Prodrugs

Stella, Valentino J.; Charman, William Neil; Naringrekar, Vijay H.

doi:10.2165/00003495-198529050-00002

Cited by 189 publications

(42 citation statements)

References 49 publications

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“…Therefore, quinols may be implicated as pharmaceutically more acceptable prodrugs (less lipophilic, more resistant to oxidative metabolism, safer͞less toxic side effects, etc.) than the parent phenolic͞estrogenic compounds (23,40,41) when used for neuroprotective therapy.…”

Section: Discussionmentioning

confidence: 99%

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Prókai

Prókai-Tátrai

Perjési

et al. 2003

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

158

175

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Substantial evidence now exists that intrinsic free-radical scavenging contributes to the receptor-independent neuroprotective effects of estrogens. This activity is inherently associated with the presence of a phenolic A-ring in the steroid. We report a previously unrecognized antioxidant cycle that maintains the ''chemical shield'' raised by estrogens against the most harmful reactive oxygen species, the hydroxyl radical ( • OH) produced by the Fenton reaction. In this cycle, the capture of • OH was shown to produce a nonphenolic quinol with no affinity to the estrogen receptors. This quinol is then rapidly converted back to the parent estrogen via an enzyme-catalyzed reduction by using NAD(P)H as a coenzyme (reductant) and, unlike redox cycling of catechol estrogens, without the production of reactive oxygen species. Due to this process, protection of neuronal cells against oxidative stress is also possible by quinols that essentially act as prodrugs for the active hormone. We have shown that the quinol obtained from a 17␤-estradiol derivative was, indeed, able to attenuate glutamate-induced oxidative stress in cultured hippocampus-derived HT-22 cells. Estrone quinol was also equipotent with its parent estrogen in reducing lesion volume in ovariectomized rats after transient middle carotid artery occlusion followed by a 24-h reperfusion. These findings may establish the foundation for a rational design of neuroprotective antioxidants focusing on steroidal quinols as unique molecular leads.hydroxyl radical ͉ ischemia ͉ prodrug

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Section: Discussionmentioning

confidence: 99%

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Prókai

Prókai-Tátrai

Perjési

et al. 2003

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

158

175

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“…1 Use of the prodrug form of pharmaceuticals can enable to be overcome pharmacokinetic and pharmacodynamic barriers. 2 However, a single modification is not always sufficient to achieve the desired alteration in the physicochemical or biological properties of the drug. One solution is to prepare a prodrug of a prodrug (or pro-prodrug) by chemical modification of a prodrug.…”

mentioning

confidence: 99%

A prodrug system for hydroxylamines based on esterase catalysis

Conejo‐García

Schofield

2005

Bioorganic & Medicinal Chemistry Letters

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“…This characteristic should allow the long term application of this molecule in humans and distinguishes this construct from xenogeneic mouse antibody -bacterial enzyme conjugates which were reported to elicit a fast neutralising antibody response in the patient (Bagshawe et al, 1991). Before the fusion protein can be considered for clinical evaluation, its pharmacodynamic (Natowicz et al, 1979) in relation to the carbohydrate content (Stahl et al, 1976) and therapeutic effects combined with appropriately designed prodrugs (Stella et al, 1985) must be studied in further preclinical model systems. Prodrug systems which are investigated presently are glucuronides of daunomycin and adriamycin.…”

mentioning

confidence: 99%

Molecular and functional characterisation of a fusion protein suited for tumour specific prodrug activation

Bosslet

Czech²,

Lorenz³

et al. 1992

Br J Cancer

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Currently, the treatment of non-disseminated solid tumours is performed by surgery and irradiation. Both methods can be considered to be relatively tumour selective, without significantly harming the rest of the body. If however the tumour has disseminated to various organ sites, the metastases can be treated by chemo-or hormone therapy only. Chemotherapy has considerable side effects and a minor influence on patients' survival due to the lack of specificity of action or the induction of resistance. Hormone therapy alone has a limited tumour spectrum.To overcome these obvious limitations of today's treatment modalities, we tailored a fusion gene consisting of the VH and CHI Exons of a humanised MAb and the human P-glucuronidase cDNA . The product encoded by the fusion gene might be suitable for performing an antibody directed enzyme prodrug therapy (ADEPT). The concept of ADEPT as developed by Philpott et al. (1973a,b;1974) and reemphasised by Bagshawe (1987) and Bagshawe et al. (1988) assumes that an antibody enzyme conjugate after selective localisation at the tumour target site, and its clearance from normal tissues, activates a nontoxic low molecular weight prodrug to a highly toxic drug in the tumour by enzymatic catalysis.The therapeutic success of this approach depends on several factors:(a) The stability of the prodrug in vivo. (j) The immunogenicity of the antibody enzyme conjugate. Despite the obvious complexity of the system, a first clinical trial with a F(ab')2 fragment of a murine anti CEA MAb chemically linked to carboxypeptidase G2 (CPG2) from

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Prodrugs

Cited by 189 publications

References 49 publications

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection

A prodrug system for hydroxylamines based on esterase catalysis

Molecular and functional characterisation of a fusion protein suited for tumour specific prodrug activation

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