- Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma
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Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e–7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
- Zhou, Ruolan,Fang, Shaoyu,Zhang, Minmin,Zhang, Qingsen,Hu, Jian,Wang, Mingping,Wang, Chongqing,Zhu, Ju,Shen, Aijun,Chen, Xin,Zheng, Canhui
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supporting information
p. 349 - 352
(2019/01/04)
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- iSPAAC: Isomer-Free Generation of a Bcl-xL-Inhibitor in Living Cells
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Strain-promoted azide–alkyne cycloadditions (SPAAC) have proven extremely useful for labeling of biomolecules, but typically produce isomeric mixtures. This is not appropriate for the formation of bioactive molecules in living cells. Here, the first use o
- Lis, Christian,Rubner, Stefan,Gr?st, Corinna,Hoffmann, Ralf,Knappe, Daniel,Berg, Thorsten
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supporting information
p. 13762 - 13766
(2018/09/14)
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- Amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide
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An amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide is disclosed. According to the method, 4-halogeno-benzenesulfonyl chloride which is used as a raw material undergoes nitration to prepare 3-nitro-4-halogeno-benzenesulfonyl chloride; and after aminolysis, 3-nitro-4-halogeno-benzenesulfonamide is prepared. By the synthesis method provided by the invention, the synthesis route by the adoption of chlorosulfonic acid is changed, and production safety is remarkably raised. The reaction condition is milder and is easy for production control. Thus, mass production of the compound is easier to implement and realize.
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Paragraph 0016; 0018
(2017/08/29)
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- INHIBITING B-CELL LYMPHOMA 2 (BCL-2) AND RELATED PROTEINS
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Novel compounds inhibiting anti-apoptosis proteins B-cell lymphoma 2 (Bcl-2) and Bcl-XL include compounds of formula (I) and formula (II) disclosed herein, as well as liposome compositions comprising Bcl-2 inhibitor compounds. These compositions are usefu
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Paragraph 00160
(2017/09/05)
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- Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites
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The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL(E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.
- Wang, Mingping,Tian, Wei,Wang, Chongqing,Lu, Shihai,Yang, Chao,Wang, Juan,Song, Yunlong,Zhou, Youjun,Zhu, Ju,Li, Zhiyu,Zheng, Canhui
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p. 5207 - 5211
(2016/11/09)
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- CHEMICAL COMPOUNDS
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The present invention relates to compounds of Formula (I): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds inhibit Bcl-2 and/or Bcl-XL activities and may be used for the treatment of cancer.
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Page/Page column 37; 38
(2012/02/15)
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- Design, synthesis, and activity evaluation of broad-spectrum small-molecule inhibitors of anti-apoptotic Bcl-2 family proteins: Characteristics of broad-spectrum protein binding and its effects on anti-tumor activity
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On the basis of the comparison of the structure of the Bim BH3: Bcl-x L complex and that of the ABT-737: Bcl-xL complex, a series of class A compounds were designed. These compounds had the basic skeleton of ABT-737 and the h2 residues of Bim BH3. These residues had shown themselves to be relevant to Bim BH3's broad-spectrum binding properties in saturation mutagenesis assays. Unlike ABT-737, which is a selective inhibitor of anti-apoptotic members of the Bcl-2 protein family, the class A compounds showed broad-spectrum binding activity to target proteins similar to those of Bim BH3 peptide. Then class B compounds were synthesized by modifying the structure of the most effective class A compound, A-4. Most of these class B compounds showed better binding affinity to the target proteins than the class A compounds had. They also showed themselves more effective than ABT-737 at inhibiting growth in multiple tumor cell lines known to express Bcl-x L, Bcl-2, and Mcl-1 proteins at high levels. Compounds B-11 and B-12 had the strongest anti-tumor activity of any compounds we produced. This study suggests that it is feasible to design small-molecule inhibitors based on the structure of Bim BH3, which shows broad-spectrum binding to Bcl-xL, Bcl-2, and Mcl-1 proteins. Our results also suggest that the broad-spectrum properties of small-molecule inhibitors binding to target proteins play a critical role in inhibiting the growth of many tumor cells. Finally, our study provides a series of lead compounds that merit further research into anti-cancer therapeutics.
- Zheng, Can-Hui,Yang, Hui,Zhang, Meng,Lu, Shi-Hai,Shi, Duo,Wang, Juan,Chen, Xiu-Hua,Ren, Xiao-Hui,Liu, Jia,Lv, Jia-Guo,Zhu, Ju,Zhou, You-Jun
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supporting information; experimental part
p. 39 - 44
(2012/02/16)
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- BIS HETEROARYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to thiazole I and its therapeutic and prophylactic uses, wherein the variables A, Q, J, R1, R3, and R5 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 21
(2012/06/01)
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- FUSED HETEROARYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to thiazole I and its therapeutic and prophylactic uses, wherein the variables A, Q, J, R1, R3, and R5 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 32
(2012/06/01)
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- PYRIDYL-THIAZOLYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to thiazole I and its therapeutic and prophylactic uses, wherein the variables Rz, Q, J, R1, R3, R5, and R6 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 40-41
(2012/06/01)
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- BISTHIAZOLE INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to bisthiazole I and its therapeutic and prophylactic uses, wherein the variables A, R5, R6, and R7 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 59
(2012/06/01)
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- TRICYCLIC INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to tricycle I and its therapeutic and prophylactic uses, wherein the variables C1, C2, Z1, Z2, Q, J, R1, and R3 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 42; 43
(2012/06/01)
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- PHENYL-THIAZOLYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to phenyl thiazole I and its therapeutic and prophylactic uses, wherein the variables Rz, Q, J, R1, R3, R5, R6, and R7 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 24
(2012/12/13)
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- APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES
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Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.
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Page/Page column 19
(2011/10/12)
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- Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo
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Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-XL function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-μM binding but were strongly deactivated in the presence of serum. The dominant component of serum deactivation was identified as domain III of human serum albumin (HSA); NMR solution structures of inhibitors bound to both Bcl-X L and HSA domain III indicated two potential optimization sites for separation of affinities. Modifications at both sites resulted in compounds with improved Bcl-XL binding and greatly increased activity in the presence of human serum, culminating in 73R, which bound to Bcl-XL with a Ki of 0.8 μM. In a cellular assay 73R reversed the protection afforded by Bcl-XL overexpression against cytokine deprivation in FL5.12 cells with an EC50 of 0.47 μM. 73R showed little effect on the viability of the human non small cell lung cancer cell line A549. However, consistent with the proposed mechanism, 73R potentiated the activity of paclitaxel and UV irradiation in vitro and potentiated the antitumor efficacy of paclitaxel in a mouse xenograft model.
- Wendt, Michael D.,Shen, Wang,Kunzer, Aaron,McClellan, William J.,Bruncko, Milan,Oost, Thorsten K.,Ding, Hong,Joseph, Mary K.,Zhang, Haichao,Nimmer, Paul M.,Ng, Shi-Chung,Shoemaker, Alexander R.,Petros, Andrew M.,Oleksijew, Anatol,Marsh, Kennan,Bauch, Joy,Oltersdorf, Tilman,Belli, Barbara A.,Martineau, Darlene,Fesik, Stephen W.,Rosenberg, Saul H.,Elmore, Steven W.
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p. 1165 - 1181
(2007/10/03)
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- N-acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula are BCL-Xl inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-Xl inhibiting compositions and methods of promoting apoptosis in a mammal.
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- N-Acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula Are BCL-X1 inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-X1 inhibiting compositions and methods of promoting apoptosis in a mammal.
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