Drug Latentiation

Digenis, George A.; Swintosky, Joseph V.

doi:10.1007/978-3-642-46314-3_3

Cited by 9 publications

(10 citation statements)

References 63 publications

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“…Given the excellent biological activity of the diamidines, methods to make orally available prodrugs of the compounds are particularly important to effective therapeutic delivery of the compounds in a broad range of environments. Many reports have appeared which describe prodrug modifications for a variety of functional groups [67][68][69][70][71][72], however only a limited number have appeared describing prodrug approaches for aryl monoamidines [73,74]. Reports of prodrugs of diamidines are also quite limited.…”

Section: Prodrug Approaches For Diamidines: Design Synthesis and Biomentioning

confidence: 99%

Dications That Target the DNA Minor Groove: Compound Design and Preparation, DNA Interactions, Cellular Distribution and Biological Activity

Wilson

Nguyen

Tanious³

et al. 2005

CMCACA

159

171

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Fluorescence microscopy of trypanosomes from drug treated mice shows that biologically active heterocyclic diamidines that target the DNA minor groove bind rapidly and specifically to parasite kinetoplast DNA (k-DNA). The observation that the kinetoplast is destroyed, generally within 24 hours, after drug treatment is very important for understanding the biological mechanism, and suggests that the diamidines may be inhibiting some critical opening/closing step of circular k-DNA. Given the uncertainties in the biological mechanism, we have taken an empirical approach to generating a variety of synthetic compounds and DNA minor groove interactions for development of improved and new biological activities. Furamidine, DB75, is a diphenyl-diamidine that has the curvature to match the DNA minor groove as expected in the classical groove interaction model. Surprisingly, a linear diamidine with a nitrogen rich linker has significantly stronger binding than furamidine due to favorable linker and water-mediated DNA interactions. The water interaction is very dependant on compound structure since other linear compounds do not have similar interactions. Change of one phenyl of furamidine to a benzimidazole does not significantly enhance DNA binding but additional conversion of the furan to a thiophene (DB818) yields a compound with ten times stronger binding. Structural analysis shows that DB818 has a very favorable curvature for optimizing minor groove interactions. It is clear that there are many ways for compounds to bind to k-DNA and exert specific effects on kinetoplast replication and/or transcription that are required to obtain an active compound.

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Section: Prodrug Approaches For Diamidines: Design Synthesis and Biomentioning

confidence: 99%

Dications That Target the DNA Minor Groove: Compound Design and Preparation, DNA Interactions, Cellular Distribution and Biological Activity

Wilson

Nguyen

Tanious³

et al. 2005

CMCACA

159

171

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“…Chemical modification of biologically active compounds to form new molecules (pro-drugs), usually biologically inactive, which can be converted in vivo to the parent molecule can potentially improve physico-chemical properties such as water solubility and lipophilicity, transport of drug to the site of action, presystemic degradation, and oral biovailability [97,98]. While numerous reports exist on the pro-drug modification of many functional groups [99][100][101][102][103], very few reports have appeared describing pro-drug approaches for aryl amidines [104,105]. It has been reported by our laboratories and others that amidoximes can be used as orally active pro-drugs for the corresponding diamidines [44,[106][107][108].…”

Section: Pro-drugs Of Carbazoles and Related Analogsmentioning

confidence: 99%

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Tidwell¹,

Boykin

2002

Small Molecule DNA and RNA Binders

159

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“…The chemical characteristics of XIV suggest that it could be considered as a potential precursor "prodrug" of methionine in ruminants (45,46). This means that XIV and its analogs could perhaps pass through the rumen and abomasum unchanged and subsequently be absorbed from the intestines where most absorption occurs.…”

Section: Resultsmentioning

confidence: 99%

Methionine Substitutes in Ruminant Nutrition I: Stability of Nitrogenous Compounds Related to Methionine during In Vitro Incubation with Rumen Microorganisms

Digenis

Amos

Yang

et al. 1974

Journal of Pharmaceutical Sciences

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4:1:2)] were scraped off, eluted into n-hexane, back-extracted into the ceric sulfate-sulfuric acid solution, and examined by the oxidation-UV method. The resulting UV absorption spectra from both the unchanged methadone and the metabolite were identical to that of benzophenone. GLC examination of the heptane following reflux further substantiated that benzophenone was formed from both the parent drug and the metabolite. DISCUSSIONThe extended linearity of the spectrophotometric method permits the use of a single aliquot of the specimen to encompass most urine methadone concentrations encountered in patients receiving methadone maintenance. Analysis by the barium peroxide method required varying specimen volumes since linearity was achieved up to a concentration of 25 pg/ml.A comparison of the procedures and results of the ceric sulfate and barium peroxide methods indicates several advantages of the former in addition to the extended linearity and elimination of the required alkaline wash. Oxidation of methadone by the method of this report gives a 84.6 f 3.2% yield of benzophenone as opposed to a 77.8 f 3.3% yield obtained with the barium peroxide method. In addition to the time saved through the elimination of an extraction step, the proposed spectrophotometric method requires a shorter reaction time; e.g., 20 min reflux with barium peroxide provided only a 48% yield of benzophenone compared to an 82% yield obtained with ceric sulfate. Additionally, reflux conditions were less critical since no significant change in percent yield was observed as the amount of primary oxidant was varied from 200 to 300 mg, the molarity of the sulfuric acid was varied from 5 to 6, or the duration of reflux was varied from 25 to 50 min. Similar variations in the barium peroxide method resulted in significantly decreased yields; changes in the amount of acid, solvent, and heat of reflux produced similar effects in both methods.The proposed methods provide rapid and sensitive quantitative methods for determining methadone a t therapeutic levels in biological specimens. Since other diphenyl-substituted drugs are susceptible to cerium sulfate, utilization of the GLC technique in conjunction with the spectrophotometric method provides a highly specific analytical methodology for methadone in biological specimens. The methods are particularly useful as a quantitative test in suspected methadone overdose cases and as a mechanism to monitor pharmacokinetic studies. In methadone maintenance programs the techniques can be used in collaboration with TLC to confirm on a relative basis that patients are receiving, within broad limits, proper dosages of the drug.Abstract Thirty-one nitrogenous compounds with possible methionine activity were included as potential nitrogen sources in media for in uitro incubation of rumen microorganisms. Compounds not supporting cellulose digestion were included in studies of ammonia release and specific analyses designed to confirm resistance of the compounds to microbial deamination. N-Acetyl-DLmethionine (IV)...

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Drug Latentiation

Cited by 9 publications

References 63 publications

Dications That Target the DNA Minor Groove: Compound Design and Preparation, DNA Interactions, Cellular Distribution and Biological Activity

Dications That Target the DNA Minor Groove: Compound Design and Preparation, DNA Interactions, Cellular Distribution and Biological Activity

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Methionine Substitutes in Ruminant Nutrition I: Stability of Nitrogenous Compounds Related to Methionine during In Vitro Incubation with Rumen Microorganisms

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