Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors

Abstract Development of Bruton’s tyrosine kinase (BTK) inhibitors is of great value and significance in the treatment of B-cell malignancies and autoimmune diseases. Herein, a novel class of pyrazolopyrimidine-based BTK inhibitors were designed and evaluated in mantle cell lymphoma (MCL) cell lines. We demonstrated that target compounds had made great progress in improvement of antiproliferative activity compared to lead compound. Compounds 13c, 13g, 13h, 13l, 13n and 13o demonstrated effectively antiproliferative activity in MCL cells lines with single-digit micromolar potency. Furthermore, compound 13l specifically disturbed mitochondrial membrane potential and increased reactive oxygen species level in Z138 cells in a dose-dependent manner. 13l induced cell apoptosis through the caspase 3- mediated apoptotic pathway in Z138 cells. Overall, this study provides valuable lead compounds for developing antitumor agents.

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Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2017.04.037 ◽

2017 ◽

Vol 135 ◽

pp. 60-69 ◽

Cited By ~ 14

Author(s):

He Liu ◽

Menghua Qu ◽

Lina Xu ◽

Xu Han ◽

Changyuan Wang ◽

...

Keyword(s):

Tyrosine Kinase ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase ◽

Design And Synthesis ◽

Btk Inhibitors

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Prostatic Acid Phosphatase (PAP) Differentiated Ultracytochemically from Lysosomal Acid Phosphate in the Rat with a PAP/Specific Substrate, Phosphorylcholine

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100115870 ◽

1975 ◽

Vol 33 ◽

pp. 450-451

Author(s):

W. Allen Shannon ◽

José A. Serrano ◽

Hannah L. Wasserkrug ◽

Anna A. Serrano ◽

Arnold M. Seligman

Keyword(s):

Acid Phosphatase ◽

Phosphate Buffer ◽

Prostatic Carcinoma ◽

Prostatic Acid Phosphatase ◽

Chemotherapeutic Agents ◽

Specific Substrate ◽

Acid Phosphate ◽

Lysosomal Acid ◽

Design And Synthesis ◽

New Chemotherapeutic Agents

During the design and synthesis of new chemotherapeutic agents for prostatic carcinoma based on phosphorylated agents which might be enzyme-activated to cytotoxicity, phosphorylcholine, [(CH3)3+NCH2CH2OPO3Ca]Cl-, has been indicated to be a very specific substrate for prostatic acid phosphatase (PAP). This phenomenon has led to the development of specific histochemical and ultracytochemical methods for PAP using modifications of the Gomori lead method for acid phosphatase. Comparative histochemical results in prostate and kidney of the rat have been published earlier with phosphorylcholine (PC) and β-glycerophosphate (βGP). We now report the ultracytochemical results.Minced tissues were fixed in 3% glutaraldehyde-0.1 M phosphate buffered (pH 7.4) for 1.5 hr and rinsed overnight in several changes of 0.05 M phosphate buffer (pH 7.0) containing 7.5% sucrose. Tissues were incubated 30 min to 2 hr in Gomori acid phosphatase medium (2) containing 0.1 M substrate, either PC or βGP.

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Tailoring microstructures of materials through biomimetics

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100148332 ◽

1993 ◽

Vol 51 ◽

pp. 500-501

Author(s):

Mehmet Sarikaya ◽

Ilhan A. Aksay

Keyword(s):

Chemical Properties ◽

Design And Synthesis ◽

Structure Sensitive ◽

Macro Scale ◽

Methods Of Synthesis ◽

Successive Level ◽

Engineering Materials ◽

Physical And Chemical ◽

And Chemical Properties ◽

Synthesis Of Materials

Biomimetics involves investigation of structure, function, and methods of synthesis of biological composite materials. The goal is to apply this information to the design and synthesis of materials for engineering applications.Properties of engineering materials are structure sensitive through the whole spectrum of dimensions from nanometer to macro scale. The goal in designing and processing of technological materials, therefore, is to control microstructural evolution at each of these dimensions so as to achieve predictable physical and chemical properties. Control at each successive level of dimension, however, is a major challenge as is the retention of integrity between successive levels. Engineering materials are rarely fabricated to achieve more than a few of the desired properties and the synthesis techniques usually involve high temperature or low pressure conditions that are energy inefficient and environmentally damaging.In contrast to human-made materials, organisms synthesize composites whose intricate structures are more controlled at each scale and hierarchical order.

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