33233-67-9Relevant articles and documents
Water soluble prodrugs of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2-(3,4,5-trimethoxyphenyl)cyclopent-2-ene-1-one
Nam, Nguyen-Hai,Kim, Yong,You, Young-Jae,Hong, Dong-Ho,Kim, Hwan-Mook,Ahn, Byung-Zun
, p. 1021 - 1029 (2003)
Fourteen prodrugs of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2-(3,4,5-trimethoxyphenyl)cyclopent-2-ene-1-one (1) were prepared to improve its water solubility and potency. These prodrugs include α-amino acid (1a-1h), aliphatic amino acid (1i-1l), phosphoramidate (1m), and phosphate (1n) derivatives. All of the prodrugs showed improved water solubility. A number of the amino acid prodrugs (1a, 1b, 1d-1f, 1h, 1j, and 1k) exhibited more potent antitumor activity compared to the parent compound (1). The phosphate prodrug 1n also offered a potent antitumor activity, but the phosphoramidate 1m did not show any antitumor activity in vivo. None of the prodrugs exhibited significant toxicities in mice. These results indicate that the design and preparation of the amino acid prodrugs (1a, 1b, 1d-1f, 1h, 1j, and 1k) and phosphate prodrug (1n) are beneficial for enhancing the antitumor activity of 1. The similar approaches may be used to improve water solubility and bioactivity of other poorly soluble aromatic amines.
Preparation and characterization of a novel Al18F–NOTA–BZA conjugate for melanin-targeted imaging of malignant melanoma
Chang, Chih-Chao,Chang, Chih-Hsien,Lo, Yi-Hsuan,Lin, Ming-Hsien,Shen, Chih-Chieh,Liu, Ren-Shyan,Wang, Hsin-Ell,Chen, Chuan-Lin
, p. 4133 - 4139 (2016)
Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel18F-labeled NOTA–benzamide
Harnessing the anti-nociceptive potential of nk2 and nk3 ligands in the design of new multifunctional μ/δ-opioid agonist–neurokinin antagonist peptidomimetics
Ballet, Steven,Gadais, Charlène,Janecka, Anna,Martin, Charlotte,Neve, Jolien De,Piekielna-Ciesielska, Justyna
supporting information, (2021/09/13)
Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or-NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharma-cophore Dmt-DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 ) and the dual μ/δ opioid agonist H-Dmt-D-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomo-lar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.
HISTONE DEMETHYLASE INHIBITORS FOR TREATING CANCERS
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, (2021/01/22)
The present disclosure provides a new series of 8-hydroxyquinoline derivatives/analogs that are potent KDM4 inhibitors with high activity and selectivity against KDM4 enzymes. Also disclosed are the pharmaceutical compositions comprising such 8-hydroxyqui
PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia
Bukhari, Shazreh,Cabral, Aaron D.,Gawel, Justyna M.,Gunning, Patrick T.,Israelian, Johan,Manaswiyoungkul, Pimyupa,Nawar, Nabanita,Olaoye, Olasunkanmi O.,Radu, Tudor B.,Raouf, Yasir S.,Sedighi, Abootaleb,Shouksmith, Andrew E.,Sina, Diana,Toutah, Krimo,de Araujo, Elvin D.
, (2020/07/03)
Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (～36× ) and low nanomolar potency (IC50 = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (～4× more selective than current clinical standards – citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
Antiglioma Activity of Aryl and Amido-Aryl Acetamidine Derivatives Targeting iNOS: Synthesis and Biological Evaluation
Maccallini, Cristina,Arias, Fabio,Gallorini, Marialucia,Amoia, Pasquale,Ammazzalorso, Alessandra,De Filippis, Barbara,Fantacuzzi, Marialuigia,Giampietro, Letizia,Cataldi, Amelia,Camacho, María Encarnación,Amoroso, Rosa
supporting information, p. 1470 - 1475 (2020/07/31)
Nitric oxide is an important inflammation mediator with a recognized role in the development of different cancers. Gliomas are primary tumors of the central nervous system with poor prognosis, and the expression of the inducible nitric oxide synthase correlates with the degree of malignancy, changes in vascular reactivity, and neo-angiogenesis. Therefore, targeting the nitric oxide biosynthesis appears as a potential strategy to impair glioma progression. In the present work a set of aryl and amido-aryl acetamidine derivatives were synthesized to obtain new potent and selective inducible nitric oxide synthase inhibitors with improved physicochemical parameters with respect to the previously published molecules. Compound 17 emerged as the most promising inhibitor and was evaluated on C6 rat glioma cell line, showing antiproliferative effects and high selectivity over astrocytes.
CHIMERIC COMPOUNDS AND METHODS OF MANAGING NEUROLOGICAL DISORDERS OR CONDITIONS
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Page/Page column 45, (2020/09/12)
This disclosure relates to chimeric compounds and methods for managing neurological conditions. In certain embodiments, the compound comprises a chemical structure of a monoamine reuptake inhibitor conjugated to a chemical structure of a histone deacetyla
Acid-Stable Ester Linkers for the Solid-Phase Synthesis of Immobilized Peptides
Budě?ínsky, Milo?,Jirá?ek, Ji?í,Mitrová, Katarína,Pícha, Jan
, p. 1297 - 1306 (2020/07/04)
A series of N-terminally Fmoc-protected linkers of the general formula Fmoc-X?CO?O?Y?COOH have been prepared, where X is ?NH?CH2?CH2- or -p-(aminomethyl)phenyl- and Y is ?(CH2)n? (n is 1 or 4) or -p-(methyl)phenyl-. These linkers can easily be covalently attached via their C-terminal carboxyl group to a resin bearing a free amino group. After cleavage of the N-terminal Fmoc group, the linkers can be extended by standard solid-phase peptide synthesis techniques. These ester linkers are acid-stable and resistant to the base-mediated diketopiperazine formation that often occurs during the synthesis of ester-bound peptides; they are stable at neutral pH in aqueous buffers for days but can be effectively cleaved with 0.1 m NaOH or aq. ammonia within minutes or hours, respectively. These properties make these ester handles well suited for use as linkers for the solid-phase peptide synthesis of immobilized peptides when the stable on-resin immobilization of the peptides and the testing of their biological properties in aqueous buffers at neutral pH are necessary.
Synthesis, biological evaluation and molecular modeling study of 2-amino-3,5-disubstituted-pyrazines as Aurora kinases inhibitors
Bo, Yong-Xin,Chen, Shi-Wu,Hao, Shu-Yi,Wang, Xing-Rong,Xiang, Rong,Xu, Yu
, (2020/02/11)
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 μM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF THEIR USE
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Page/Page column 157; 158, (2019/07/20)
The present invention provides a compound of formula (II): an inhibitor of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases. Its prodrugs are disclosed.
