Alkyl Esters of Camptothecin and 9-Nitrocamptothecin:  Synthesis, in Vitro Pharmacokinetics, Toxicity, and Antitumor Activity

Cao, Ziping; Harris, N.; Kozielski, Anthony J.; Vardeman, Dana; Stehlin, John S.; Giovanella, Beppino C.

doi:10.1021/jm9607562

Cited by 96 publications

(78 citation statements)

References 31 publications

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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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Section: Discussionmentioning

confidence: 99%

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

2006

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“…Animal weight, tumor size, animal appearance, behavior, and survival rate were monitored for four weeks after administration. Weight loss over 20% and tumor growth over 1500 mm 3 were counted as lethalities (animals were euthanized).…”

Section: In Vivo Antineoplastic Activity and Toxicitymentioning

confidence: 99%

“…Acylation of the (O20) lactone ring hydroxyl significantly increases the stability. 3,4 Hydrophilization of the CPT molecule results in water soluble forms, e.g., Irinotecan (CPT-11). The latter is the most widely used soluble prodrug, which (as well as other CPT prodrugs) requires endoplasmic activation, mainly in the liver, for conversion into the active form (SN38 5 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t 1/2 = 2.2 ± 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t 1/2 = 2.1 ± 0.2 h, while the conjugate half-life was 14.2 ±1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

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“…In efforts of finding better camptothecin analogues for treatment, we previously synthesized many different camptothecin esters by attaching an ester chain in position C-20 and subsequently evaluated these compounds (23,24). The treatment of human tumors grown as xenografts in nude mice with our synthetic camptothecin esters was effective and toxicity in mice was minimal (25,26).…”

Section: Introductionmentioning

confidence: 99%

Crystalline Camptothecin-20(S)-O-Propionate Hydrate:A Novel Anticancer Agent with Strong Activity against 19 Human Tumor Xenografts

Cao¹,

Kozielski²,

Liu³

et al. 2009

Cancer Research

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To find a more effective and less toxic chemotherapeutic agent, we have successfully prepared crystalline camptothecin-20(S)-O-propionate hydrate (CZ48) by reacting camptothecin with propionic anhydride using concentrated sulfuric acid as catalyst. The biological effectiveness of this new anticancer agent was evaluated by using xenografts of human cancers in nude mice as the testing models. The extensive treatment of 21 human tumors with various dose levels of CZ48 has shown that this agent is highly effective against many different human tumors tested with a striking lack of toxicity. Of the 21 human tumor lines tested, 9 regressed, 5 were <10% of the control, 3 were <20%, and 2 were <40%. Two tumors did not respond. The total response rate was 90%

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Alkyl Esters of Camptothecin and 9-Nitrocamptothecin: Synthesis, in Vitro Pharmacokinetics, Toxicity, and Antitumor Activity

Cited by 96 publications

References 31 publications

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

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

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

Crystalline Camptothecin-20(S)-O-Propionate Hydrate:A Novel Anticancer Agent with Strong Activity against 19 Human Tumor Xenografts

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