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1.
Eur J Med Chem ; 191: 112152, 2020 Apr 01.
Article in English | MEDLINE | ID: mdl-32088495

ABSTRACT

Protein kinase inhibitors and epigenetic regulatory molecules are two main kinds of anticancer drugs developed in recent years. Both kinds of drugs harbor their own advantages and disadvantages in the treatment of cancer, and the development of small molecules which could target at kinases and epigenetic targets simultaneously can avoid the defects of drugs which only targets at kinases or epigenetic proteins. In this study, a series of 4,5-dihydro-[1,2,4]triazolo [4,3-f]pteridine derivatives were designed and synthesized based on the structure of PLK1 inhibitor BI-2536. Subsequent targets affinity screen and antiproliferative activity test led to the discovery of the most potent dual PLK1/BRD4 inhibitor 9b with good potency for both PLK1 (IC50 = 22 nM) and BRD4 (IC50 = 109 nM) as well as favorable antiproliferative activity against a panel of cancer cell lines. 9b could induce cell cycle arrest and apoptosis in acute myeloid leukemia cell line MV 4-11 in a concentration dependent manner. It could also downregulate the transcription of several proliferation-related oncogenes, including c-MYC, MYCN and BCL-2. Finally, in a MV4-11 mouse xenograft model, 9b exhibited favorable in vivo antitumor activity with 66% tumor growth inhibition (TGI) at a dose of 60 mg/kg while without obvious toxicity. This study thus provided us a start point for the development of new dual PLK1/BRD4 inhibitors as anticancer agents.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pteridines/pharmacology , Transcription Factors/antagonists & inhibitors , Triazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle Proteins/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Pteridines/chemical synthesis , Pteridines/chemistry , Structure-Activity Relationship , Transcription Factors/metabolism , Triazoles/chemical synthesis , Triazoles/chemistry , Tumor Cells, Cultured , Polo-Like Kinase 1
2.
Pharmazie ; 74(6): 321-325, 2019 06 01.
Article in English | MEDLINE | ID: mdl-31138367

ABSTRACT

The non-structural protein 4B (NS4B) of hepatitis C virus (HCV) has emerged as a promising target for chronic hepatitis C treatment. The thieno[2,3-b]pyridine HCV inhibitor 2 has demonstrated properties as a NS4B inhibitor. Subsequent hybridization of 2 with our recently published imidazo[2,1-b]thiazole NS4B inhibitor 3 resulted in the discovery of several more potent compounds with sub-micromolar EC50 against HCV genotype 1b replicon. More importantly, the resistant profile study of the new synthesized HCV inhibitors illustrated that the bicyclic scaffold would mediate the resistance of H3R and Q26R mutations, while the piperazinone motif would mediate the resistance of H94R, F98C and V105M mutations, and the C3- amino group would disrupt the interaction between piperazinone motif and NS4B. This structure-resistance relationship detail could help us to develop new NS4B inhibitors with higher resistant barrier in the future.


Subject(s)
Antiviral Agents/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Hepacivirus , Humans , Virus Replication/drug effects
3.
Bioorg Med Chem Lett ; 25(7): 1373-6, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25754492

ABSTRACT

Tuberculosis (TB) remains a major human health problem. New therapeutic antitubercular agents are urgent needed to control the global tuberculosis pandemic. We synthesized a new series of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives and evaluated their anti-mycobacterial activities against Mycobacterium tuberculosis H37Ra as well as their druggabilities. The results showed that most of these derivatives, especially the compounds with simple alkyl side chains, exhibited good antitubercular activities and favorable aqueous solubilities with no obvious cytotoxicity. It suggested that the 4-carbonyl piperazine substituents in benzothiazinone scaffold were well tolerated, in which the compound 8h, with an antitubercular activity of MIC 0.008 µM, exhibited an excellent aqueous solubility of 104 µg/mL, which was 100-fold better than the potent DprE1 inhibitor Comp.1 (BTZ038), also more soluble than PBTZ169.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Piperazines/pharmacology , Thiazines/pharmacology , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Chlorocebus aethiops , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Piperazine , Piperazines/chemical synthesis , Piperazines/chemistry , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/chemistry , Vero Cells
4.
J Med Chem ; 58(6): 2764-78, 2015 Mar 26.
Article in English | MEDLINE | ID: mdl-25710739

ABSTRACT

The design, synthesis, and SAR studies of novel inhibitors of HCV NS4B based on the imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50 = 16 nM) and 28g (EC50 = 31 nM). The resistance profile studies revealed that 26f and 28g targeted HCV NS4B, more precisely the second amphipathic α helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct-acting antiviral agents targeting NS3/4A, NS5A, and NS5B was not observed. For the first time, the synergism of a series of combinations based on 4BAH2 inhibitors was evaluated. The results demonstrated that our 4BAH2 inhibitor 26f was synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitor daclatasvir, and NS5B inhibitor sofosbuvir, and it could also reduce the dose of these drugs at almost all effect levels. Our study suggested that favorable effects could be achieved by combining 4BAH2 inhibitors such as 26f with these approved drugs and that new all-oral antiviral combinations based on 4BAH2 inhibitors were worth developing to supplement or even replace current treatment regimens for curing HCV infection.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Thiazoles/chemistry , Thiazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Cell Line , Drug Synergism , Genotype , Hepacivirus/genetics , Hepacivirus/metabolism , Hepatitis C/virology , Humans , Mutation , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
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