Abstract:
:Highly potent and novel derivatives of doxorubicin were linked to monoclonal antibodies (mAbs) for site-specific drug delivery. Drug linker 5 consisted of a dipeptide linker attached directly to the daunosamine nitrogen of the n-butyldiacetate doxorubicin derivative 2a. Upon hydrolysis of the peptide linker and acetate groups, the free daunosamine nitrogen is able to form the highly potent 2-pyrrolinodoxorubicin (3a). The second approach involved the use of an oxazolidine carbamate (13) to mask an activating aldehyde group until proteolytic hydrolysis releases 3a. Both drug linkers were shown to be substrates for the lysosomal enzyme cathepsin B. Each molecule was conjugated to the mAbs c1F6 (anti-CD70) and cAC10 (anti-CD30) to give potent drug conjugates against renal cell carcinoma and anaplastic large cell lymphoma cell lines, respectively. The activities were immunologically selective, since antigen negative cell lines were much less sensitive to treatment with the drug conjugates. The approaches described here for attaching highly potent doxorubicin derivatives to mAbs are novel and allow for control of drug stability while covalently bound to the delivery agent.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Jeffrey SC,Nguyen MT,Andreyka JB,Meyer DL,Doronina SO,Senter PDdoi
10.1016/j.bmcl.2005.09.081subject
Has Abstractpub_date
2006-01-15 00:00:00pages
358-62issue
2eissn
0960-894Xissn
1464-3405pii
S0960-894X(05)01261-8journal_volume
16pub_type
杂志文章abstract::A series of novel pyrazole peptidomimetics was synthesized from 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic acid and amino acid ester. Structures of the compounds were characterized by means of IR, (1)H NMR and mass spectroscopy. Compounds 5e and 5k suppress effectively the growth of A549 lung cancer cells. Prelimina...
journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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journal_title:Bioorganic & medicinal chemistry letters
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doi:10.1016/j.bmcl.2007.02.052
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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journal_title:Bioorganic & medicinal chemistry letters
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journal_title:Bioorganic & medicinal chemistry letters
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2015.05.003
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2010.07.108
更新日期:2010-09-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2008.06.030
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2017.05.076
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(99)00481-3
更新日期:1999-10-04 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2009.10.011
更新日期:2009-12-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2004.05.003
更新日期:2004-07-16 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(02)00692-3
更新日期:2002-11-18 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2009.04.022
更新日期:2009-06-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2003.10.020
更新日期:2004-01-05 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2005.03.060
更新日期:2005-06-02 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(03)00481-5
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journal_title:Bioorganic & medicinal chemistry letters
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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更新日期:2016-02-01 00:00:00
abstract::The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar an...
journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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更新日期:2018-03-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2009.11.030
更新日期:2010-01-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
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doi:10.1016/j.bmcl.2018.05.019
更新日期:2018-09-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2009.08.095
更新日期:2009-11-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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更新日期:2000-08-07 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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更新日期:2018-09-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2018.11.028
更新日期:2019-01-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2018.01.056
更新日期:2018-04-01 00:00:00
abstract::Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a thera...
journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2019.126888
更新日期:2020-02-15 00:00:00