- PRODRUGS WITH A TRIDENTATE SELF-IMMOLATIVE LINKER
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The present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L1, L2, L3, n, m, p, X, T, TR, and D are as described herein. Methods of using of these compounds to treat diseases advantageously treatable by drug D are also described.
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- Rational design of novel irreversible inhibitors for human arginase
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Parasites have developed a variety of strategies for invading hosts and escaping their immune response. A common mechanism by which parasites escape nitric oxide (NO) toxicity is the activation of host arginase. This activation leads to a depletion of L-arginine, which is the substrate for NO synthase, resulting in lower levels of NO and increased production of polyamines that are necessary for parasite growth and differentiation. For this reason, small molecule inhibitors for arginase show promise as new anti-parasitic chemotherapeutics. However, few arginase inhibitors have been reported. Here, we describe the discovery of novel irreversible arginase inhibitors, and their characterization using biochemical, kinetic, and structural studies. Importantly, we determined the site on human arginase that is labeled by one of the small molecule inhibitors. The tandem mass spectra data show that the inhibitor occupies the enzyme active site and forms a covalent bond with Thr135 of arginase. These findings pave the way for the development of more potent and selective irreversible arginase inhibitors.
- Guo, Xuefeng,Chen, Yiming,Seto, Christopher T.
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p. 3939 - 3946
(2018/06/19)
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- SELF-IMMOLATIVE LINKERS CONTAINING MANDELIC ACID DERIVATIVES, DRUG-LIGAND CONJUGATES FOR TARGETED THERAPIES AND USES THEREOF
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The invention provides a therapeutic drug and targeting conjugate, pharmaceutical compositions containing these conjugates in pharmaceutical composition, and uses of these conjugates in anti-neoplastic and other therapeutic regimens. Also provided are novel intermediates thereof. The conjugates provide a therapeutic drug fragment or prodrug fragment bound to a targeting moiety via a linker which comprises a substrate cleavable by a protease such as Cathepsin B. The targeting moiety is a ligand which targets a cell surface molecule, such as a cell surface receptor on an anti-neoplastic cell. The ligand may function solely as a targeting moiety or may itself have a therapeutic effect. Following administration of the therapeutic drug and targeting conjugate of formula I and exposure of the conjugate to the protease specific for the substrate, the linker is cleaved and the targeting moiety is separated from the conjugate, which causes the drug fragment or prodrug fragment to convert to the drug or prodrug. The recited conjugates are useful in anti-neoplastic therapies. Also provided are methods of making the therapeutic drug and targeting conjugates and intermediates thereof, and kits comprising the therapeutic drug and targeting conjugates.
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- Chemoselective reduction and self-immolation based FRET probes for detecting hydrogen sulfide in solution and in cells
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Hydrogen sulfide (H2S) has been regarded as the third gaseous transmitter. Based on the mechanism of chemoselective azido reduction and self-immolation, five fluorescence resonance energy transfer (FRET) probes for the detection of H2S were designed and synthesized. The effect of functional substitution of the self-immolative moiety on azido reduction and quinone-methide rearrangement were investigated. Their fluorescence responses and chemoselectivity for H2S detection were evaluated in solutions and in cells. This strategy may provide a general route for designing H 2S probes with many commercially available FRET pairs. the Partner Organisations 2014.
- Chen, Bifeng,Wang, Peng,Jin, Qingqing,Tang, Xinjing
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p. 5629 - 5633
(2014/07/22)
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- Developing novel activity-based fluorescent probes that target different classes of proteases.
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In this article, we report the design and synthesis of a group of novel activity-based probes that target different protease sub-classes based on their substrate specificities, rather than their enzymatic mechanisms. The feasibility of our approach has be
- Zhu, Qing,Girish, Aparna,Chattopadhaya, Souvik,Yao, Shao Q
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p. 1512 - 1513
(2007/10/03)
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