Maleimide-oligo(ethylene glycol) Derivatives of Camptothecin as Albumin-Binding Prodrugs:  Synthesis and Antitumor Efficacy

Warnecke, André; Kratz, Felix

doi:10.1021/bc0256289

Cited by 72 publications

(55 citation statements)

References 23 publications

(50 reference statements)

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“…4,21,22 A high degree of protein-binding, especially to albumin, is generally considered a disadvantage because only the free drug can exert its pharmacological effect, the incorporation of an acid-sensitive or enzymatically cleavable bond between the drug and the albumin-binding moiety ensures a specific release of the drug at its site of action. As a result of our preclinical work, DOXO-EMCH emerged as a clinical candidate because of its rapid and selective binding to circulating albumin, high plasma stability and high water-solubility, 4 its superior efficacy in 3 murine tumor models, and an 3-to 5-fold increase in the MTD in mice, rats and dogs when compared with doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Lebrecht

Geist

Ketelsen

et al. 2006

Intl Journal of Cancer

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Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the longterm and explain in part the delayed onset of heart dysfunction. DOXO-EMCH a 6-maleimidocaproyl hydrazone derivative of doxorubicin, is an albumin binding prodrug which has entered clinical trials because of its superior antitumor and toxicological profile. In the present work, we examined the chronic cardiotoxicity of DOXO-EMCH in direct comparison with doxorubicin. Rats (11 weeks of age) were treated with intravenous doxorubicin (0.8 mg/kg weekly for 7 weeks), an equimolar dose of DOXO-EMCH (1.1 mg/kg), or with 3.3 mg/kg of DOXO-EMCH. Controls received saline. Animals were euthanized at 48th week. Rats exposed to doxorubicin had a severe clinical, and histopathological cardiomyopathy with depressed myocardial activity of cytochrome c-oxidase (COX, 26% of controls), reduced expression of the mtDNA-encoded COX II subunit, decreased mtDNA copy numbers (46% of controls), and high levels of malondialdehyde and superoxide (787% of controls). All parameters were highly correlated with myocardial damage. Both DOXO-EMCH groups did not differ from controls with regard to clinical symptomatology, mortality and mitochondrial enzymes, although the myocardia of the high-dose group had slightly increased histopathological abnormalities, depressed mtDNA copies (74% of controls) and elevated superoxide levels (347% of controls). Doxorubicin-exposed hearts and to a lesser extent the myocardia of both DOXO-EMCH groups contained mtDNA-deletions. In summary both DOXO-EMCH doses were superior over doxorubicin with respect to clinical and histopathological evidence of cardiomyopathy, myocardial COX-activity, COX II expression, mtDNA-content, mtDNA mutation loads and superoxide production in rats. ' 2006 Wiley-Liss, Inc.Key words: doxorubicin prodrug; mitochondria cytochrome oxidase; DNA mitochondrial; reactive oxygen species Doxorubicin is an antineoplastic anthracycline that is widely used in the treatment of leukemia and lymphoma, breast and ovarian carcinoma and many other solid tumors. Bone marrow suppression with maximum toxicity after 7-10 days and a rapid recovery thereafter generally limits the escalation of single doses. Cumulative doses of doxorubicin exceeding 500 mg/m 2 in contrast, are curtailed by a late-onset and irreversible cardiotoxicity. The antitumor potency and toxicological profile of anthracyclines has been the impetus for a diligent search for more effective and less toxic anthracycline analogues, and 2,000 derivatives have been developed during the past 20 years.2 Despite these efforts, daunorubicin, epirubicin, idarubicin, pirarubicin, zorubicin, aclarubicin and carminomycin have not satisfactorily improved the therapeutic index of anthracyclines in clinical practice. 3To improve the therapeutic potential of doxorubicin, we have developed a macromolecular prodrug in which doxorubicin is derivatized at its C-13 keto-position with a thiol-binding spacer molecule (i.e., 6-maleimidocaproyl ...

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Section: Discussionmentioning

confidence: 99%

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Lebrecht

Geist

Ketelsen

et al. 2006

Intl Journal of Cancer

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“…[21][22][23][24][25][26] However, the resulting esters are highly sterically hindered and thus pro-moiety removal by enzymatic attack at the ester linkage is unlikely. Chemical (i.e., non-enzymatic) conversion may also be quite slow.…”

Section: Discussionmentioning

confidence: 99%

Kinetics and Mechanisms of Activation of α-Amino Acid Ester Prodrugs of Camptothecins

2006

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The α-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analog, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a non-enzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiorthoester (I′). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiorthoester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either α-NH 2 or α-NHCH 3 and their corresponding hemiorthoesters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37°C and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiorthoester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiorthoesters were found to be more cytotoxic than the N-methylglycinates or their corresponding hemiorthoester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these α-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.

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“…Doxorubicin hydrochloride (MW 580.0) was purchased from Hande Tech Development Co. USA, Inc.; Mal-Ser-Ser-Tyr-Tyr-Ser-Gly-OH, Mal-Asn-Ser-Ser-Tyr-Phe-Gln-OH (Mal ϭ maleimidotriethyleneglycol acid) and 6-maleimidohexanoyl-Arg-Arg-Ser-Ser-TyrTyr-Ser-Gly-OH was custom-made by BACHEM AG (Bubendorf, Switzerland); maleimidotriethylene glycol acid was prepared according to our published procedure [5]; organic solvents: HPLC grade (Merck, Darmstadt, Germany). All other chemicals used were at least reagent grade and obtained from Sigma-Aldrich (Deisenhofen, Germany) or Merck and used without further purification.…”

Section: Chemicals Materials and Spectroscopymentioning

confidence: 99%

Development of Albumin‐binding Doxorubicin Prodrugs that are Cleaved by Prostate‐specific Antigen

Kratz¹,

Mansour²,

Soltau³

et al. 2005

Archiv der Pharmazie

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Prostate-specific antigen (PSA) is a serine protease that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this work, we developed albumin-binding prodrugs with the structures MT-Ser-Ser-Tyr-Tyr- Ser-Gly-DOXO, MT-Asn-Ser-Ser-Tyr-Phe-Gln-DOXO (MT = maleimidotriethyleneglycol acid; DOXO = Doxorubicin) or EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO (EMC = epsilon-maleimidocaproic acid; X = amino acid). The maleimide Doxorubicin derivatives bound rapidly to the cysteine-34 position of endogenous and exogenous albumin and were efficiently cleaved by PSA at the P(1)-P'(1) scissile bond, releasing a respective Doxorubicin dipeptide (Ser-Gly-DOXO or Phe-Gln-DOXO). The derivative containing arginine residues (EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO) exhibited excellent water solubility for intravenous administration. Subsequent biological evaluation was focused on a PSA-negative xenograft model (PC 3) and a PSA-positive xenograft model (CWR22) in order to assess the selectivity of our therapeutic approach. EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO showed no in vivo activity in the PSA-negative PC 3 model, but good activity in the CWR22 PSA-positive model that was comparable to Doxorubicin.

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Maleimide-oligo(ethylene glycol) Derivatives of Camptothecin as Albumin-Binding Prodrugs: Synthesis and Antitumor Efficacy

Cited by 72 publications

References 23 publications

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Kinetics and Mechanisms of Activation of α-Amino Acid Ester Prodrugs of Camptothecins

Development of Albumin‐binding Doxorubicin Prodrugs that are Cleaved by Prostate‐specific Antigen

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