Design and synthesis of novel prodrugs of 2′-deoxy-2′-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues

Kohchi, Yasunori; Hattori, Kazuo; Oikawa, Nobuhiro; Mizuguchi, Eisaku; Isshiki, Yoshiaki; Aso, Kohsuke; Yoshinari, Kiyoshi; Shirai, Haruyoshi; Miwa, Masanori; Inagaki, Yukiko; Ura, Masako; Ogawa, Kotaroh; Okabe, Hisafumi; Ishitsuka, Hideo; Shimma, Nobuo

doi:10.1016/j.bmcl.2007.01.066

Cited by 7 publications

(6 citation statements)

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“…The substrate selectivity of DPEP1 has been exploited to activate prodrugs. DPEP1 is overexpressed in human colorectal and stomach tumor tissue (Kohchi et al 2007). The DPEP1-catalyzed hydrolysis of the dipeptide moiety of prodrug 244 (Figure 21) in these tissues gives an intermediate that spontaneously releases the antitumor agent, 2 0 -deoxy-2 0methylidenecytidine (245, Figure 21).…”

Section: Membrane-bound Dipeptidasesmentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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Section: Membrane-bound Dipeptidasesmentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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“…Although it describes a strictly enzymatic pathway for drug release, this work constitutes another relevant example of the key role of peptide carriers in prodrug design. In this connection, cutting-edge work by Kohchi et al proposes membrane dipeptidase (MDP)-mediated activation of prodrugs 18 of the anti-tumoral 2'-deoxy-2'-methylidenecytidine (DMDC, 19) [70]. MDP specifically cleaves amide bonds in dipeptides and is over-expressed in tumors, which makes it an attractive target for anti-cancer therapy.…”

Section: Two-step Activationmentioning

confidence: 99%

“…MDP specifically cleaves amide bonds in dipeptides and is over-expressed in tumors, which makes it an attractive target for anti-cancer therapy. Prodrugs 18 are activated by MDP in tumors by hydrolysis of the dipeptide bond followed by spontaneous cyclization of the promoiety, as depicted in Scheme 11 [70]. Scheme 11.…”

Section: Two-step Activationmentioning

confidence: 99%

“…Scheme 11. Enzymatic cleavage followed by intramolecular aminolysis of DMDC prodrugs [70]. Other two-step prodrugs based on nitrogen nucleophiles have been developed, for instance, by Atwell et al, who proposed 2-nitroaryl amides as bio-reductive two-step prodrugs capable of releasing cytotoxic aminoaniline mustards by spontaneous cyclization of the corresponding 2-aminoaryl amides produced in a previous bio-reduction step [71].…”

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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“…Today, with data available from genome, proteome, and metaborome databases of both human and experimental animals, it is possible to identify the metabolic enzymes for prodrug design [44]. The most critical issue experienced in the discovery of capecitabine was interspecies difference in the types, activities, and tissue distribution patterns of metabolic enzymes necessary for prodrug design.…”

Section: Discussionmentioning

confidence: 99%

Capecitabine Preclinical Studies: From Discovery to Translational Research

Ishitsuka

Shimma²

2008

Modified Nucleosides

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The most desirable formulation for anti-cancer drugs requiring frequent administration would be a tablet, similar to the treatment of many other diseases. Oral treatment would not only reduce medical treatment costs but also allow cancer patients to spend less time in hospital and more time with their family and friends. In fact, cancer patients prefer oral treatment if it is as effective as parenteral treatment [1]. In addition, a tablet is most appropriate for the long-term frequent treatment of cancer cells. Although many cytotoxic drugs effectively inhibit tumor cells only in particular processes of the cell cycle, such as the S phase and M phase, not all tumor cells are present in the tissues during such processes. In order to be effective, cytotoxic drugs should be administered continuously over a period of time which is longer than one cell cycle. However, the daily administration of cytotoxic drugs is limited because of the accumulation of non-tumor-selective toxicity. When given orally, cytotoxic drugs generally lead to high concentrations of the drug, predominantly at the local sites, such as the intestine and liver, and this results in treatmentassociated adverse effects on these organs. On the other hand, oral doses of cytotoxic drugs are generally larger than parenteral doses, because drugs given orally are often subjected to first-pass metabolic effects in the intestinal tract and liver. Unfortunately, a reduction in dose to spare such local organ toxicity results in an insufficient efficacy compared with that of parenteral administration.In 1986, the present authors commenced studies into the design and synthesis of orally available cytotoxic compounds with high tumor selective activity and low myelotoxicity or intestinal toxicity, and which therefore would be safe for daily oral treatment over prolonged periods of time in the comfort of the home. The strategy employed, specifically identifying new cytotoxic compounds with high tumor-selective action, included the design and synthesis of a prodrug that, from oral administration, generates an active cytotoxic component from enzymes

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Design and synthesis of novel prodrugs of 2′-deoxy-2′-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues

Cited by 7 publications

References 7 publications

The mercapturic acid pathway

The mercapturic acid pathway

Cyclization-activated Prodrugs

Capecitabine Preclinical Studies: From Discovery to Translational Research

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