16803-94-4Relevant academic research and scientific papers
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
Wu, Zhongzhi,Gu, Lubing,Zhang, Sicheng,Liu, Tao,Lukka, Pradeep B.,Meibohm, Bernd,Bollinger, John C.,Zhou, Muxiang,Li, Wei
, p. 1930 - 1950 (2021/03/01)
Murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP) are important cell survival proteins in tumor cells. As a dual MDM2/XIAP inhibitor reported previously, compound MX69 has low potency with an IC50 value of 7.5 μM against an acute lymphoblastic leukemia cell line EU-1. Herein, we report the structural optimization based on the MX69 scaffold, leading to the discovery of a 25-fold more potent analogue 14 (IC50 = 0.3 μM against EU-1). We demonstrate that 14 maintains its mode of action by dual targeting of MDM2 and XIAP through inducing MDM2 protein degradation and inhibiting XIAP mRNA translation, respectively, which resulted in cancer cell growth inhibition and cell death. The results strongly suggest that the scaffold based on 14 is promising for further optimization to develop a new therapeutic agent for leukemia and possibly other cancers where MDM2 and XIAP are dysregulated.
QUINOLINE DERIVATIVES AND USES IN MANAGING CANCER
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, (2021/03/19)
Provided herein are compounds, pharmaceutical compositions including such compounds, and methods of using such compounds to treat diseases or disorders associated with MDM2 activity.
Synthesis and biological evaluation of naphthoquinone analogs as a novel class of proteasome inhibitors
Lawrence, Harshani R.,Kazi, Aslamuzzaman,Luo, Yunting,Kendig, Robert,Ge, Yiyu,Jain, Sanjula,Daniel, Kenyon,Santiago, Daniel,Guida, Wayne C.,Sebti, Said M.
experimental part, p. 5576 - 5592 (2010/09/15)
Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure-activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the β5 and β6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the β6 subunit.
Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors
Zheng, Xiaoxia,Oda, Hiroyuki,Takamatsu, Kayo,Sugimoto, Yukio,Tai, Akihiro,Akaho, Eiichi,Ali, Hamed Ismail,Oshiki, Toshiyuki,Kakuta, Hiroki,Sasaki, Kenji
, p. 1014 - 1021 (2007/10/03)
In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance.
