- PENICILLIN-BINDING PROTEIN INHIBITORS
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Described herein are certain boron-containing compounds, compositions, preparations and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds describ
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Paragraph 00208
(2021/06/04)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Paragraph 000588; 000589
(2021/03/02)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Page/Page column 12; 214-215
(2019/07/17)
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- Polyamidoamines as drug carriers: Synthesis of polymers featuring extrachain-type primary amino groups as drug-anchoring sites
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The versatile polymerization of bisacrylamides with mono- and difunctional amines, first investigated and greatly expanded in Ferruti's laboratory, 1-3 is utilized in the present project for the synthesis of macromolecular drug carriers. Specifically, we report on the preparation of linear polyamidoamines possessing primary amino groups as terminals of short side chains, designed to function as drug attachment sites. In the first reaction step, performed in aqueous medium, methylenebisacrylamide (MBA) is copolymerized with two types of comonomer: (1) primary amines bearing solubilizing functionality, such as tert-amine or hydroxyl groups, and (2) a variety of mono-N-Boc-protected primary diamines (Boc = tert-butoxycarbonyl). In other reactions, MBA is allowed to react with a mono-N-protected diamine to give a macromonomer, which is polymerized with an oligo- or poly(ethylene oxide) terminated at both ends by a primary amino group. The intermediary polymers so obtained, as yet featuring N-protected amino side groups, are treated with trifluoroacetic acid for deprotection. Further work-up by aqueous dialysis (25 000 mwco tubing) and freeze-drying affords the target polymers as water- and methanol-soluble solids in ultimate yields of 10-25%. 1H NMR spectroscopy serves to confirm the structural assignments 1-12. In order to demonstrate the drug-carrying potential of these polymers, an exemplifying polyamidoamine (11) is allowed to react with an active ester of 4-ferrocenylbutanoic acid in methanolic solution. A water-soluble conjugate (11-Fc) is thus obtained, in which 93% of available primary amine side-chain terminals are acylated by the ferrocenylation agent.
- N'Da, David D.,Neuse, Eberhard W.
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- Conjugates with reduced adverse systemic effects
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A conjugate of an active agent and a targeting moiety having affinity for a target cell, in which the active agent has been modified by attachment of a cell membrane-impermeabilizing group so that, if the active agent so modified is cleaved from the conjugate in the blood plasma instead of inside the target cell, the cell membrane-impermeabilizing group prevents or limits entry of the modified active agent into cells, thus reducing its systemic or non-specific adverse effects, including toxicity.
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Page/Page column 11
(2008/06/13)
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- Preparation and biological assessment of hydroxycinnamic acid amides of polyamines
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Many plants contain hydroxycinnamic acid conjugates of polyamines that are remarkably similar in general structure to the acylated polyamines found in spider and wasp toxins. In an effort to determine whether these compounds might play a role in the chemical defense of plants against arthropod pests we synthesized a variety of analogues of the coumaric (4-hydroxycinnamic) acid conjugates of di-, tri-, and tetraamines using common protection and acylation strategies. N1- and N8-coumaroyl spcrmidinc spermidine were tested in feeding trials with insect larvae including the European corn borer (Ostrinia nuhilalis), the tobacco budworm (Heliothis verescens) and the oblique banded leaf roller (Choristoneura rosaceana). Antifeedant assays with the rice weevil Sitophilus oryzae were also performed. Neither the naturally occurring coumaric acid conjugates of polyamines nor their analogues showed notable toxicity towards insects, despite precautions to maintain these easily oxidized materials in the wet diet. However, more direct bioassays of these compounds on glutamate dependent neuroreceptors including the deep abdominal extensor muscles of crayfish, or mammalian NMDA, 62, and AMPA receptors, clearly showed that these compounds were inhibitory. N1-Coumnaoryl spermine, a dodecyl and a cyclohexyl analogue were especially active at NMDA NR1/NR2B receptors. The latter had an IC50 of 300 μM in the crayfish. N1-Coumaroyl spermine had an IC50 in the crayfish preparation of 70-300 μM and against the mammalian NR1/ NR2B receptor of 38 nM. Structure-activity variations show similar trends of length and hydrophobicity as has been seen previously with analogues of spider toxins. We conclude from this work that while the coumaric acid polyamine conjugates are active when directly applied to neuroreceptors, they show no overt toxicity when ingested by insect larvae.
- Fixon-Owoo, Solomon,Levasseur, Frederic,Williams, Keith,Sabado, Thomas N.,Lowe, Mike,Klose, Markus,Mercier, A. Joffre,Fields, Paul,Atkinson, Jeffrey
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p. 315 - 334
(2007/10/03)
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- Synthesis and evaluation of Taxol-folic acid conjugates as targeted antineoplastics
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A series of Taxol derivatives tethered at C2′ and C-7 to glutamate and folate have been synthesized for evaluation as prodrugs which release Taxol via hydrolytic lability of their α-alkoxy and α-amino esters. The half-time for hydrolysis of these materials was determined in pH 7 and pH 5 buffer. The in vitro cytotoxicity has been assessed in cell culture against A-549 lung cancer, MCF-7 breast cancer, and HT-29 colon cancer. Selected agents were further screened for folate binding and competitive binding with free folic acid. One agent (54), further evaluated in animal studies was found to increase the lifespan in mice, but was less effective than Taxol itself.
- Lee, Jae Wook,Lu, June Y.,Low,Fuchs
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p. 2397 - 2414
(2007/10/03)
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