- Precision therapeutic targeting of human cancer cell motility
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Increased cancer cell motility constitutes a root cause of end organ destruction and mortality, but its complex regulation represents a barrier to precision targeting. We use the unique characteristics of small molecules to probe and selectively modulate cell motility. By coupling efficient chemical synthesis routes to multiple upfront in parallel phenotypic screens, we identify that KBU2046 inhibits cell motility and cell invasion in vitro. Across three different murine models of human prostate and breast cancer, KBU2046 inhibits metastasis, decreases bone destruction, and prolongs survival at nanomolar blood concentrations after oral administration. Comprehensive molecular, cellular and systemic-level assays all support a high level of selectivity. KBU2046 binds chaperone heterocomplexes, selectively alters binding of client proteins that regulate motility, and lacks all the hallmarks of classical chaperone inhibitors, including toxicity. We identify a unique cell motility regulatory mechanism and synthesize a targeted therapeutic, providing a platform to pursue studies in humans.
- Xu, Li,Gordon, Ryan,Farmer, Rebecca,Pattanayak, Abhinandan,Binkowski, Andrew,Huang, Xiaoke,Avram, Michael,Krishna, Sankar,Voll, Eric,Pavese, Janet,Chavez, Juan,Bruce, James,Mazar, Andrew,Nibbs, Antoinette,Anderson, Wayne,Li, Lin,Jovanovic, Borko,Pruell, Sean,Valsecchi, Matias,Francia, Giulio,Betori, Rick,Scheidt, Karl,Bergan, Raymond
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- Transient and Recyclable Halogenation Coupling (TRHC) for Isoflavonoid Synthesis with Site-Selective Arylation
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A transient and recyclable C?H iodination has been designed for the synthesis of isoflavonoids through the domino reactions of o-hydroxyphenyl enaminones and aryl boronic acids in the presence of catalytic KI and Pd catalyst. Instead of the conventional cross-coupling strategy employing pre-halogenated substrates, this method transforms raw C?H bond by means of a transient C?H halogenation to smoothly relay the subsequent C-arylation. Consequently, such a method avoids the pre-functionalization for C?halogen bond installation as well as the generation of stoichiometric halogen-containing waste following the cross-coupled product, disclosing an intriguing new coupling protocol to forge the C?C bond in the virgin area between classical C?X (X=halogen) bond cross coupling and the C?H activation.
- Wan, Jie-Ping,Tu, Zhi,Wang, Yuyun
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supporting information
p. 6907 - 6910
(2019/05/10)
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- METHODS FOR PRECISION THERAPEUTIC TARGETING OF HUMAN CANCER CELL MOTILITY AND KITS THEREOF
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Disclosed are methods for identifying an agent of interest that alters binding or activity of a client protein to a chaperone and kits thereof.
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Page/Page column 53; 54; 55
(2019/08/29)
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- Pot-economic synthesis of diarylpyrazoles and pyrimidines involving Pd-catalyzed cross-coupling of 3-trifloxychromone and triarylbismuth
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Abstract: The present study reveals the formation of 3,4-diarylpyrazole and 4,5-diarylpyrimidine in one-pot operation starting from 3-trifloxychromone and triarylbismuth. The complete process encompasses two steps in the one-pot operation. The first step leads to the formation of isoflavone via cross-coupling reaction of 3-trifloxychromone and triarylbismuth as a threefold arylating reagent. These isoflavones were further converted into 3,4-diarylpyrazole and 4,5-diarylpyrimidine using hydrazine hydrate and guanidinium chloride in the successive step in the same pot. Interestingly the formation of 3,4-diarylpyrazole was achieved in the shortest reaction time i.e., 30 min that too at room temperature. Overall the developed methodology provides easy access to the medicinally important diarylpyrazole and pyrimidine moiety in one-pot operation and in short reaction time. Graphical Abstract: Synopsis The work presented here describes the novel methodology for the formation of medicinally important heterocycles 3,4-diarylpyrazole and 4,5-diarylpyrimidine in one-pot operation starting from 3-trifloxychromone and triarylbismuth.
- Kumar, Abhijeet,Rao, Maddali L N
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- INHIBITION OF CANCER CELL MOTILITY
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Provided herein are compositions and methods for inhibiting cancer cell motility and/or metastasis. In particular embodiments, KBU2046 (or an analog thereof) and one or more additional therapies (e.g., cancer therapies (e.g., hormone therapies and chemotherapies) are provided to inhibit cancer cell motility, inhibit metastasis, and/or treat cancer (e.g., prostate cancer, lung cancer, breast cancer, colon cancer, etc.).
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Page/Page column 41
(2016/06/01)
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- A novel synthesis of isoflavones via copper(I)-catalyzed intramolecular cyclization reaction
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Isoflavone derivatives were synthesized via intramolecular cyclization of 3-(2-bromophenyl)-3-oxopropanal derivatives, using CuI as the catalyst, 2-picolinic acid (=pyridine-2-carboxylic acid) as the ligand, K 2CO3 as the base, and DMF as the solvent, in up to 96% yield. The synthesis is functional group-tolerant. Copyright
- Li, Qiu-Lian,Liu, Qi-Lun,Ge, Zhi-Yuan,Zhu, Yong-Ming
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p. 1304 - 1309
(2011/09/15)
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- Synthesis of fluorine-containing 3-hydroxyflavanones and isoflavones
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Fluorine-containing 3-hydroxyflavanones and isoflavones were synthesized by epoxidation of F-containing chalcones by hydrogen peroxide under basic conditions and subsequent intramolecular cyclization of the resulting epoxides using BF3·Et2O. The ratio of products depended on the presence and position of the F atom.
- Khlebnikova,Piven,Khripach,Lakhvich
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- Oxidative rearrangements of 2'-hydroxychalcones with lh-l-hydroxy-5-methyl- l,2,3-benziodoxathiole 3,3-dioxide
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1H-l-hydroxy-5-methyl-l,2,3-benziodoxathiole 3,3-dioxide (HMBI) has been found to effect the direct conversion of 2'-hydroxychalcones with various B-ring substituents to isoflavones in moderate to good yield (34-83%) in methanol under reflux. The reduced byproduct of HMBI is easily recovered by aqueous extraction and can be recycled and reused with high efficiency. Previous reports of conversions of this type required the use of toxic thallium(III) salts or initial protection of the 2'-hydroxyl group.
- Justik, Michael W.,Zimmerman, Alyssa K.
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scheme or table
p. 67 - 71
(2010/03/03)
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- A general method for the synthesis of isoflavones by oxidative rearrangement of flavanones using thallium (III) perchlorate
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Oxidation of flavanones with thallium(III) perchlorate in acetonitrile or dimethoxyethane leads to 2,3-aryl migration providing a general method for the synthesis of isoflavones having electron relasing as well as electron withdrawing substituents at C2-aryl ring and the mechanism in relaltion to in vivo is discussed.
- Singh, Om V.,Kapil, Randhir S.
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p. 911 - 915
(2007/10/02)
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- ONE-STEP CONVERSION OF FLAVANONES INTO ISOFLAVANONES: A NEW FACILE BIOMIMETIC SYNTHESIS OF ISOFLAVONES
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One-step chemical conversion of flavanones into isoflavones by use of thallium trinitrate (TTN) is reported, and the mechanism of a 2,3-aryl migration in this reaction is discussed in relation to in vivo rearrangement process of flavanone precursors in the isoflavone biosynthesis.
- Kinoshita, Takeshi,Ichinose, Koji,Sankawa, Ushio
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p. 7355 - 7356
(2007/10/02)
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- Novel Synthesis of Isoflavones by the Palladium-Catalyzed Cross-Coupling Reaction of 3-Bromochromones with Arylboronic Acids or Its Esters
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The synthesis of isoflavone derivatives by means of palladium-catalyzed cross-coupling reaction between 3-bromochromones and arylboronic acids or its butyl esters is described.
- Hoshino, Yukio,Miyaura, Norio,Suzuki, Akira
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p. 3008 - 3010
(2007/10/02)
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