299182-03-9Relevant academic research and scientific papers
CONJUGATES AND METHODS OF USING THE SAME
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, (2020/03/05)
Disclosed are conjugates including a recognition element covalently bonded to or linked through a linker to a payload. The payload is a pharmaceutical agent (e.g., an antineoplastic agent, anti-infective agent, or anti-inflammatory agent) or a diagnostic agent. Also disclosed are methods of using the conjugates.
Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain
Boudreau, Paul D.,Miller, Bailey W.,McCall, Laura-Isobel,Almaliti, Jehad,Reher, Raphael,Hirata, Ken,Le, Thu,Siqueira-Neto, Jair L.,Hook, Vivian,Gerwick, William H.
, p. 9026 - 9044 (2019/10/16)
Gallinamide A, originally isolated with a modest antimalarial activity, was subsequently reisolated and characterized as a potent, selective, and irreversible inhibitor of the human cysteine protease cathepsin L. Molecular docking identified potential modifications to improve binding, which were synthesized as a suite of analogs. Resultingly, this current study produced the most potent gallinamide analog yet tested against cathepsin L (10, Ki = 0.0937 ± 0.01 nM and kinact/Ki = 8 730 000). From a protein structure and substrate preference perspective, cruzain, an essential Trypanosoma cruzi cysteine protease, is highly homologous. Our investigations revealed that gallinamide and its analogs potently inhibit cruzain and are exquisitely toxic toward T. cruzi in the intracellular amastigote stage. The most active compound, 5, had an IC50 = 5.1 ± 1.4 nM, but was relatively inactive to both the epimastigote (insect stage) and the host cell, and thus represents a new candidate for the treatment of Chagas disease.
Cyclic Depsipeptide BE-43547A2: Synthesis and Activity against Pancreatic Cancer Stem Cells
Sun, Yuanjun,Ding, Yahui,Li, Dongmei,Zhou, Ruifei,Su, Xiuwen,Yang, Juan,Guo, Xiaoqian,Chong, Chuanke,Wang, Jinghan,Zhang, Weicheng,Bai, Cuigai,Wang, Liang,Chen, Yue
, p. 14627 - 14631 (2017/11/14)
Asymmetric total synthesis of the cyclic depsipeptide BE-43547A2 was achieved in 15 linear steps on a 350 mg scale in one batch. The synthesis features the highly diastereoselective construction of an α-hydroxy-β-ketoamide through α-hydroxylation with a d.r. of up to 86:1. BE-43547A2 significantly reduces the percentage of pancreatic cancer stem cells (PCSCs) in Panc-1 cell cultures, and dramatically reduces the tumorsphere-forming capability of Panc-1 cells. An in vivo tumor-initiation assay, a gold standard for cancer stem cell assays, confirmed that BE-43547A2 can abolish the tumorigenesis of Panc-1 cells. The anti-PCSC activity of BE-43547A2 could make this depsipeptide scaffold a promising starting point for discovering new PCSC-targeting drugs.
Sudemycin k: A synthetic antitumor splicing inhibitor variant with improved activity and versatile chemistry
Makowski, Kamil,Vigevani, Luisa,Albericio, Fernando,Valcarcel, Juan,Alvarez, Mercedes
, p. 163 - 173 (2017/11/30)
Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore's oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives.
Self-assembly to function: Design, synthesis, and broad spectrum antimicrobial properties of short hybrid e -vinylogous lipopeptides
Shankar, S. Shiva,Benke, Sushil N.,Nagendra, Narem,Srivastava, Prabhakar Lal,Thulasiram, Hirekodathakallu V.,Gopi, Hosahudya N.
, p. 8468 - 8474 (2013/12/04)
Nonribosomal E-vinylogous γ-amino acids are widely present in many peptide natural products and have been exploited as inhibitors for serine and cysteine proteases. Here, we are reporting the broad spectrum antimicrobial properties and self-assembled nanostructures of various hybrid lipopeptides composed of 1:1 alternating α- and E-vinylogous residues. Analysis of the results revealed that self-assembled nanostructures also play a significant role in the antimicrobial and hemolytic activities. In contrast to the α-peptide counterparts, vinylogous hybrid peptides displayed excellent antimicrobial properties against various bacterial and fungal strains. Peptides that adopted nanofiber structures displayed less hemolytic activity, while peptides that adopted nanoneedle structures displayed the highest hemolytic activity.
The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains
Stolze, Sara Christina,Deu, Edgar,Kaschani, Farnusch,Li, Nan,Florea, Bogdan I.,Richau, Kerstin H.,Colby, Tom,Van Der Hoorn, Renier A.L.,Overkleeft, Hermen S.,Bogyo, Matthew,Kaiser, Markus
, p. 1546 - 1555 (2013/02/25)
The marine natural product symplostatin 4 (Sym4) has been recognized as a potent antimalarial agent. However, its mode of action and, in particular, direct targets have to date remained elusive. We report a chemical synthesis of Sym4 and show that Sym4-treatment of P. falciparum-infected red blood cells (RBCs) results in the generation of a swollen food vacuole phenotype and a reduction of parasitemia at nanomolar concentrations. We furthermore demonstrate that Sym4 is a nanomolar inhibitor of the P. falciparum falcipains in infected RBCs, suggesting inhibition of the hemoglobin degradation pathway as Sym4's mode of action. Finally, we reveal a critical influence of the unusual methyl-methoxypyrrolinone (mmp) group of Sym4 for potent inhibition, indicating that Sym4 derivatives with such a mmp moiety might represent viable lead structures for the development of antimalarial falcipain inhibitors.
Total synthesis, stereochemical assignment, and antimalarial activity of gallinamide A
Conroy, Trent,Guo, Jin T.,Linington, Roger G.,Hunt, Nicholas H.,Payne, Richard J.
, p. 13544 - 13552 (2012/01/13)
The total synthesis and stereochemical assignment of gallinamideA, an antimalarial depsipeptide of cyanobacterial origin, is described. Synthesis of the four possible N-terminal diastereoisomers of gallinamideA (including the natural product symplostatin4) was achieved using a divergent strategy from a common imide fragment. The natural product and corresponding diastereoisomers were synthesized in 30-33% overall yield in a longest linear sequence of 8 steps. Comparative NMR spectroscopic studies of the four synthetic diastereoisomers with the isolated natural product demonstrated that gallinamideA possesses a dimethylated L-isoleucyl residue at the N-terminus. As such, we have shown that gallinamideA is structurally and stereochemically identical to symplostatin4. GallinamideA and its N-terminal diastereoisomers were also shown to possess significant antimalarial activity with IC 50 values in the nanomolar range against the 3D7 strain of Plasmodium falciparum. Naturally active: The total synthesis of gallinamideA, a cyanobacterium-derived depsipeptide, is described. Four N-terminal diastereoisomers of gallinamide A were prepared by using two key fragments (see scheme). Spectroscopic comparison to the isolated natural product enabled the absolute configuration of the N,N-dimethylated isoleucyl residue to be determined as 25S, 26S. GallinamideA (and its diastereoisomers) were also shown to possess potent antimalarial activity. Copyright
Total synthesis and antimalarial activity of symplostatin 4
Conroy, Trent,Guo, Jin T.,Hunt, Nicholas H.,Payne, Richard J.
, p. 5576 - 5579 (2011/04/15)
The first total synthesis of symplostatin 4, a marine cyanobacterium- derived natural product, is described. Notable features of the route include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings. Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED50 of 74 nM against Plasmodium falciparum, strain 3D7).
Stereoselective synthesis of vinylogous peptides
Grison, Claude,Genève, Stéphane,Halbin, Etienne,Coutrot, Philippe
, p. 4903 - 4923 (2007/10/03)
A trans or cis ethenyl group has been inserted between the α-carbon and the carboxyl group of α-aminoacids by Horner stereoselective olefination of α-aminoaldehydes. Numerous pure cis and trans vinylogous α-aminoacids have been obtained thus and coupled w
Trifluoroacetic acid-mediated intramolecular formal N-H insertion reactions with amino-α-diazoketones: A facile and efficient synthesis of optically pure pyrrolidinones and piperidinones
Yang, Hua,Jurkauskas, Valdas,Mackintosh, Nicole,Mogren, Tobias,Stephenson, Corey R. J.,Foster, Katherine,Brown, William,Roberts, Edward
, p. 800 - 808 (2007/10/03)
Trifluoroacetic acid (TFA) was found to promote intramolecular formal N-H insertion reactions. Upon treatment with TFA, optically pure N-Boc-β′-amino-α-diazoketones (5a-c) and N-Boc-γ′-amino-α-diazoketones (10a-d) can be converted, with retention of chira
