Tag: M.W=450-500

Lee, Bo Bin published the artcileMetformin and tenovin-6 synergistically induces apoptosis through LKB1-independent SIRT1 down-regulation in non-small cell lung cancer cells, HPLC of Formula: 1011557-82-6, the publication is Journal of Cellular and Molecular Medicine (2019), 23(4), 2872-2889, database is CAplus and MEDLINE.

Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non-histone proteins; however, antitumor effects by suppressing SIRT1 activity in non-small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathol. significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin-6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin-fixed paraffin-embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence-free survival after adjusted for histol. and pathol. stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin-6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin-6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin-6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1-deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up-regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase-3-dependent apoptosis. The study concluded that metformin with tenovin-6 may enhance antitumor effects through LKB1-independent SIRT1 down-regulation in NSCLC cells.

Journal of Cellular and Molecular Medicine published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H34N4O2S, HPLC of Formula: 1011557-82-6.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Vanheer, Leen N. published the artcileActivity Comparison of Epigenetic Modulators against the Hemoprotozoan Parasites Babesia divergens and Plasmodium falciparum, Recommanded Product: 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, the publication is ACS Infectious Diseases (2021), 7(8), 2277-2284, database is CAplus and MEDLINE.

Babesiosis is a tick-borne parasitic disease of humans and livestock that has dramatically increased in frequency and geog. range over the past few decades. Infection of cattle often causes large economic losses, and human infection can be fatal in immunocompromised patients. Unlike for malaria, another disease caused by hemoprotozoan parasites, limited treatment options exist for Babesia infections. As epigenetic regulation is a promising target for new antiparasitic drugs, we screened 324 epigenetic inhibitors against Babesia divergens blood stages and identified 75 (23%) and 17 (5%) compounds that displayed ≥90% inhibition at 10 and 1μM, resp., including over a dozen compounds with activity in the low nanomolar range. We observed differential activity of some inhibitor classes against Babesia divergens and Plasmodium falciparum parasites and identified pairs of compounds with a high difference in activity despite a high similarity in chem. structure, highlighting new insights into the development of epigenetic inhibitors as antiparasitic drugs.

ACS Infectious Diseases published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C44H28ClFeN4, Recommanded Product: 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Groves, M. J. published the artcilep53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia, Recommanded Product: 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, the publication is British Journal of Cancer (2013), 109(9), 2434-2444, database is CAplus and MEDLINE.

Background: Activation of wild-type p53 with the small mol. sirtuin inhibitor Tenovin-6 (Tnv-6) induces p53-dependent apoptosis in many malignant cells. In contrast, Tnv-6 reduces chronic lymphocytic leukemia (CLL) cell viability with dysregulation of autophagy, without increasing p53-pathway activity. Methods: Here, we have investigated whether a quiescent phenotype (unique to CLL) determines the Tnv-6 response, by comparing the effects of Tnv-6 on activated and proliferating CLL. We further studied if these responses are p53-dependent. Results: Unlike quiescent cells, cell death in activated cultures treated with Tnv-6 was consistently associated with p53 upregulation. However, p53 acetylation remained unchanged, without caspase-3 cleavage or apoptosis on electron microscopy. Instead, cellular ultrastructure and protein profiles indicated autophagy inhibition, with reduced ubiquitin-proteasome activity. In specimens with mutant TP53 cultured with Tnv-6, changes in the autophagy-associated protein LC3 occurred independently of p53. Cells treated with Tnv-6 analogs lacking sirtuin inhibitory activity had attenuated LC3 lipidation compared with Tnv-6 (P≤0.01), suggesting that autophagy dysregulation occurs predominantly through an effect on sirtuins. Conclusion: These cell cycle and p53-independent anti-leukemic mechanisms potentially offer novel therapeutic approaches to target leukemia-sustaining cells in CLL, including in disease with p53-pathway dysfunction. Whether targets in addition to sirtuins contribute to autophagy dysregulation by Tnv-6, requires further investigation.

British Journal of Cancer published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H34N4O2S, Recommanded Product: 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Sanders, Brandi D. published the artcileIdentification and characterization of novel sirtuin inhibitor scaffolds, HPLC of Formula: 1011557-82-6, the publication is Bioorganic & Medicinal Chemistry (2009), 17(19), 7031-7041, database is CAplus and MEDLINE.

The sirtuin proteins are broadly conserved NAD⁺-dependent deacetylases that are implicated in diverse biol. processes including DNA recombination and repair, transcriptional silencing, longevity, apoptosis, axonal protection, insulin signaling, and fat mobilization. Because of these associations, the identification of small mol. sirtuin modulators has been of significant interest. Here we report on high throughput screening against the yeast sirtuin, Hst2, leading to the identification of four unique inhibitor scaffolds that also inhibit the human sirtuins, SIRT1-3, and are able to inhibit telomeric silencing of yeast Sir2 in vivo. The identified inhibitor scaffolds range in potency from IC₅₀ values of 6.5-130 μM against Hst2. Each of the inhibitor scaffolds binds reversibly to the enzyme, and kinetic anal. reveals that each of the inhibitors is non-competitive with respect to both acetyl-lysine and NAD⁺ binding. Limited SAR anal. of the scaffolds also identifies which functional groups may be important for inhibition. These sirtuin inhibitors are low mol. weight and well-suited for lead mol. optimization, making them useful chem. probes to study the mechanism and biol. roles of sirtuins and potential starting points for optimization into therapeutics.

Bioorganic & Medicinal Chemistry published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H34N4O2S, HPLC of Formula: 1011557-82-6.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

van Leeuwen, Ingeborg M. M. published the artcileMechanism-specific signatures for small-molecule p53 activators, COA of Formula: C25H34N4O2S, the publication is Cell Cycle (2011), 10(10), 1590-1598, database is CAplus and MEDLINE.

Recent advances in the field of pharmacol. activation of the p53 tumor suppressor are beginning to be translated into the clinic. In addition, small mols. that activate p53 through established mechanisms of action are proving invaluable tools for basic research. Here we analyze and compare the effects of nutlin-3, tenovin-6 and low doses of actinomycin-D on p53 and its main neg. regulator, mdm2. We reveal striking differences in the speed at which these compounds increase p53 protein levels, with nutlin-3 having a substantial impact within minutes. We also show that nutlin-3 is very effective at increasing the synthesis of mdm2 mRNA, mdm2 being not only a modulator of p53 but also a transcriptional target. In addition, we show that nutlin-3 stabilizes mdm2’s conformation and protects mdm2 from degradation These strong effects of nutlin-3 on mdm2 correlate with a remarkable rate of recovery of p53 levels upon removal of the compound We discuss the potential application of our results as mol. signatures to assess the on-target effects of small-mol. mdm2 inhibitors. To conclude, we discuss the implications of our observations for using small-mol. p53 activators to reduce the growth of tumors retaining wild-type p53 or to protect normal tissues against the undesired side effects of conventional chemotherapy.

Cell Cycle published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H47NO8, COA of Formula: C25H34N4O2S.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Makhortova, Nina R. published the artcileA screen for regulators of survival of motor neuron protein levels, SDS of cas: 1011557-82-6, the publication is Nature Chemical Biology (2011), 7(8), 544-552, database is CAplus and MEDLINE.

The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. The authors executed an image-based screen of annotated chem. libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chem. inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chem. inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, the authors have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.

Nature Chemical Biology published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H34N4O2S, SDS of cas: 1011557-82-6.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Pontiki, Eleni published the artcileHistone deacetylase inhibitors (HDACIs). Structure-activity relationships: history and new QSAR perspectives, Computed Properties of 1011557-82-6, the publication is Medicinal Research Reviews (2012), 32(1), 1-165, database is CAplus and MEDLINE.

A review. Histone deacetylase (HDAC) inhibition is a recent, clin. validated therapeutic strategy for cancer treatment. HDAC inhibitors (HDACIs) block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumor cells. In this article, a survey of published quant. structure-activity relationships (QSARs) studies are presented and discussed in the hope of identifying the structural determinants for anticancer activity. Secondly a two-dimensional QSAR study was carried out on biol. results derived from various types of HDACIs and from different assays using the C-QSAR program of Biobyte. The QSAR anal. presented here is an attempt to organize the knowledge on the HDACIs with the purpose of designing new chem. entities with enhanced inhibitory potencies and to study the mechanism of action of the compounds This study revealed that lipophilicity is one of the most important determinants of activity. Addnl., steric factors such as the overall molar refractivity (CMR), molar volume (MgVol), the substituent’s molar refractivity (MR) (linear or parabola), or the sterimol parameters B₁ and L are important. Electronic parameters indicated as σ_p, are found to be present only in one case. © 2010 Wiley Periodicals, Inc. Med Res Rev 32:1-165, 2012.

Medicinal Research Reviews published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H34N4O2S, Computed Properties of 1011557-82-6.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Pryyma, Alla published the artcileRapid, high-yielding solid-phase synthesis of cathepsin-B cleavable linkers for targeted cancer therapeutics, COA of Formula: C21H33N5O7, the publication is Bioconjugate Chemistry (2020), 31(12), 2685-2690, database is CAplus and MEDLINE.

Antibody-drug conjugates (ADCs) constitute an emerging class of anticancer agents that deliver potent payloads selectively to tumors while avoiding systemic toxicity associated with conventional chemotherapeutics. Critical to ADC development is a serum-stable linker designed to decompose inside targeted cells thereby releasing the toxic payload. A protease-cleavable linker comprising a valine-citrulline (Val-Cit) motif has been successfully incorporated into three FDA-approved ADCs and is found in numerous preclin. candidates. Herein, we present a high-yielding and facile synthetic strategy for a Val-Cit linker that avoids extensive protecting group manipulation and laborious chromatog. associated with previous syntheses and provides yields that are up to 10-fold higher than by standard methods. This method is easily scalable and takes advantage of cost-effective coupling reagents and high loading 2-chlorotrityl chloride (2-CTC) resin. Modularity allows for introduction of various conjugation handles in final stages of the synthesis. Facile access to such analogs serves to expand the repertoire of available enzymically cleavable linkers for ADC generation. This methodol. empowers a robust and facile library generation and future exploration into linker analogs containing unnatural amino acids as a selectivity tuning tool.

Bioconjugate Chemistry published new progress about 916746-27-5. 916746-27-5 belongs to amides-buliding-blocks, auxiliary class ADC Linker,Enzymatic Cleavage Linker, name is (S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanoic acid, and the molecular formula is C21H33N5O7, COA of Formula: C21H33N5O7.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

MacCallum, Stephanie F. published the artcileDysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6, Recommanded Product: 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, the publication is Scientific Reports (2013), 1275, 8 pp., database is CAplus and MEDLINE.

Tenovin-6 (Tnv-6) is a bioactive small mol. with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.

Scientific Reports published new progress about 1011557-82-6. 1011557-82-6 belongs to amides-buliding-blocks, auxiliary class Epigenetics,Sirtuin, name is 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide, and the molecular formula is C25H34N4O2S, Recommanded Product: 4-(tert-Butyl)-N-((4-(5-(dimethylamino)pentanamido)phenyl)carbamothioyl)benzamide.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics

Rouleau, Cecile published the artcileAnti-Endosialin Antibody-Drug Conjugate: Potential in Sarcoma and Other Malignancies, HPLC of Formula: 916746-27-5, the publication is Molecular Cancer Therapeutics (2015), 14(9), 2081-2089, database is CAplus and MEDLINE.

Endosialin/TEM1/CD248 is a cell surface protein expressed at high levels by the malignant cells of about 50% of sarcomas and neuroblastomas. The antibody-drug conjugate (ADC) anti-endosialin-MC-VC-PABC-MMAE was selectively cytotoxic to endosialin-pos. cells in vitro and achieved profound and durable antitumor efficacy in preclin. human tumor xenograft models of endosialin-pos. disease. MC-VC-PABC-MMAE was conjugated with anti-endosialin with 3-4 MMAE mols. per ADC. The anti-endosialin-MC-VC-PABC-MMAE conjugate was tested for activity in four human cell lines with varied endosialin levels. The HT-1080 fibrosarcoma cells do not express endosialin, A-673 Ewing sarcoma cells and SK-N-AS neuroblastoma cells are moderate expressers of endosialin, and SJSA-1 osteosarcoma cells express very high levels of endosialin. To determine whether endosialin expression was maintained in vivo, A-673 Ewing sarcoma, SK-N-AS neuroblastoma, and SJSA-1 osteosarcoma cells were grown as xenograft tumors in nude mice. The SK-N-AS neuroblastoma and the A-673 Ewing sarcoma lines were selected for in vivo efficacy testing of the anti-endosialin-MC-VC-PABC-MMAE conjugate. The treatment groups included a vehicle control, unconjugated anti-endosialin, an admix control consisting of anti-endosialin and a dose of free MMAE equivalent to the dose administered as the ADC, and the anti-endosialin-MC-VC-PABC-MMAE conjugate. The unconjugated anti-endosialin had no antitumor activity and resulted in similar tumor growth as the vehicle control. The admix control produced a modest tumor growth delay. Administration of the anti-endosialin-MC-VC-PABC-MMAE conjugate resulted in a marked prolonged tumor response of both xenograts. These proof-of-concept results break new ground and open a promising drug discovery approach to these rare and neglected tumors. Mol Cancer Ther; 14(9); 2081-9. ©2015 AACR.

Molecular Cancer Therapeutics published new progress about 916746-27-5. 916746-27-5 belongs to amides-buliding-blocks, auxiliary class ADC Linker,Enzymatic Cleavage Linker, name is (S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanoic acid, and the molecular formula is C21H33N5O7, HPLC of Formula: 916746-27-5.

Referemce:
https://en.wikipedia.org/wiki/Amide,
Amide – an overview | ScienceDirect Topics