☆ 4.7 Article

Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY (2012)

期刊

BIOORGANIC & MEDICINAL CHEMISTRY

卷 20, 期 18, 页码 5496-5506

出版社

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bmc.2012.07.039

关键词

Hedgehog; Hh signaling inhibitor; Pyrrolo[3,2-c]quinoline-4-one

类别

Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic

向作者/读者索取更多资源

Protocol

Reagent

摘要

The Hedgehog (Hh) signaling pathway plays a significant role in the regulation of cell growth and differentiation during embryonic development. Since activation of the Hh signaling pathway is implicated in several types of human cancers, inhibitors of this pathway could be promising anticancer agents. Using high throughput screening, thieno[3,2-c] quinoline-4-one derivative 9a was identified as a compound of interest with potent in vitro activity but poor metabolic stability. Our efforts focused on enhancement of in vitro inhibitory activity and metabolic stability, including core ring conversion and side chain optimization. This led to the discovery of pyrrolo[3,2-c] quinoline-4-one derivative 12b, which has a structure distinct from previously reported Hh signaling inhibitors. Compound 12b suppressed stromal Gli1 mRNA expression in a murine model and demonstrated antitumor activity in a murine medulloblastoma allograft model. (C) 2012 Elsevier Ltd. All rights reserved.

作者

我是这篇论文的作者

点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7

评分不足

次要评分

新颖性

-

重要性

-

科学严谨性

-

评价这篇论文

推荐

Article Chemistry, Medicinal

Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

Zhongzhi Wu, Lubing Gu, Sicheng Zhang, Tao Liu, Pradeep B. Lukka, Bernd Meibohm, John C. Bollinger, Muxiang Zhou, Wei Li

Summary: The study reports a structurally optimized dual MDM2/XIAP inhibitor, leading to the discovery of a more potent analogue against EU-1, which exerts dual targeting effects and can induce cell death. The results suggest that the scaffold based on 14 shows promise for further development as a potential therapeutic agent for leukemia and other cancers.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

添加到收藏夹

Article Biochemistry & Molecular Biology

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators

Veronika Antonyova, Ameneh Tatar, Tereza Brogyanyi, Zdenek Kejik, Robert Kaplanek, Frederic Vellieux, Nikita Abramenko, Alla Sinica, Jan Hajduch, Petr Novotny, Bettie Sue Masters, Pavel Martasek, Milan Jakubek

Summary: In this study, we synthesized a series of pyrrolopyrrole derivatives and found that the basic pyrrolo[3,2-b]pyrrole derivative 1 exhibited strong inhibitory activity against TET1 protein. Furthermore, derivative 1 showed potent anticancer activity and exclusive mitochondrial localization.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

添加到收藏夹

Article Biochemistry & Molecular Biology

Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1,4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Amany Belal, Nagwa M. Abdel Gawad, Ahmed B. M. Mehany, Mohammed A. S. Abourehab, Hazem Elkady, Ahmed A. Al-Karmalawy, Ahmed S. Ismael

Summary: A new series of compounds with potential EGFR inhibitory activity were designed and synthesized. These compounds showed promising anticancer activity and have the potential for therapeutic use.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY (2022)

添加到收藏夹

Article Chemistry, Applied

Pd-Catalyzed One-Pot Sequential Sonogashira Coupling and Dual Annulations Cascade for the Synthesis of Benzofuro[3,2-c]-Triazalo/Pyrrolo-Quinolines

Dipak B. Deokar, Soumi Laha, B. Sridhar, Dharmendra Kumar Tiwari, Pravin R. Likhar

Summary: A palladium-catalyzed coupling reaction followed by dual annulation has been developed for the synthesis of various triazolo/pyrrolo fused benzofuro-quinolines from readily available starting materials. This method involves palladium-catalyzed Sonogashira coupling, benzan-nulation, and C-H activation triggered second annulation reaction cascades in a single pot. The polycyclic compound formed by this method consists of three different heterocyclic structures: benzofuran, quinoline, and triazole/pyrrole. The method provides a simple access to obtain a range of fused benzofurotriazalo/pyrroloquinolines in good to moderate yields.

ADVANCED SYNTHESIS & CATALYSIS (2022)

添加到收藏夹

Article Chemistry, Organic

Temperature Tunable Synthesis of Tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-ones and Dihydro-1H-benzo[b]azepines from 2-Aminobenzonitriles and Donor-Acceptor Cyclopropanes

Bikoshita Porashar, Subhamoy Biswas, Archana Kumari Sahu, Archana Chutia, Anil K. Saikia

Summary: In this study, tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-ones and dihydro-1H-benzo[b]azepines were efficiently synthesized from 2-aminobenzonitriles and donor-acceptor cyclopropanes using SnCl4 as a catalyst. The reaction involves cyclopropane ring opening and nucleophilic attack by amine, followed by unprecedented rearrangement at two different reaction temperatures, resulting in the formation of two nitrogen heterocycles. This methodology can be used for the synthesis of hexahydropyrrolo[3,2-c]quinolinone derivatives, which are present in biologically active molecules.

ORGANIC LETTERS (2022)

添加到收藏夹

Article Chemistry, Medicinal

Synthesis of pyrrolo[3,2-d]pyrimidineone derivatives as novel FXa inhibitors

Jiabin Yang, Bolang Su, Ruizhu Liao, Jinrui Wang, Shuyu Bo

Summary: A series of novel FXa inhibitors, pyrrolo[3,2-d]pyrimidineone compounds, were designed and synthesized. The tested compounds showed moderate to excellent anticoagulant potency in vitro. In rats, further evaluation revealed that compound 17a exhibited good FXa inhibitory activity (IC50 = 1.57 nM) and in vivo antithrombotic potency. The dose-dependent anticoagulant effects of compound 17a were confirmed both in vitro and in vivo.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2023)

添加到收藏夹

Article Biochemistry & Molecular Biology

Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors

Rongrong Su, Yanyan Diao, Wenjie Sha, Dou Dou, Zhixiao Yu, Limin Leng, Zhenjiang Zhao, Zhuo Chen, Honglin Li, Yufang Xu

Summary: This study developed selective non-covalent BTK inhibitors by scaffold hopping and found that compound 2 and 4 exhibited high BTK inhibition potency. These compounds showed great ability to inhibit tumor growth in cell and animal models.

BIOORGANIC CHEMISTRY (2022)

添加到收藏夹

Article Engineering, Biomedical

Anti-miR-96 and Hh pathway inhibitor MDB5 synergistically ameliorate alcohol-associated liver injury in mice

Virender Kumar, Bharti Sethi, Dalton W. Staller, Xiaofei Xin, Jingyi Ma, Yuxiang Dong, Geoffrey A. Talmon, Ram I. Mahato

Summary: Alcohol-associated liver disease (ALD) is a significant health problem worldwide. In this study, the role of miR-96 and Sonic Hedgehog (SHH) signaling in ALD was investigated. Inhibition of miR-96 and SHH signaling reduced inflammation and fibrosis-related gene expression, suggesting their potential therapeutic targets for ALD.

BIOMATERIALS (2023)

添加到收藏夹

Article Chemistry, Multidisciplinary

Bowl-Shaped Pentagon- and Heptagon-Embedded Nanographene Containing a Central Pyrrolo[3,2-b]pyrrole Core

Maciej Krzeszewski, Lukasz Dobrzycki, Andrzej L. Sobolewski, Michal K. Cyranski, Daniel T. Gryko

Summary: The synthesis of a bowl-shaped nitrogen-doped nanographene involves a concise strategy using multicomponent synthesis and sequential intramolecular direct arylation reactions with different reactivity of bonds, resulting in interesting properties in the final structure.

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2021)

添加到收藏夹

Article Multidisciplinary Sciences

Heat promotes melanogenesis by increasing the paracrine effects in keratinocytes via the TRPV3/Ca2+/Hh signaling pathway

Lan Zhang, Hongliang Zeng, Ling Jiang, Chuhan Fu, Yushan Zhang, Yibo Hu, Xiaolin Zhang, Lu Zhu, Fan Zhang, Jinhua Huang, Jing Chen, Qinghai Zeng

Summary: Global warming and rising temperature lead to increased heat stress, which affects inflammation, aging, and skin melanogenesis. Heat stress promotes melanogenesis in pigment cells by increasing the paracrine effects of keratinocytes, which is mediated by the activation of the Hedgehog (Hh) signaling pathway. TRPV3 agonists activate the Hh signaling in keratinocytes and enhance its paracrine effect on melanogenesis. The heat-induced activation of the Hh signaling is dependent on TRPV3-mediated Ca2+ influx. These findings provide insights into the mechanisms of heat-induced skin pigmentation.

ISCIENCE (2023)

添加到收藏夹

Article Multidisciplinary Sciences

Noncanonical activation of GLI signaling in SOX2+ cells drives medulloblastoma relapse

Marzena Swiderska-Syn, Julia Mir-Pedrol, Alexander Oles, Olga Schleuger, April D. Salvador, Sean M. Greiner, Cara Seward, Fan Yang, Benjamin R. Babcock, Chen Shen, Daniel T. Wynn, Avencia Sanchez-Mejias, Timothy R. Gershon, Vanesa Martin, Heather J. McCrea, Kathryn G. Lindsey, Carsten Krieg, Jezabel Rodriguez-Blanco

Summary: Single-cell transcriptomic analysis of medulloblastoma revealed that vismodegib treatment increased Sox2-expressing astrocyte-like cells. These Sox2(+) cells relied on Sonic Hedgehog (SHH) signaling, with MYC-dependent activation downstream of Smo. GLI inhibitors depleted resistant Sox2(+) cells, reduced their engraftment ability, and increased symptom-free survival.

SCIENCE ADVANCES (2022)

添加到收藏夹

Article Biochemistry & Molecular Biology

Hydrogen-Bonded Cyclic Dimers at Large Compression: The Case of 1H-pyrrolo[3,2-h]quinoline and 2-(2′-pyridyl)pyrrole

Dominik Kurzydlowski, Taisiia Chumak, Jakub Rogoza, Arkadiusz Listkowski

Summary: This study investigates the high-pressure behavior of PQ and PP molecular crystals using experimental and computational methods. The results show that compression strengthens the intermolecular hydrogen bonds, while the intramolecular N-H···N interactions are either weakly affected or weakened due to compression-induced distortions of the molecules.

MOLECULES (2021)

添加到收藏夹

Review Chemistry, Multidisciplinary

Diverse synthesis of pyrrolo/indolo[3,2-c]coumarins as isolamellarin-A scaffolds: a brief update

Khokan Samanta, Prasanta Patra, Gandhi Kumar Kar, Shaishab Kumar Dinda, Dibyendu Shekhar Mahanty

Summary: This paper reviews a wide range of literature on synthetic methodologies, biological properties, and fluorescence activities of pyrrolo/indolo[3,2-c]coumarin derivatives published in the last 20 years. The synthesized compounds have been reported in the literature using classical reaction protocols and green reaction protocols starting from suitable precursors.

NEW JOURNAL OF CHEMISTRY (2021)

添加到收藏夹

Article Chemistry, Organic

Total synthesis of pyrrolo[2,3-c ]quinoline alkaloid: trigonoine B

Takashi Nishiyama, Erina Hamada, Daishi Ishii, Yuuto Kihara, Nanase Choshi, Natsumi Nakanishi, Mari Murakami, Kimiko Taninaka, Noriyuki Hatae, Tominari Choshi

Summary: The first total synthesis of the pyrrolo[2,3-c]quinoline alkaloid trigonoine B was achieved through a six-step sequence, providing a framework for the preparation of various N-substituted 4-aminopyrroloquinolines with different biological activities.

BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY (2021)

添加到收藏夹

Article Biochemistry & Molecular Biology

An efficient domino strategy for synthesis of 3-substituted 4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine derivatives in water

Xiaopeng Yang, Chunmei Li, Furen Zhang, Chenze Qi

Summary: The catalyst-free domino reaction in water for synthesizing pyrrolo[3,2-c]pyridine derivatives shows high yields and is characterized by simple and efficient operation.

MOLECULAR DIVERSITY (2022)

添加到收藏夹

Article Biochemistry & Molecular Biology

Synthesis and evaluation of hedgehog signaling inhibitor with novel core system

Tomohiro Ohashi, Yuta Tanaka, Zenyu Shiokawa, Hiroshi Banno, Toshio Tanaka, Sachio Shibata, Yoshihiko Satoh, Hiroko Yamakawa, Yukiko Yamamoto, Harumi Hattori, Shigeru Kondo, Maki Miyamoto, Hideaki Tojo, Atsuo Baba, Satoshi Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY (2015)

添加到收藏夹

Article Chemistry, Medicinal

Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors

Ryo Mizojiri, Daisuke Nakata, Yoshihiko Satoh, Daisuke Morishita, Sachio Shibata, Misa Iwatani-Yoshihara, Yohei Kosugi, Mai Kosaka, Junpei Takeda, Shigekazu Sasaki, Kazuaki Takami, Koichiro Fukuda, Masahiro Kamaura, Shinobu Sasaki, Ryosuke Arai, Douglas R. Cary, Yasuhiro Imaeda

ACS MEDICINAL CHEMISTRY LETTERS (2017)

添加到收藏夹

Article Multidisciplinary Sciences

CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens

Tsuyoshi Ishii, Takuro Okai, Misa Iwatani-Yoshihara, Manabu Mochizuki, Satoko Unno, Masako Kuno, Masato Yoshikawa, Sachio Shibata, Masanori Nakakariya, Takatoshi Yogo, Tomohiro Kawamoto

SCIENTIFIC REPORTS (2017)

添加到收藏夹

Article Biochemistry & Molecular Biology

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

Takuto Kojima, Yasutomi Asano, Osamu Kurasawa, Yasuhiro Hirata, Naoki Iwamura, Tzu-Tshin Wong, Bunnai Saito, Yuta Tanaka, Ryosuke Arai, Kazuko Yonemori, Yasufumi Miyamoto, Yoji Sagiya, Masahiro Yaguchi, Sachio Shibata, Akio Mizutani, Osamu Sano, Ryutaro Adachi, Yoshinori Satomi, Megumi Hirayama, Kazunobu Aoyama, Yuto Hiura, Atsushi Kiba, Shuji Kitamura, Shinichi Imamura

BIOORGANIC & MEDICINAL CHEMISTRY (2018)

添加到收藏夹

Article Biochemistry & Molecular Biology

Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility

Tomohiro Ohashi, Yuya Oguro, Toshio Tanaka, Zenyu Shiokawa, Yuta Tanaka, Sachio Shibata, Yoshihiko Sato, Hiroko Yamakawa, Harumi Hattori, Yukiko Yamamoto, Shigeru Kondo, Maki Miyamoto, Mitsuhiro Nishihara, Yoshimasa Ishimura, Hideaki Tojo, Atsuo Baba, Satoshi Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY (2012)

添加到收藏夹

Article Biochemistry & Molecular Biology

Improvement of pulmonary arterial hypertension, inflammatory response, and epithelium injury by dual activation of cAMP/cGMP pathway in a rat model of monocrotaline-induced pulmonary hypertension

Yo Muraki, Takako Naito, Kimio Tohyama, Sachio Shibata, Kanako Kuniyeda, Yasunori Nio, Masatoshi Hazama, Takanori Matsuo

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY (2019)

添加到收藏夹

Article Multidisciplinary Sciences

Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor

Kenichi Iwai, Tadahiro Nambu, Ryo Dairiki, Momoko Ohori, Jie Yu, Kristine Burke, Masamitsu Gotou, Yukiko Yamamoto, Shunsuke Ebara, Sachio Shibata, Ryosuke Hibino, Satoru Nishizawa, Tohru Miyazaki, Misaki Homma, Yuya Oguro, Takashi Imada, Nobuo Cho, Noriko Uchiyama, Akifumi Kogame, Toshiyuki Takeuchi, Osamu Kurasawa, Kazunori Yamanaka, Huifeng Niu, Akihiro Ohashi

SCIENCE ADVANCES (2019)

添加到收藏夹

Article Multidisciplinary Sciences

Synergistic apoptotic effects in cancer cells by the combination of CLK and Bcl-2 family inhibitors

Aiko Murai, Shunsuke Ebara, Satoshi Sasaki, Tomohiro Ohashi, Tohru Miyazaki, Toshiyuki Nomura, Shinsuke Araki

PLOS ONE (2020)

添加到收藏夹

Article Chemistry, Medicinal

Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore

Yuta Tanaka, Masaki Seto, Keiko Kakegawa, Kazuaki Takami, Fumiaki Kikuchi, Takeshi Yamamoto, Minoru Nakamura, Masaki Daini, Masataka Murakami, Tomohiro Ohashi, Takahito Kasahara, Junsi Wang, Zenichi Ikeda, Yasufumi Wada, Florian Puenner, Takahiro Fujii, Masakazu Inazuka, Sho Sato, Tomohiko Suzaki, Jeong-Ho Oak, Yuichi Takai, Hiroshi Kohara, Kouya Kimoto, Hideyuki Oki, Satoshi Mikami, Minoru Sasaki, Yuta Tanaka

Summary: This study reports the discovery of novel brain-penetrant GCS inhibitors, which have the potential to treat Gaucher's disease and Parkinson's disease. The optimization of the structure and ADMETox profile resulted in the identification of T-036 as a potent GCS inhibitor in vivo. Scaffold hopping led to the development of another GCS inhibitor, T-690, with lower toxicological risk. The structural aspects of the compounds were discussed in terms of their unique inhibition mode and reduced cardiovascular risk.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

添加到收藏夹

Article Biochemistry & Molecular Biology

Antitumor activity of a novel and orally available inhibitor of serine palmitoyltransferase

Masahiro Yaguchi, Sachio Shibata, Yoshinori Satomi, Megumi Hirayama, Ryutaro Adachi, Yasutomi Asano, Takuto Kojima, Yasuhiro Hirata, Akio Mizutani, Atsushi Kiba, Yoji Sagiya

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2017)

添加到收藏夹

Article Pharmacology & Pharmacy

Pharmacokinetic and Pharmacodynamic Modeling of Hedgehog Inhibitor TAK-441 for the Inhibition of Gli1 messenger RNA Expression and Antitumor Efficacy in Xenografted Tumor Model Mice

Akifumi Kogame, Yoshihiko Tagawa, Sachio Shibata, Hideaki Tojo, Maki Miyamoto, Kimio Tohyama, Takahiro Kondo, Shimoga Prakash, Wen Chyi Shyu, Satoru Asahi

DRUG METABOLISM AND DISPOSITION (2013)

添加到收藏夹

暂无数据

© Peeref 2019-2024. All rights reserved.