- Synthesis and biological evaluation of novel 2,4-dianilinopyrimidine derivatives as potent dual janus kinase 2 and histone deacetylases inhibitors
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Dual or multiple-targeting inhibition of oncogenic targets in a single molecule could be an alternative approach to drug combinations. Previous studies have revealed that histone deacetylases (HDAC) inhibitor in combination with janus kinase (JAK) inhibitor could exhibit synergistically anti-proliferative effects in cancer treatment. Herein, we presented a novel series of 2,4-dianilinopyrimidine derivatives, which could simultaneously inhibit JAK2 and HDAC1. Among which, 7l was found to be the most potent compound and displayed balanced inhibitory activity against HDAC1 (IC50 = 1.9 nM) and JAK2 (IC50 = 0.5 nM), respectively. 7l also demonstrated good antiproliferative activity against tested cancer cell lines (A549, HepG-2, MDA-MB-231 and Jurkat). Moreover, flow cytometric analysis showed that 7l induced apoptosis and cell cycle arrest in a dose-dependent manner, and the insight into mechanisms of 7l indicated that it could decrease the phosphorylation of STAT-3 and promote histone acetylation. In conclusion, these results together suggested that 7l would be a promising lead candidate and deserved further research and development.
- Gan, Zongjie,Jiang, Junhao,Lu, Jinyu,Ran, Dongzhi,Zhou, Haiping
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- Sustainable synthesis of potential antitumor new derivatives of Abemaciclib and Fedratinib via C-N cross coupling reactions using Pd/Cu-free Co-catalyst
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Herein, chitosan as an inexpensive, abundant, and biodegradable bio-material, produced from a key constituent of the exoskeletons of crustaceans, was used to generate the cobalt-based magnetic silica nanocomposite for the performance of the C-N cross-coupling reaction as the main step of the synthesis of Abemaciclib and Fedratinibs. Several derivatives of these recently FDA-approved anti-cancer drugs were synthesized for the first time by using Pd/Cu-free co-catalyzed under both, the conventional heating and microwave (MW) irradiation conditions. The potential anticancer activity of synthesized compounds was investigated by molecular docking study.
- Khorsandi, Zahra,Keshavarzipour, Fariba,Varma, Rajender S.,Hajipour, Abdol R.,Sadeghi-Aliabadi, Hojjat
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- One class HDAC and JAK dual targeting inhibitors. Preparation method and application
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HDAC And JAK dual-targeted inhibitors have the structure shown HDAC, and JAK and I dual-targeting inhibitors have good inhibitory activity on HDAC HDAC and JAK JAK kinases. The invention also provides a preparation method HDAC of the JAK and and dual-targeting inhibitor and an application of the inhibitor in the treatment of tumor diseases of mammals. The HDAC and JAK dual targeting inhibitors of the present invention may also be configured as corresponding pharmaceutical compositions or pharmaceutical preparations to improve the convenience of administration.
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Paragraph 0115-0121
(2021/09/26)
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- A Pd/Cu-Free magnetic cobalt catalyst for C-N cross coupling reactions: synthesis of abemaciclib and fedratinib
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Herein, the synthesis of a nano-catalytic system comprising magnetic nanoparticles as the core and edible natural ligands bearing functional groups as supports for cobalt species is described. Subsequent to its characterization, the efficiency of the catalyst was investigated for C-N cross-coupling reactions using assorted derivatives of amines and aryl halides. This novel and easily accessible Pd- and Cu-free catalyst exhibited good catalytic activity in these reactions using γ-valerolactone (GVL) at room temperature; good recyclability bodes well for the future application of this strategy. The introduced catalytic system is attractive in view of the excellent efficiency in an array of coupling reactions and its versatility is illustrated in the synthesis of abemaciclib and fedratinib, which are FDA-approved new and significant anti-cancer medicinal compounds that are prepared under green reaction conditions.
- Hajipour, Abdol R.,Khorsandi, Zahra,Sarfjoo, Mohamad Reza,Varma, Rajender S.
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supporting information
p. 5222 - 5229
(2021/07/29)
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- Diphenylamino pyrimidine compound for inhibiting kinase activity
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The invention provides a diphenylamino pyrimidine compound for inhibiting the kinase activity, and particularly provides a medicinal composition of a substituted diphenylamino pyrimidine compound andapplication thereof. The compound is a compound as shown in a formula (I) in the specification, or pharmaceutically acceptable salt, prodrug, hydrate thereof or solvent compound, crystal form, N-oxideand various diastereomers thereof. The compound can be used for treating diseases which can be treated with JAK2 kinase inhibitors.
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- OXOINDOLINE DERIVATIVES AS PROTEIN FUNCTION MODULATORS
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The present invention provides chimeric compounds of formula (II) that modulate protein function, to restore protein homeostasis, including cytokine, aiolos, and/or ikaros activity, TNF-alpha activity, CKl-alpha activity and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as cytokine-mediated diseases, disorders, and conditions, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant rejection, and cancer, are provided.
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Paragraph 0542; 0554
(2017/12/16)
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- COMPOSITIONS AND METHODS FOR TREATING MYELOFIBROSIS
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Provided herein are compositions and methods for treating myelofibrosis in a subject. The methods comprise administering to the subject an effective amount of compound which is which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl] amin
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Page/Page column 42
(2012/05/20)
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- BI-ARYL META-PYRIMIDINE INHIBITORS OF KINASES
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The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non receptor kinases.
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Page/Page column 109
(2008/06/13)
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