Xie, Yi Kong, Xiong Zhu
Summary: PAR4 antagonists are crucial in reducing the risk of heart attack and thrombotic complications in stroke. Highly selective PAR4 antagonists, such as 13 and 30g, have shown promising activity and selectivity, potentially serving as starting points for further research in this area.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Chih-Wei Huang, Hsiu-Chen Liu, Chia-Pei Shen, Yi-Tong Chen, Sung-Jai Lee, Matthew D. Lloyd, Hwei-Jen Lee
BIOCHEMICAL JOURNAL
(2016)
Article
Chemistry, Medicinal
Amit Nathubhai, Teemu Haikarainen, Penelope C. Hayward, Silvia Munoz-Descalzo, Andrew S. Thompson, Matthew D. Lloyd, Lari Lehtio, Michael D. Threadgill
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Organic
Maksims Yevglevskis, Guat L. Lee, Jenny Sun, Shiyi Zhou, Xiaolong Sun, Gabriele Kociok-Koehn, Tony D. James, Timothy J. Woodman, Matthew D. Lloyd
ORGANIC & BIOMOLECULAR CHEMISTRY
(2016)
Article
Chemistry, Multidisciplinary
Pawan Jolly, Anna Miodek, Deng-Kai Yang, Lin-Chi Chen, Matthew D. Lloyd, Pedro Estrela
Article
Chemistry, Medicinal
Amit Nathubhai, Teemu Haikarainen, Jarkko Koivunen, Sudarshan Murthy, Francoise Koumanov, Matthew D. Lloyd, Geoffrey D. Holman, Taina Pihlajaniemi, David Tosh, Lari Lehtio, Michael D. Threadgill
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Biochemistry & Molecular Biology
Maksims Yevglevskis, Guat L. Lee, Amit Nathubhai, Yoana D. Petrova, Tony D. James, Michael D. Threadgill, Timothy J. Woodman, Matthew D. Lloyd
BIOORGANIC CHEMISTRY
(2018)
Article
Chemistry, Multidisciplinary
Adam C. Sedgwick, Jordan E. Gardiner, Gyoungmi Kim, Maksims Yevglevskis, Matthew D. Lloyd, A. Toby A. Jenkins, Steven D. Bull, Juyoung Yoon, Tony D. James
CHEMICAL COMMUNICATIONS
(2018)
Article
Biochemistry & Molecular Biology
Maksims Yevglevskis, Amit Nathubhai, Katty Wadda, Guat L. Lee, Suzanne Al-Rawi, Tingying Jiao, Paul J. Mitchell, Tony D. James, Michael D. Threadgill, Timothy J. Woodman, Matthew D. Lloyd
BIOORGANIC CHEMISTRY
(2019)
Article
Biochemistry & Molecular Biology
Yoana D. Petrova, Katty Wadda, Amit Nathubhai, Maksims Yevglevskis, Paul J. Mitchell, Tony D. James, Michael D. Threadgill, Timothy J. Woodman, Matthew D. Lloyd
BIOORGANIC CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Matthew D. Lloyd
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Jing Li, Ping Cheng, Shoufeng Li, Pengfei Zhao, Bing Han, Xiaoyuan Ren, Julia Li Zhong, Matthew D. Lloyd, Charareh Pourzand, Arne Holmgren, Jun Lu
Summary: The study found that both the Trx and GSH systems are sensitive to APAP toxicity in vivo, and that the thiol-dependent redox environment is crucial in determining the severity of APAP-induced hepatotoxicity. Dietary selenium and selenoproteins play critical roles in protecting mice from APAP overdose.
ANTIOXIDANTS & REDOX SIGNALING
(2021)
Review
Cell Biology
Vega Widya Karisma, Wei Wu, Mingxing Lei, Huawen Liu, Muhammad Farrukh Nisar, Matthew D. Lloyd, Charareh Pourzand, Julia Li Zhong
Summary: This review discusses the potential of UVA radiation as a light source for photo-controlled drug release, utilizing methods such as photo-isomerization and photo-cleavage to control drug release.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Chemistry, Multidisciplinary
Matthew D. Lloyd, Maksims Yevglevskis, Amit Nathubhai, Tony D. James, Michael D. Threadgill, Timothy J. Woodman
Summary: Racemases and epimerases are important enzymes in biotechnology and drug research, with potential applications. Research focuses on their catalytic mechanisms and development of corresponding inhibitors, including rational design of inhibitors and development of transition-state mimics.
CHEMICAL SOCIETY REVIEWS
(2021)
Article
Chemistry, Multidisciplinary
Maksims Yevglevskis, Guat L. Lee, Amit Nathubhai, Yoana D. Petrova, Tony D. James, Michael D. Threadgill, Timothy J. Woodman, Matthew D. Lloyd
CHEMICAL COMMUNICATIONS
(2017)