A self-immolative dendritic glucuronide prodrug of doxorubicin

Grinda, Marion; Clarhaut, Jonathan; Renoux, Brigitte; Tranoy-Opalinski, Isabelle; Papot, Sébastien

doi:10.1039/c1md00193k

Cited by 39 publications

(26 citation statements)

References 19 publications

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“…Enzyme activationp roved to be highly sensitivet o sterich indrance:T he half-life associatedw ithe nzymatic activationb yp lasmind ropped from 42 to 4min whent he activationw as combinedw itht he cyclizationo fN , N ' -ethylenediamine.A ntibody3 8C2-mediateda ctivation by ar etroaldol retro-Michael reactionhas been implementedtoliberate drugs or 4-nitrophenol (entry2,T able 2). b-Glucuronidase (b-GUS) [33,40,43] (entry 5, Table2)a nd b-Galactosidase [110][111][112] (entry 6, Table2)h aveb eens uccessfully implementedtospecifically deliver bioactive substrates in tumors and in bacteria. b-Glucuronidase (b-GUS) [33,40,43] (entry 5, Table2)a nd b-Galactosidase [110][111][112] (entry 6, Table2)h aveb eens uccessfully implementedtospecifically deliver bioactive substrates in tumors and in bacteria.…”

Section: Enzymatic Activationmentioning

confidence: 99%

“…[42,45,[100][101][102][103] Penicillin Ga midase (PGA) andB ovine Serum Albumin( BSA) have beenu sedt oc leave the phenylacetamide moiety (entry3,T able2) [34,38,44,45,55,92,96,99,100,[104][105][106][107][108] and ac arbamate [109] (entry 4, Table2), andl iberatev ariouss ubstrates. b-Glucuronidase (b-GUS) [33,40,43] (entry 5, Table2)a nd b-Galactosidase [110][111][112] (entry 6, Table2)h aveb eens uccessfully implementedtospecifically deliver bioactive substrates in tumors and in bacteria. [110] Eventually afluorogenic probe containing as elf-immolative spacer thatw as alkaline phosphatase (ALP) sensitive was implementedf or the quantitative analysis of ALP activity (entry 7, Table2).…”

Section: Enzymatic Activationmentioning

confidence: 99%

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Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chemical bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller molecules. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chemistry, analytical chemistry, and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic experiments and fully exploit the rich perspectives of self-immolative spacers.

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Section: Enzymatic Activationmentioning

confidence: 99%

Section: Enzymatic Activationmentioning

confidence: 99%

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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“…These results were also supported by studies of other groups. 23,24 ■ SELF-IMMOLATIVE DENDRITIC MOLECULAR PROBES Self-immolative dendrimers can principally act as molecular amplifiers. 25 A single event at an analyte-responsive group leads to release of multiple end-units from the dendrimer periphery.…”

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

Quinone-Methide Species, A Gateway to Functional Molecular Systems: From Self-Immolative Dendrimers to Long-Wavelength Fluorescent Dyes

2014

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Over the last 30 years, the quinone-methide elimination has served as a valuable tool for achieving various important molecular functions. Molecular adaptors based on quinone-methide or aza-quinone-methide reactivity have been designed, synthesized, and used in diagnostic probes, molecular amplifiers, drug delivery systems, and self-immolative dendritic/polymeric molecular systems. These unique adaptors function as stable spacers between an enzyme- or reagent-responsive group and a reporter moiety and can undergo 1,4-, 1,6-, or 1,8-type elimination reactions upon cleavage of the triggering group. Such reactivity results in the release of the reporter group through formation of a quinone-methide species. This type of elimination was applied to design distinct molecular adaptors capable of multiple quinone-methide eliminations. Using this chemistry, we have developed unique molecular structures that are known today as self-immolative dendrimers. These dendrimers disassemble upon a single triggering event in a domino-like manner from the focal point to their periphery with the consequent release of multiple end-groups. Such molecular structures are used in self-immolative dendritic prodrugs and in diagnostic probes to obtain a significant amplification effect. To further enhance amplification, we have developed the dendritic chain reaction, which uses simple molecules to achieve functionality of high-generation virtual self-immolative dendrimers. In addition, we harnessed the quinone-methide elimination reactivity to design polymers that disassemble from head-to-tail initiated by an analyte-responsive event. Following this example, other chemical reactivities were demonstrated by scientists to design such polymeric molecules. In a manner analogous to the quinone-methide elimination, electron rearrangement can lead to formation of conjugated quinone-methide-type dyes with long-wavelength emission of fluorescence. We have recently applied an intramolecular charge transfer to form a unique kind of quinone-methide type derivative based on a donor-two-acceptors molecular structure. This intramolecular charge transfer produces a new fluorochrome with an extended conjugation of π-electron system that is used for the design of long-wavelength fluorogenic probes with a turn-ON option. The rapidly expanding use of quinone-methide species, reflected in the increased number of examples reported in the literature, indicates the importance of this tool in chemistry. These species provide a useful gateway to functional molecular structures with distinct reactivities and spectroscopic characteristics.

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“…In this context, numerous glucuronide prodrugs (Grinda et al 2011(Grinda et al , 2012Thomas et al 2008;Tietze et al 2011) that can be activated by β-glucuronidase present in the tumor microenvironment (Bosslet et al 1995;Connors and Whisson 1966) have been investigated to enhance the selectivity of cancer chemotherapy. The β-glucuronidase is a lysosomal enzyme released mainly by the immune and inflammatory cells of the necrotic area (Bosslet et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

et al. 2014

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.

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A self-immolative dendritic glucuronide prodrug of doxorubicin

Cited by 39 publications

References 19 publications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Quinone-Methide Species, A Gateway to Functional Molecular Systems: From Self-Immolative Dendrimers to Long-Wavelength Fluorescent Dyes

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

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