Self-Assembling Cytotoxins

Rideout, Darryl

doi:10.1126/science.3523757

Cited by 107 publications

(72 citation statements)

References 8 publications

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“…This can be explained by PKC-inhibitory activity caused by A and B (see Fig. 2A (1)(2)(3). As reported by some of us in a previous publication (3), the combination of aldehyde A and hydrazine derivative B (Fig.…”

Section: Resultssupporting

confidence: 52%

“…The carcinoma-selective synergism observed for combinations of A and B is probably due to selective accumulation of both A and B inside the carcinoma cells, followed by selective condensation to form the more cytotoxic hydrazone (C) inside the tumor cells (3). This carcinoma-selective synergism is particularly interesting in terms of a rational design of drug combinations with enhanced therapeutic indexes (1,3,23).…”

Section: Resultsmentioning

confidence: 99%

“…One approach to combination chemotherapy of tumors involves "self-assembling antineoplastic agents"-i.e., direct covalent combination of less toxic prodrugs to form a more active drug in situ (1)(2)(3). When the prodrugs assemble into the active drug in or near cells, the prodrugs exhibit synergistic cytotoxic effects.…”

mentioning

confidence: 99%

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A self-assembling protein kinase C inhibitor.

Rotenberg

Calogeropoulou

Jaworski

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies have described a dicationic anticarcinoma agent that can chemically assemble in situ from monocationic phosphonium salts. The chemical combination of these monocationic precursors in the micromolar concentration range, occurring after their uptake by cells, was probably responsible for their synergistic inhibition of cell growth and for their selective cytotoxicity to Ehrlich ascites murine carcinoma cells relative to untransformed epithelial cells. Here, we report that the dicationic product that forms in this assembly reaction is an in vitro inhibitor of protein kinase C (PKC) a and When PKC is exposed to combinations of the two precursors, the enzymatic activity decreases steadily as a function of time. Using dose-response data and HPLC kinetic studies, we show that when the two precursor compounds are added as a combination to PKC under these conditions, the rate of formation of the inhibitory product follows the observed time course of decline in PKC activity under identical conditions. We discuss the possibility that antiproliferative effects against carcinoma cells of the preformed dication and of the combined monocationic precursors involve inhibition of PKC.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

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A self-assembling protein kinase C inhibitor.

Rotenberg

Calogeropoulou

Jaworski

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…Herein we report our early results of the design and simplification of azide-bearing N o -methylcarbamoyl-L-arginine substrate as a smaller analog of macrocyclic peptide natural product 1 and the use of target-guided synthesis (TGS) (for reports of TGS, see Rideout, 14 Rideout, 15 Ingelese and Benkovic, 16 Boger et al, 17 Maly et al, 18 Nicolaou et al, 19 Greasley et al, 20 Nguyen and Huc, 21 Nicolaou et al, 22 Kehoe et al, 23 Poulin-Kerstein and Dervan, 24 and Hu et al 25 ) for the screening of new and more potent chitinase inhibitors, using the 1,3-dipolar cycloaddition 26 between an azide ligand and a library of acetylenes. The in situ click chemistry for drug discovery is dependent on irreversibly reacting reagents that are inert under physiological conditions, 27 as shown earlier by the discovery of highly potent inhibitors of acetylcholine esterase, [28][29][30][31] carbonic anhydrase II 32 and HIV-1 protease.…”

Section: Introductionmentioning

confidence: 99%

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

et al. 2009

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In situ click chemistry is a target-guided synthesis technique for discovering potent protein ligands by assembling azides and alkynes into triazoles inside the affinity site of a target protein. We report the rapid discovery of a new and potent inhibitor of bacterial chitinases by the use of in situ click chemistry. We observed a target-templated formation of a potent triazole inhibitor of the chitinase-catalyzed chitin hydrolysis, through in situ click chemistry between a biologically active azide-containing scaffold and structurally unrelated alkyne fragments. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and antiasthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. As a result of our efforts at developing a chitinase inhibitor from an azide-bearing argifin fragment and the application of the chitinase template and a library of alkynes, we rapidly obtained a very potent and new 1,5-disubstituted triazole inhibitor against Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed 300-fold increase in the inhibitory activity against SmChiB compared with that of argifin. To the best of our knowledge, our finding of an enzyme-made 1,5-disubstituted triazole, using in situ click chemistry is the second example reported in the literature.

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“…25 Due to resemblance with amide moiety in size, dipolar moment, and H-bond acceptor capacity, the 1,2,3-triazole ring can serve as its non-classic bioisostere. 44,45,87,88 Since 1,2,3-triazoles are basic aromatic heterocyclic compounds, they are bioisosteres of aromatic rings and double bonds. 65,66 Additionally, the aforementioned physicochemical properties of 1,2,3-triazole moiety together with similarity to amide bond, make it a useful linker to generate "twin drugs", 42,67,83 bidentate inhibitors, [83][84][85]89 linkers to immobilized fluorescent tags or small molecules, 71 and anion receptors.…”

Section: The Huisgen's 13-dipolar Cycloadditionmentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

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Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

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Self-Assembling Cytotoxins

Cited by 107 publications

References 8 publications

A self-assembling protein kinase C inhibitor.

A self-assembling protein kinase C inhibitor.

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

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