- REPLICATION PROTEIN A (RPA)-DNA INTERACTION INHIBITORS
-
This invention relates to RPA compounds or pharmaceutically acceptable salts thereof, and for the use of the compounds to treat cancer.
- -
-
Paragraph 0169; 0170
(2021/06/22)
-
- Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors
-
Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents.
- Gavande, Navnath S.,Gavande, Navnath S.,Vandervere-Carozza, Pamela S.,Pawelczak, Katherine S.,Vernon, Tyler L.,Jordan, Matthew R.,Turchi, John J.,Turchi, John J.,Turchi, John J.
-
supporting information
p. 1118 - 1124
(2020/02/06)
-
- Quinoline Based Monocarbonyl Curcumin Analogs as Potential Antifungal and Antioxidant Agents: Synthesis, Bioevaluation and Molecular Docking Study
-
In search for new fungicidal and free radical scavenging agents, we synthesized a focused library of 2-chloroquinoline based monocarbonyl analogs of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans, respectively. Most of the synthesized MACs displayed promising antifungal activity compared to the standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α-demethylase (CYP51) could provide insight into the plausible mechanism of antifungal activity. MACs were also screened for in vitro radical scavenging activity using butylated hydroxytoluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity compared to BHT.
- Akolkar, Satish V.,Khedkar, Vijay M.,Nagargoje, Amol A.,Sangshetti, Jaiprakash N.,Shingate, Bapurao B.,Siddiqui, Madiha M.,Subhedar, Dnyaneshwar D.
-
-
- Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study
-
Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.
- Schiedel, Matthias,Rumpf, Tobias,Karaman, Berin,Lehotzky, Attila,Oláh, Judit,Gerhardt, Stefan,Ovádi, Judit,Sippl, Wolfgang,Einsle, Oliver,Jung, Manfred
-
supporting information
p. 1599 - 1612
(2016/03/05)
-
- MATERIALS AND METHOD FOR INHIBITING REPLICATION PROTEIN A AND USES THEREOF
-
Targeting uncontrolled cell proliferation and resistance to DNA damaging chemotherapeutics with at least one reagent has significant potential in cancer treatment. Replication Protein A, the eukaryotic single-strand (ss) DNA binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. Reported herein are small molecules that inhibit the in vitro, in vivo, and cellular ssDNA binding activity of RPA, thereby disrupting the eukaryotic cell cycle, inducing cytotoxicity and increasing the efficacy of chemotherapeutic agents damage DNA, and/or disrupt its replication and/or function. These results provide new insights into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. This represents a molecularly targeted eukaryotic DNA binding inhibitor and demonstrates the utility of targeting a protein-DNA interaction as a means of studying the cell cycle and providing a therapeutic strategy for cancer treatment.
- -
-
Paragraph 00109; 00110
(2016/06/06)
-
- Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5
-
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.
- Herbert, Mark R.,Siegel, Dana L.,Staszewski, Lena,Cayanan, Charmagne,Banerjee, Urmi,Dhamija, Sangeeta,Anderson, Jennifer,Fan, Amy,Wang, Li,Rix, Peter,Shiau, Andrew K.,Rao, Tadimeti S.,Noble, Stewart A.,Heyman, Richard A.,Bischoff, Eric,Guha, Mausumee,Kabakibi, Ayman,Pinkerton, Anthony B.
-
scheme or table
p. 5718 - 5721
(2010/11/05)
-
- Polymer Supported Acetylaminophenoxide Anion: Convenient Method for O-Alkylation
-
Alkylation of acetylaminophenoxide supported on Amberlyst A-26 gives O-alkylated products in high yields and purity.In addition to ease and simplicity of the method and regeneration of polymeric by-product, the polymeric reagent seems to increase the nucleophilicity of the anions.
- Salunkhe, D. G.,Jagdale, M. H.,Shinde, S. S.,Salunkhe, M. M.
-
-