Coumarin-based prodrugs 2. Synthesis and bioreversibility studies of an esterase-sensitive cyclic prodrug of dadle, an opioid peptide

Wang, Binghe; Wang, Wei; Zhang, Huijuan; Shan, Daxian; Smith, Terrill D.

doi:10.1016/s0960-894x(96)00526-4

Cited by 28 publications

(16 citation statements)

References 11 publications

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“…Simple coumarins have also been applied in this field. As examples, one can refer to the coumarin-based prodrug systems that have been developed for the preparation of esterase-sensitive drugs containing amines, peptides, and peptidomimetics [352][353][354][355][356][357][358]. As expected, the drug release rates from these prodrug systems were found to be dependent on the structural features of the drug.…”

Section: Prodrug Strategymentioning

confidence: 90%

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Borges¹,

Roleira²,

Milhazes³

et al. 2005

CMC

883

458

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Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.

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Section: Prodrug Strategymentioning

confidence: 90%

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Borges¹,

Roleira²,

Milhazes³

et al. 2005

CMC

883

458

View full text Add to dashboard Cite

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“…Scheme 15. Cyclic two-step prodrugs of peptides based on: (A) the "trimethyl lock" [80,81] and, (B) coumarinic acid derivatives [85][86][87][88][89][90][91]. Another approach, quite similar to the "trimethyl lock" concept, for the design of two-step prodrugs has been based on coumarinic acid derivatives, as these equally undergo facile lactonization [83].…”

Section: Two-step Activationmentioning

confidence: 99%

“…Another approach, quite similar to the "trimethyl lock" concept, for the design of two-step prodrugs has been based on coumarinic acid derivatives, as these equally undergo facile lactonization [83]. In this case, the "conformation lock" that favors lactonization is due to the cis double bond of the coumarinic acid aliphatic chain (Scheme 15B), and enzyme-sensitive two-step prodrugs can be conceived in a virtually superimposable way to that depicted above in Scheme 13 for "trimethyl lock"-based pro-prodrugs [6,[83][84][85][86][87][88]. This approach yielded model two-step prodrugs of amines that were released upon incubation in the presence of porcine liver esterase, with t 1/2 between 1.7 and 35 min [6,84].…”

Section: Two-step Activationmentioning

confidence: 99%

“…This approach yielded model two-step prodrugs of amines that were released upon incubation in the presence of porcine liver esterase, with t 1/2 between 1.7 and 35 min [6,84]. The most relevant example of application of such coumarinic acid derivatives concerns cyclic proprodrugs of the opioid peptide DADLE (22), depicted in Scheme 15B [85,86]. This approach was also employed to oxymethyl-modified cyclic pro-prodrugs of DADLE (23, Scheme 15B), designed to promote better intrinsic cell permeation while preserving the desired sensitivity to esterases [87][88][89][90][91], and to RGD peptidomimetics [92].…”

Section: Two-step Activationmentioning

confidence: 99%

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Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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“…The synthetic methodology to make coumarinic acid linker was previously developed by Wang et al . (10,11). These cyclic peptide prodrugs can be converted to the parent peptides by esterases in the biological milieu.…”

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confidence: 99%

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

Ouyang

Borchardt

Siahaan

et al. 2002

The Journal of Peptide Research

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The coumarinic acid-based cyclic DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) prodrug 1a exhibited more favorable physicochemical properties than did DADLE for permeation across the intestinal mucosa. However, prodrug 1a, whose bioconversion to DADLE was slow, was subject to extensive biliary clearance when administered to rats in vivo. To increase the rate of esterase-catalyzed bioconversion of prodrug 1a, thus decreasing its biliary clearance, the oxymethyl-modified prodrug 1, in which an aldehyde equivalent is inserted between the phenolic group of the promoiety and the carboxylic acid group of the peptide, was synthesized from benzofuran-2-carboxylic acid 16 via a nine-step procedure. Briefly, phenacyl-protected 3-(2-hydroxyphenyl)-propynoic acid 17 was coupled with Boc-d-Leu-OCH(2)I 5 to give the intermediate 18, which was further elaborated and conjugated with tetrapeptide 4 to give linear precursor 2. Precursor 2 was then deprotected and cyclized to obtain compound 1 using a high dilution technique. In an attempt to investigate the effect of the physicochemical properties and the conformation of prodrug 1 on its permeation characteristics, we calculated its physicochemical parameters and determined its solution conformation using spectroscopic techniques (CD and NMR) and molecular dynamics simulations. Prodrug 1 showed a cLogP value and a molecular size similar to that of prodrug 1a. The deconvoluted CD spectra indicated that prodrug 1 has more random component (71%) than prodrug 1a (42%). 2D-NMR studies of prodrug 1 showed no signals for amide-amide hydrogen interactions and few ROE cross-peaks in ROESY spectra. Using distance restraints constructed from ROESY spectra, molecular dynamics simulations of prodrug 1 generated five conformation families. One family satisfied most of the distance restraints and all of the dihedral angles measured by NMR coupling constants. In summary, prodrug 1 showed favorable physicochemical properties for permeation of the intestinal mucosa. Prodrug 1 adopted a more random conformation in solution than prodrug 1a. These differences in solution conformation could affect the permeation of the prodrugs across the intestinal mucosa by passive diffusion and/or their ability to interact with efflux transporter(s) that would limit their transcellular permeation.

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Coumarin-based prodrugs 2. Synthesis and bioreversibility studies of an esterase-sensitive cyclic prodrug of dadle, an opioid peptide

Cited by 28 publications

References 11 publications

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity

Cyclization-activated Prodrugs

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

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