Bioactivation of carbamate-based 20(S)-camptothecin prodrugs

Pessah, Neta; Reznik, Mika; Shamis, Marina; Yantiri, Ferda; Xin, Hu; Bowdish, Katherine S.; Shomron, Noam; Ast, Gil; Shabat, Doron

doi:10.1016/j.bmc.2004.01.039

Cited by 49 publications

(25 citation statements)

References 17 publications

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“…The two moieties are bridged through a self-immolative linker that carries a pair of fluorescein molecules. Masking of the camptothecinhydroxyl functional group leads to generation of an inactive drug [15,16]. Cleavage of the phenylacetamide group by PGA followed by a 1,6-elimination of azaquinone-methide and subsequent decarboxylation revels the amino-aniline group of the self-immolative linker (compound 1a).…”

Section: Resultsmentioning

confidence: 99%

Modular theranostic prodrug based on a FRET-activated self-immolative linker

Redy

Shabat

2012

Journal of Controlled Release

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Section: Resultsmentioning

confidence: 99%

Modular theranostic prodrug based on a FRET-activated self-immolative linker

Redy

Shabat

2012

Journal of Controlled Release

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“…16) with relative stability at physiological pH, lower toxicity and considerable solubility. These CPT prodrugs (87,88) can be activated and hydrolysized by Escherichia coli penicillin-G amidase (PGA) or by catalytic antibody 38C2 [88]. ethylene glycol (PEG) to prepare 20-ester prodrugs has led to the development of Prothecan (89) (Fig.…”

Section: Conjugated Analogsmentioning

confidence: 99%

Review Camptothecin: Current Perspectives

Zu²,

Shi³

et al. 2006

CMC

248

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The review provides a detailed discussion of recent advances in the medicinal chemistry of camptothecin, a potent antitumor agent that targets topoisomerase I. Thousands of CPT derivatives have been synthesized. Two of them, Topotecan and Irinotecan, are commercially approved for use in clinic as antitumor agents while more are still in clinic trials. This review summarizes the current status of the modern synthetic approaches to CPT, the mechanism of action of CPT, the structure-activity relationship(SAR), a number of novel CPT analogs and their biologic activity. There is a systematic evaluation of A-, B- and E-ring- modified camptothecins reported recently.

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“…This derivative could be reduced with triphenylphosphine on solid support to cleanly give amine 19 ,19 which was then converted to the carbamate 2 in excellent yield20 (the overall yield of 2 from 16 is 12.6%). In a similar way the alcohol 16 was converted to the p -nitrophenylcarbonate intermediate 22 , which was deprotected and amidation with (S,Z)-4-(dimethyl- t -butylsilyloxy) pent-2-enoic acid (prepared according to the published method)10 to give amide 23 in good yield.…”

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confidence: 99%

Antitumor Compounds Based on a Natural Product Consensus Pharmacophore

et al. 2008

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We report the design and highly enantioselective synthesis of a potent analog of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogs. We present results on the in vitro activity for this compound against several tumor cell lines.A novel mechanism of anti-tumor activity was recently elucidated for two structurally distinct fermentation products (see Figure 1) 1 and pladienolide 2 (actually a set of closely related compounds that have been designated pladienolides A-G, isolated from Streptomyces platensis) 3 and FR901464 (isolated from Pseudomonas sp. No 2663). 4-6 These natural products have previously been reported to have a similar novel effect on the cell cycle in mammalian cell lines; cell cycle arrest at the G1 and G2/M phases. 3, 4 . This effect on the cell cycle distinguished these compounds from other anti-tumor agents that also inhibit proliferation in tumors and act at previously identified molecular targets. 3-5 This interaction with the spliceosome leads to the inhibition of mRNA splicing and the translation of unspliced mRNA, which ultimately results in the observed effects on the cell cycle. 2, 7 The first of these natural products to be discovered, FR901464, showed activity in in vivo cancer animal models, but showed a relatively narrow therapeutic window. 4 On the other hand pladienolide-based compounds (first reported in 2004) have shown a very broad therapeutic window. 2 Of the seven pladienolides, pladienolide B was reported to have the most promising anti-cancer activity in vivo, and it has recently been reported that a derivative of pladienolide B has entered human clinical trials for cancer. 2Motivated by the recognition that FR901464 and pladienolide have a very similar (or possibly identical) mechanism of action, we compared overlays of molecular models of the two natural products. Upon inspection of these overlays we recognized that despite the gross dissimilarities *To whom correspondence should be addressed. . E-mail: E-mail: thomas.webb@stjude.org. Supporting Information Available: The supporting information includes the general experimental methods, procedures for the synthesis of 9-13 and 15-18, as well as full experimental methods for the cell cycle analysis and the in vitro cytotoxicity assays. This material is available free of charge via theInternet at http://pubs.acs.org. between FR901464 and pladienolide, both molecules share certain common key features (which are known to be critical to their activity) that can overlap in low energy conformations in three dimensions (see Figure 2). It is known from previous studies that the orientation of the acetyl group and the presence of the epoxide are important in conferring activity to FR901464 analogs, 8, 9 but that the glycosidic hydroxyl group...

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Bioactivation of carbamate-based 20(S)-camptothecin prodrugs

Cited by 49 publications

References 17 publications

Modular theranostic prodrug based on a FRET-activated self-immolative linker

Modular theranostic prodrug based on a FRET-activated self-immolative linker

Review Camptothecin: Current Perspectives

Antitumor Compounds Based on a Natural Product Consensus Pharmacophore

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