Chemically stable, lipophilic prodrugs of phosphoramide mustard as potential anticancer agents

Kwon, Chul‐Hoon; Moon, Ki Young; Baturay, Nesrine Z.; Shirota, Frances N.

doi:10.1021/jm00106a018

Cited by 15 publications

(11 citation statements)

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“…Rat liver S-9 cytosolic and microsomal fractions were prepared as described previously. 32 Protein concentrations were determined by the method of Bradford (Protein Assay Kit, Bio-Rad Laboratories, Inc.) using bovine serum albumin as standard. Protein concentrations for various rat liver fractions were obtained as follows: Uninduced rat liver S-9 fraction, 22.5 mg/mL; phenobarb-induced rat liver S-9 fraction, 17.9 mg/mL (preparation I) and 18.2 mg/mL (preparation II); phenobarb-induced rat liver cytosolic fraction, 12.7 mg/mL; phenobarb-induced rat liver microsomal fraction, 6.3 mg/mL.…”

Section: -(5-nitro-12-benzisoxazol-3-yl)ethyl Nn-bis(2-chloroethyl)ph...mentioning

confidence: 99%

1,2-Benzisoxazole Phosphorodiamidates as Novel Anticancer Prodrugs Requiring Bioreductive Activation

Jain

Kwon

2003

J. Med. Chem.

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Several 1,2-benzisoxazole phosphorodiamidates have been designed as prodrugs of phosphoramide mustard requiring bioreductive activation. Enzymatic reduction of 1,2-benziosoxazole moiety is expected to result in the formation of imine intermediate due to the cleavage of the N-O bond. The imine should then be spontaneously hydrolyzed to a ketone metabolite, thereby facilitating base-catalyzed beta-elimination of cytotoxic phosphoramide mustard. As expected, the proposed prodrugs 4, 9, and 12 were at least 3-5-fold more potent cytotoxins than control compounds 5 and 15, which lack in the phosphoramide mustard group. Upon incubation with phenobarb-induced rat liver S-9 fraction, compounds 4, 9, and 12 underwent extensive NADPH-dependent metabolism with concomitant generation of alkylating activity under both hypoxic and oxic conditions. Corresponding ketone metabolites were detected for 9 and 15. NADPH-dependent bioreduction of 15 to its ketone metabolite 16 was located in the microsomal fraction and inhibited by SKF-525A and pCMBA. Compared with phenobarb-induced rat liver microsomal fraction, incubation of 15 with rat or human p450 reductase microsomes showed moderate generation of 16. Microsomal cytochrome p450 and/or p450 reductase appear to be involved in the reductive metabolism of 1,2-benzisoxazole moiety under hypoxic as well as oxic conditions.

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Section: -(5-nitro-12-benzisoxazol-3-yl)ethyl Nn-bis(2-chloroethyl)ph...mentioning

confidence: 99%

1,2-Benzisoxazole Phosphorodiamidates as Novel Anticancer Prodrugs Requiring Bioreductive Activation

Jain

Kwon

2003

J. Med. Chem.

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“…Such results suggest that benzyl analogues of iPAM 2a-d are poor substrates for cytochrome P450. Much better microsomal activation was previously achieved for benzyl analogues of phosphoramide mustard, an active metabolite of cyclophosphamide [18]. One can assume that higher steric hindrance around the benzylic carbon in benzyl analogues of iPAM, compared with the steric hindrance in phosphoramide mustard derivatives, is responsible for the observed difference in reactivity of these two types of compounds.…”

Section: Resultsmentioning

confidence: 90%

Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT).

Misiura¹,

Szymanowicz²,

Kuśnierczyk³

et al. 2002

Acta Biochim Pol

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Two types of prodrugs, benzyl analogues of isophosphoramide mustard (iPAM), activated by cytochrome P450, and acylthioethyl analogues, activated by esterases, were designed. In contrast to iPAM that hydrolyse rapidly, the examined compounds are stable in phosphate-buffered saline and Tris buffer. Benzyl analogues of iPAM are poor substrates for cytochrome P450, are not cytotoxic and posses no antitumour activity. Acylthioethyl analogues of iPAM are good substrates for pig liver esterase, are cytotoxic and exert antitumour activity against L1210 leukaemia in mice. The observed correlation for iPAM analogues between their susceptibility to hydrolysis and cytotoxicity and antitumour activity suggests possible application of these compounds as the prodrugs in gene-directed enzyme-prodrug therapy.

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“…Fractions were collected (50 x 8 mL). Fractions (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) were pooled, and the solvent was removed in vacuo to give 5 as a yellow oil (yield, 42.9%): TLC Rf= 0.88 in C^CVMeOH jV-Methyl-cis-4-(diethyldithiocarbamoyl)cyclophosphamide (6). O-3-Butenyl N,/V-bis(2-chloroethyl)-/V'-methylphosphordiamidate (3) (4.01 g, 15.5 mmol)14 was dissolved in acetone/water (2:1,150 mL) and ozonized at 4 °C for 40 min.…”

Section: Methodsmentioning

confidence: 99%

“…Fractions (36 x 20 mL) were collected. Fractions (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) were pooled and evaporated in vacuo to give 6 as a semisolid which solidified on cooling. The solid was recrystallized from anhydrous ether to give 1.37 g of 6 as a white solid (20.9% Stability Test Under Physiological Conditions.…”

Section: Methodsmentioning

confidence: 99%

Chemically Stable N-Methyl-4-(alkylthio)cyclophosphamide Derivatives as Prodrugs of 4-Hydroxycyclophosphamide

Moon

Shirota²,

Baturay³

et al. 1995

J. Med. Chem.

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Two prototype N-methyl-4-thio-substituted cyclophosphamide (CP) derivatives (5 and 6), prodrugs of 4-hydroxycyclophosphamide (4-HO-CP), were designed to undergo oxidative N-demethylation to release the active alkylating agent. These prodrugs were chemically stable until oxidatively N-demethylated in the presence of hepatic microsomal P-450 enzymes. While the metabolism of 5 was enhanced in the presence of phenobarbital-induced microsomes, 6 was unaffected. Compound 6 was more active than 5 against L1210 leukemia cells grown in mice and exhibited statistically significant activity against the small cell lung cancer panel in the National Cancer Institute anticancer drug screen. Compound 5, like CP (1), was inactive in this screen. Thus, placement of a dithioester at the 4-position of N-methyl-HO-CP as in 6 markedly changes its spectrum of activity and has resulted in a new type of CP-based prodrug with antitumor activity against small cell lung cancer as well as leukemia cells in vitro as shown by their ability to inhibit tumor cell growth at concentrations as low as 10(-6) M.

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Chemically stable, lipophilic prodrugs of phosphoramide mustard as potential anticancer agents

Cited by 15 publications

References 0 publications

1,2-Benzisoxazole Phosphorodiamidates as Novel Anticancer Prodrugs Requiring Bioreductive Activation

1,2-Benzisoxazole Phosphorodiamidates as Novel Anticancer Prodrugs Requiring Bioreductive Activation

Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT).

Chemically Stable N-Methyl-4-(alkylthio)cyclophosphamide Derivatives as Prodrugs of 4-Hydroxycyclophosphamide

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