- TARGETED ABERRANT ALPHA-SYNUCLEIN SPECIES AND INDUCED UBIQUITINATION AND PROTEOSOMAL CLEARANCE VIA CO-RECRUITMENT OF AN E3-LIGASE SYSTEM
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Disclosed are bispecific compounds (degraders) that target α-synuclein protein for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat neurodegenerative diseases.
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Paragraph 00142-00143
(2022/02/06)
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- Metal-chelating benzothiazole multifunctional compounds for the modulation and 64Cu PET imaging of Aβ aggregation
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While Alzheimer's Disease (AD) is the most common neurodegenerative disease, there is still a dearth of efficient therapeutic and diagnostic agents for this disorder. Reported herein are a series of new multifunctional compounds (MFCs) with appreciable affinity for amyloid aggregates that can be potentially used for both the modulation of Aβ aggregation and its toxicity, as well as positron emission tomography (PET) imaging of Aβ aggregates. Firstly, among the six compounds tested HYR-16 is shown to be capable to reroute the toxic Cu-mediated Aβ oligomerization into the formation of less toxic amyloid fibrils. In addition, HYR-16 can also alleviate the formation of reactive oxygen species (ROS) caused by Cu2+ ions through Fenton-like reactions. Secondly, these MFCs can be easily converted to PET imaging agents by pre-chelation with the 64Cu radioisotope, and the Cu complexes of HYR-4 and HYR-17 exhibit good fluorescent staining and radiolabeling of amyloid plaques both in vitro and ex vivo. Importantly, the 64Cu-labeled HYR-17 is shown to have a significant brain uptake of up to 0.99 ± 0.04 percentID per g. Overall, by evaluating the various properties of these MFCs valuable structure-activity relationships were obtained that should aid the design of improved therapeutic and diagnostic agents for AD. This journal is
- Bandara, Nilantha,Cho, Hong-Jun,Huang, Yiran,Mirica, Liviu M.,Rogers, Buck E.,Sun, Liang,Tran, Diana
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p. 7789 - 7799
(2020/08/19)
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- Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers
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A series of colchicine site binding tubulin inhibitors were synthesized by the modification of the combretastatin pharmacophore. The ring B was replaced by the pharmacologically relevant benzothiazole scaffolds, and the cis configuration of the olefinic b
- Subba Rao,Swapna, Konderu,Shaik, Siddiq Pasha,Lakshma Nayak,Srinivasa Reddy,Sunkari, Satish,Shaik, Thokhir Basha,Bagul, Chandrakant,Kamal, Ahmed
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p. 977 - 999
(2017/02/05)
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- 2-Arylaminobenzothiazole-arylpropenone conjugates as tubulin polymerization inhibitors
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A new series of 2-arylaminobenzothiazole-arylpropenone conjugates 5-6(a-r) was designed, synthesized and investigated for their cytotoxic potency against the various human cancer cell lines. Most of these conjugates exhibited cytotoxic activity and inhibi
- Subba Rao,Rao, Bala Bhaskara,Sunkari, Satish,Shaik, Siddiq Pasha,Shaik, Bajee,Kamal, Ahmed
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p. 924 - 941
(2017/07/12)
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- Synthesis of 2-arylbenzothiazoles via direct condensation between in situ generated 2-aminothiophenol from disulfide cleavage and carboxylic acids
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In this work we describe a simple and efficient general methodology for 2-arylbenzothiazole preparation employing disulfides and carboxylic acids. The reaction is promoted by tributylphosphine that acts both in disulfide bond cleavage and as activating agent for coupling with carboxylic acids. The reaction scope was studied using bis(2-aminophenyl)disulfide and different carboxylic acids with donor/withdrawing substituents, which resulted in the desired 2-arylbenzothiazole with moderate to good yields. The method was tested with success in preparation of the amyloid probe 2-(4-aminophenyl)-6-methoxybenzothiazole that employed a substituted bis(2-aminophenyl)disulfide.
- Coelho, Felipe L.,Campo, Leandra F.
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p. 2330 - 2333
(2017/05/29)
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- Design, synthesis and antimetastatic evaluation of 1-benzothiazolylphenylbenzotriazoles for photodynamic therapy in oral cancer cells
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We have designed and synthesized a new series of 1-benzothiazolylphenylbenzotriazoles 9a-p and studied their antimetastatic mechanism involved in photosensitive effects induced by UVA in oral cancer cell Ca9-22. Our results revealed that the compounds plus UVA significantly suppressed migration and invasion, as detected by wound healing assay and Boyden chamber assay. Quantitative RT-PCR assay indicated that compound 9i plus UVA induced an antimetastatic effect through up-regulation of syndecan-1 and TIMP-3 and down-regulation of heparanase, MMP-2 and MMP-9 mRNA expressions. Western blot analysis showed that Ca9-22 treated with 9i plus UVA resulted in decreased levels of p-EGFR and p-ERK, MMP-2 and MMP-9, and an increased level of TIMP-3. These results are the first to report the function of UVA-activated 1-benzothiazolylphenylbenzotriazoles in tumor metastasis and their underlying molecular mechanism, and thus suggest that compound 9i plus PDT may serve as a potential ancillary modality for the treatment of oral cancer.
- Senadi, Gopal Chandru,Liao, Chieh-Ming,Kuo, Kung-Kai,Lin, Jian-Cheng,Chang, Long-Sen,Wang, Jeh Jeng,Hu, Wan-Ping
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p. 1151 - 1158
(2016/07/06)
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- For nerve degenerative disease is in the field of PET imaging agent precursor and the standard method for the synthesis of (by machine translation)
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A novel PET imaging agent precursor and standard and its preparation method, in order to 4-nitro cinnamic aldehyde, the methoxylphenylboronic ethylamine as a reaction initiator, synthesis of the precursor (compound 10) 4 - (6 - (2-P-toluene-sulfonic acid ethoxycarbonyl)-oxy-2-quinolyl)-N-tert-butoxy-carbonyl-N-n-pentyl-( [N-methyl-N-tert-butoxy carbonyl] - 2 - [4 ˊ - (methylamino) phenyl]-benzothiazole aniline) - 6-ether) aniline and standard (compound 25) 4 - (6 - (2-F)-oxy-2-quinolyl)-N-n-pentyl-( [N-methyl] - 2 - [4 ˊ - (methylamino) phenyl]-benzothiazole aniline) - 6-ether) aniline, at the same time provides A β protein specific binding agent 11 C-6-OH-BTA-1 an important intermediate for preparing (compound 7) method for the preparation of, the preparation method is a brand new synthetic route, step is simple, moderate reaction. (by machine translation)
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Paragraph 0071-0073
(2017/01/26)
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- Synthesis of 2-(4-aminophenyl)benzothiazoles using MF resin supported H+ under solvent free conditions
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Abstract A simple and convenient approach to 2-(4-aminophenyl)benzothiazole derivatives by condensation of o-aminothiophenol with (un)substituted p-aminobenzoic acid under the action of melamine formaldehyde resin (MFR) supported sulfuric acid under microwave irradiation (MW) and solvent-free conditions has been developed. Structures of the corresponding products were elucidated by IR, 1H NMR spectra, and elemental analysis. The resin could be easily recovered and reused for subsequent reactions.
- Lei, Yingjie,Wu, Xinshi,Zhang, Guochun,Ai, Cuiling
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p. 679 - 682
(2015/05/05)
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- The flocculated acryloyldimethyltauric molecule ligand
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Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example: formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
- -
-
Paragraph 0420; 0461; 0462
(2016/10/08)
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- Gd3+ complexes conjugated to Pittsburgh compound B: Potential MRI markers of β-amyloid plaques Topical Issue on Metal-Based MRI Contrast Agents. Guest editor: Valerie C. Pierre
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In an effort towards the visualization of β-amyloid (Aβ) plaques by T 1-weighted magnetic resonance imaging for detection of Alzheimer's disease, we report the synthesis and characterization of stable, noncharged Gd3+ complexes of th
- Martins, André F.,Morfin, Jean-Fran?ois,Geraldes, Carlos F. G. C.,Tóth, éva
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p. 281 - 295
(2014/03/21)
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- PiB-conjugated, metal-based imaging probes: Multimodal approaches for the visualization of β-amyloid plaques
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In an effort toward the visualization of β-amyloid plaques by in vivo imaging techniques, we have conjugated an optimized derivative of the Pittsburgh compound B (PiB), a well-established marker of Aβ plaques, to DO3A-monoamide that is capable of forming
- Martins, Andre F.,Morfin, Jean-Francois,Kubickova, Anna,Kubicek, Vojtech,Buron, Frederic,Suzenet, Franck,Salerno, Milena,Lazar, Adina N.,Duyckaerts, Charles,Arlicot, Nicolas,Guilloteau, Denis,Geraldes, Carlos F. G. C.,Toth, Eva
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p. 436 - 440
(2013/07/11)
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- Synthesis and study of benzothiazole conjugates in the control of cell proliferation by modulating Ras/MEK/ERK-dependent pathway in MCF-7 cells
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By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.
- Kamal, Ahmed,Faazil, Shaikh,Ramaiah, M. Janaki,Ashraf, Md.,Balakrishna,Pushpavalli,Patel, Nibedita,Pal-Bhadra, Manika
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p. 5733 - 5739
(2013/10/01)
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- Straightforward synthesis of PET tracer precursors used for the early diagnosis of Alzheimers disease through Suzuki-Miyaura cross-coupling reactions
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In positron emission tomography [11C]PIB, Pittsburgh Compound-B, is currently the most widely used radiopharmaceutical for the early diagnosis of Alzheimer's disease. Synthetic routes for the preparation of the precursor of [11C]PIB are reported in the literature. These strategies require multiple steps and the use of protecting groups. This paper describes a simple one-step synthesis of the precursor of [11C]PIB through a Suzuki-Miyaura coupling reaction using thermal conditions or microwave activation. These methods were successfully applied to the synthesis of various 2-arylbenzothiazole and 2-pyridinylbenzothiazole compounds including [ 18F] precursor derivatives of PIB containing a nitro function.
- Bort, Guillaume,Sylla-Iyarreta Veitía, Maité,Ferroud, Clotilde
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p. 7345 - 7353
(2013/08/23)
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- Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents
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To continue our efforts toward the development of 99mTc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of 99mTc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to Aβ1-40 fibrils. These Re complexes were designed and synthesized via the integrated approach, so their 99mTc analogs would have a greater chance of crossing the blood-brain barrier. While the lipophilicities (log PC18 = 1.59-3.53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki = 30-617 nM) to Aβ1-40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore. For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (99mTc analogs for more widespread application via the use of SPECT scanners.
- Pan, Jinhe,Mason, Neale S.,Debnath, Manik L.,Mathis, Chester A.,Klunk, William E.,Lin, Kuo-Shyan
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p. 1720 - 1726
(2013/04/10)
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- Synthesis of 2-(4-aminophenyl) benzothiazole derivatives and use thereof
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The present invention provides a method of preparing a compound of formula 6 comprising: (a) reacting a compound of formula 1 with a compound of formula 2 to form a compound of formula 3 wherein X of formula 2 is Cl or OH; (b) treating the compound formula 3 with Lawesson's reagent to form a compound of formula 4 (c) reacting a compound of formula 4 with potassium ferricyanide to produce a compound of formula 5 and (d) performing catalytic reduction of nitro group of the compound of formula 5 with palladium on charcoal to generate the compound of formula 6, wherein R1 of formulae 1-6 is H, C1-10 alkyl, C1-10 alkoxy or C1-10 haloalkyl, and R2 of formulae 1-6 is H or C1-10 alkyl. The present invention also provides a photodynamic therapy to a patient having at least one tumor comprising the steps of: administering a compound of formula 6 (wherein R1 and R2 are defined as the above) in a pharmaceutically acceptable carrier to the patient; waiting for a sufficient time to allow the administered compound to be taken up by a target tissue having the at least one tumor; and irradiating a region of the patient containing the target tissue; wherein growth of the tumor is inhibited.
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Page/Page column 13; 14
(2013/12/03)
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- (3-FLUORO-2-HYDROXY)PROPYL-FUNCTIONALIZED ARYL DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT FOR THE DIAGNOSIS OR TREATMENT OF NEURODEGENERATIVE BRA
-
The present invention relates to (3-fluoro-2-hydroxy)propyl-functionalized aryl derivatives or to the pharmaceutically acceptable salt thereof, to a method for preparing same, and to a pharmaceutical composition containing same as active ingredients for t
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-
-
- SYNTHESIS OF 2-(4-AMINOPHENYL) BENZOTHIAZOLE DERIVATIVES AND USE THEREOF
-
The present invention provides a method of preparing a compound of formula 6 comprising: (a) reacting a compound of formula 1 with a compound of formula 2 to form a compound of formula 3 wherein X of formula 2 is Cl or OH; (b) treating the compound formula 3 with Lawesson's reagent to form a compound of formula 4 (c) reacting a compound of formula 4 with potassium ferricyanide to produce a compound of formula 5 and (d) performing catalytic reduction of nitro group of the compound of formula 5 with palladium on charcoal to generate the compound of formula 6, wherein R1 of formulae 1-6 is H, C1-10 alkyl, C1-10 alkoxy or C1-10 haloalkyl, and R2 of formulae 1-6 is H or C1-10 alkyl. The present invention also provides a photodynamic therapy to a patient having at least one tumor comprising the steps of: administering a compound of formula 6 (wherein R1 and R2 are defined as the above) in a pharmaceutically acceptable carrier to the patient; waiting for a sufficient time to allow the administered compound to be taken up by a target tissue having the at least one tumor; and irradiating a region of the patient containing the target tissue; wherein growth of the tumor is inhibited.
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- Hybrids of privileged structures benzothiazoles and pyrrolo[2,1-c] [1,4]benzodiazepin-5-one, and diversity-oriented synthesis of benzothiazoles
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Privileged structures like Benzothiazole and Pyrrolobenzodiazepine offer wonderful opportunity to explore in anti-cancer drug discovery as a mean to counter drug-resistance problem. BT-PBD hybrids and diverse BT derivatives have been synthesized and their in vitro cytotoxic activities were screened against five cancer cell lines have been discussed. The novel compounds showed promising results as compared with the marketed drug etoposide and could well be used in future anti-cancer drug development studies.
- Subhas Bose,Idrees, Mohd.,Todewale, Ismail K.,Jakka,Venkateswara Rao
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experimental part
p. 27 - 38
(2012/07/01)
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- An efficient one-pot synthesis of benzothiazolo-4β-anilino- podophyllotoxin congeners: DNA topoisomerase-II inhibition and anticancer activity
-
An efficient one-pot iodination methodology for the synthesis of benzothiazolo-4β-anilino-podophyllotoxin (5a-h) and benzothiazolo-4β- anilino-4-O-demethylepipodophyllotoxin (6a-h) congeners has been successfully developed by using zirconium tetrachloride
- Kamal, Ahmed,Kumar, B. Ashwini,Suresh, Paidakula,Shankaraiah, Nagula,Kumar, M. Shiva
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scheme or table
p. 350 - 353
(2011/02/27)
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- Synthesis, and biological evaluation of 2-(4-aminophenyl)benzothiazole derivatives as photosensitizing agents
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Photodynamic therapy (PDT) employing exogenous photosensitizers is currently being approved for treatment of basal cell carcinoma (BCC). 2-(4-Aminophenyl)benzothiazoles (6) consist of chromophoric structure and absorb light in the UVA (315-400 nm). These results encouraged us to design and synthesize a diversity of 2-phenylbenzothiazoles (6). Studies on the apoptotic mechanism involved in photosensitive effects induced by UVA-activated 6 in BCC cells are carried out in the present article. 6-UVA-treated cells displayed several features of apoptosis, including an increase in the sub-G1 population, a significantly increased annexin V binding, and activation of caspase-3. 6-UVA induced a decrease in mitochondrial membrane potential (Δψ mt) and ATP via enhanced ROS generation and promoted phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK expression. These results suggest that 6-UVA elicits photosensitive effects in mitochondria processes which involve ERK and p38 activation, and ultimately lead to BCC cell apoptosis.
- Hu, Wan-Ping,Chen, Yin-Kai,Liao, Chao-Cheng,Yu, Hsin-Su,Tsai, Yi-Min,Huang, Shu-Mei,Tsai, Feng-Yuan,Shen, Ho-Chuan,Chang, Long-Sen,Wang, Jeh-Jeng
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experimental part
p. 6197 - 6207
(2010/10/02)
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- Substituted 2-arylbenzothiazoles as kinase inhibitors: Hit-to-lead optimization
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Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range.
- Tasler, Stefan,Mueller, Oliver,Wieber, Tanja,Herz, Thomas,Pegoraro, Stefano,Saeb, Wael,Lang, Martin,Krauss, Rolf,Totzke, Frank,Zirrgiebel, Ute,Ehlert, Jan E.,Kubbutat, Michael H.G.,Schaechtele, Christoph
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supporting information; experimental part
p. 6728 - 6737
(2009/12/09)
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- Synthesis and evaluation of two uncharged 99mTc-labeled derivatives of thioflavin-T as potential tracer agents for fibrillar brain amyloid
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Thioflavin-T is a fluorescent dye for in vitro detection of fibrillar amyloid b, a protein found in the brain of patients suffering from Alzheimer's disease. We synthesized and biologically evaluated two uncharged 99mTc-labeled derivatives of thioflavin-T. The precursors for labeling were synthesized by coupling an S,S′-bis-triphenylmethyl-N-tert- butoxycarbonyl bis-amino-bis-thiol tetradentate ligand via a propoxy spacer to 2-(4′-aminophenyl)-1,3-benzothiazole at the 6-position or the 2′-position. Deprotection and labeling with 99mTc were done via a one-pot procedure (15% yield) after which the labeled compound was isolated by high performance liquid chromatography (LC). LC in combination with mass spectrometry (MS) was used for identity confirmation of the labeled compounds. Results of electrophoresis and log P determination supported the assumption that the radiolabeled compounds could cross the blood-brain barrier by passive diffusion. However, in normal mice both compounds showed a low brain uptake 2 min post injection. They were mainly excreted through the hepatobiliary system, with some accumulation in the stomach. Sixty minutes after intravenous injection, 37% of the 99mTc-activity in the blood corresponded to the original compound. In view of the low brain uptake, it is concluded that the studied 99mTc-labeled derivatives of thioflavin-T are not suitable as tracer agents for in vivo visualization of amyloid in brain. Copyright
- Serdons,Vanderghinste,Van Eeckhoudt,Cleynhens,De Groot,Bormans,Verbruggen
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experimental part
p. 227 - 235
(2010/06/14)
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- In Vivo or in Vitro Method For Detecting Amyloid Deposits Having at Least One Amyloidogenic Protein
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An amyloid deposit can be detected by administering to a subject or applying to a sample a compound of Formula (I) or Formula (II) or structures 1-45, as described, and then imaging to detect binding of the compound to an amyloid deposit, where the amyloi
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- 2-arylbenzothiazole analogues and uses thereof
-
The present invention relates to compounds of the general formula (I) and salts, prodrugs, and stereoisomers thereof, wherein Y independently represents S, O, NR2, SO, SO2; A independently represents a fife- or six-membered aromatic carbocycle or heterocycle and wherein R1 to R20 in formula (I) represent independently of each other a variety of different substituents comprising alkyl, aryl, aralkyl, alkylaryl, heteroaryl groups and monofunctional moieties.
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Page/Page column 17
(2008/06/13)
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- 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
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The present invention relates to anticancer compounds of the general formula (I) and salts and physiologically functional derivatives thereof, wherein Y independently represents S, O, NR 2 , SO, SO 2 ; A independently represents a five- or six-membered aromatic carbocycle or heterocycle and wherein R 1 in formula (I) represents one of the heteroaryl groups defined in the claims.
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Page/Page column 34
(2010/11/25)
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- AMYLOID IMAGING AS A SURROGATE MARKER FOR EFFICACY OF ANTI-AMYLOID THERAPIES
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The present method for determining the efficacy of therapy in the treatment of amyloidosis involves administering to a patient in need thereof a compound of formula (I) or Formula (II) or structures 1-45 and imaging the patient. After said imaging, at lea
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Page/Page column 50; 52
(2010/10/19)
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- A METHOD OF DIAGNOSING PRODROMAL FORMS OF DISEASES ASSOCIATED WITH AMYLOID DEPOSITION
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A method of identifying a patient as prodromal to a disease associated with amyloid deposition by imaging techniques is provided. In addition, a method of identifying amyloid deposition diseases in patients who present with a dementing disorder of questio
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Page/Page column 44; 46
(2010/10/19)
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- One-step synthesis of 2-arylbenzothiazole ('BTA') and -benzoxazole precursors for in vivo imaging of β-amyloid plaques
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We report the simple and efficient synthesis of 2-arylbenzothiazoles ('BTA') and 2-arylbenzoxazoles by direct coupling of benzothiazoles or benzoxazoles with aryl bromides. This method permits direct one-step access to precursors of radiolabeled BTA-1 and
- Alagille, David,Baldwin, Ronald M.,Tamagnan, Gilles D.
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p. 1349 - 1351
(2007/10/03)
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- Therapeutic compounds
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Compounds of the formula (I) for use as an estrogen receptor-β-selective ligand are described wherein: X is O or S; and R1, R3 R6 are as described in the specification. The use of these compounds in treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis and prostate cancer is described; as are processes for making them.
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- Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents.
-
The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported. Radiolabeling with high specific activity [(11)C]methyl iodide provided derivatives for in vivo evaluation. Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude. Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]6-OH-BTA-1) was selected as the lead compound for further evaluation. The radiolabeled metabolites of [(11)C]6-OH-BTA-1 were polar and did not enter brain. The binding affinities of [N-methyl-(3)H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Abeta(1-40) fibrils were similar (K(d) = 1.4 nM and 4.7 nM, respectively), but the ligand-to-Abeta peptide binding stoichiometry was approximately 400-fold higher for AD brain than Abeta(1-40) fibrils. Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid. The encouraging in vitro and in vivo properties of [(11)C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Abeta deposition.
- Mathis, Chester A,Wang, Yanming,Holt, Daniel P,Huang, Guo-Feng,Debnath, Manik L,Klunk, William E
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p. 2740 - 2754
(2007/10/03)
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- Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
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This invention relates to novel thioflavin derivatives, methods of using the derivatives in, for example, in vivo imaging of patients having neuritic plaques, pharmaceutical compositions comprising the thioflavin derivatives and method of synthesizing the
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- Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition
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This invention relates to novel thioflavin derivatives, methods of using the derivatives in, for example, in vivo imaging of patients having neuritic plaques, pharmaceutical compositions comprising the thioflavin derivatives and method of synthesizing the
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- Antitumor benzothiazoles. 8.1 Synthesis, metabolic formation, and biological properties of the C- and N-oxidation products of antitumor 2-(4- aminophenyl)-benzothiazoles
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2-(4-Aminophenyl)benzothiazoles 1 and their N-acetylated forms have been converted to C and N-hydroxylated derivatives to investigate the role of metabolic oxidation in the mode of action of this series of compounds. 2-(4- Amino-3-methylphenyl)benzothiazole (1a, DF 203, NSC 674495) is a novel and potent antitumor agent with selective growth inhibitory properties against human cancer cell lines. Very low IC50 values (14C]1a derived radioactivity was observed in the sensitive MCF-7 cell line but not in the insensitive MDA-MB-435 cell line. The mechanism of growth inhibition by 1a, which is unknown, may be dependent on the differential metabolism of the drug to an activated form by sensitive cell lines only and its covalent binding to an intracellular protein. However, the 6-hydroxy derivative 6c is not the 'active' metabolite since, like all other C- and N-hydroxylated benzothiazoles examined in this study, it is devoid of antitumor properties in vitro.
- Kashiyama, Eiji,Hutchinson, Ian,Chua, Mei-Sze,Stinson, Sherman F.,Phillips, Lawrence R.,Kaur, Gurmeet,Sausville, Edward A.,Bradshaw, Tracey D.,Westwell, Andrew D.,Stevens, Malcolm F. G.
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p. 4172 - 4184
(2007/10/03)
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- Benzazole compounds
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There are disclosed herein benzazole compounds, exemplified by 2-(4-aminophenyl)benzothiazole and analogues or salts thereof, which exhibit very significant selective cytotoxic activity in respect of tumor cells, especially breast cancer cells, and which provide potentially useful chemotherapeutic agents for treatment of breast cancer.
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- Antitumor benzothiazoles. 3. Synthesis of 2-(4- aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo
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A new series of 2-(4-aminophenyl)benzothiazoles substituted in the phenyl ring and benzothiazole moiety has been synthesized by simple, high- yielding routes. The parent molecule 5a shows potent inhibitory activity in vitro in the nanomolar range against a panel of human breast cancer cell lines, but is inactive (IC50 > 30 μM) against other cell types: activity against the sensitive breast lines MCF-7 and MDA 468 is characterized by a biphasic dose-response relationship. Structure-activity relationships derived using these cell types has revealed that activity follows the heterocyclic sequence benzothiazole > benzoxazole >> benzimidazole and that 2-(4-aminophenyl)benzothiazoles bearing a 3'-methyl- 9a, 3'-bromo- 9c, 3'- iodo- 9f, and 3'-chloro-substituent 9i are especially potent and their activity extends to ovarian, lung, and renal cell lines. Four compounds have been evaluated in vivo against human mammary carcinoma models in nude mice. Compound 9a showed the most potent growth inhibition against the ER+ (MCF- 7 and BO) and ER- (MT-1 and MT-3) tumors. Our efforts to identify a pharmacological mechanism of action for these intriguing compounds have not, as yet, been successful.
- Shi, Dong-Fang,Bradshaw, Tracey D.,Wrigley, Samantha,McCall, Carol J.,Lelieveld, Peter,Fichtner, Iduna,Stevens, Malcolm F. G.
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p. 3375 - 3384
(2007/10/03)
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