Yongying Jiang

Nitrobenzocyclophosphamides as potential prodrugs for bioreductive activation: Synthesis, stability, enzymatic reduction, and antiproliferative activity in cell culture

In efforts to obtain potential anticancer prodrugs for gene-directed enzyme prodrug therapy using Eschericia coli nitroreductase, a series of four benzocyclophosphamide analogues were designed and synthesized incorporating a strategically placed nitro group in a position para to the benzylic carbon for reductive activation. All four analogues were found to be stable in phosphate buffer at pH 7.4 and 37 degrees C and were good substrates of E. coli nitroreductase with half lives between 7 and 24 min at pH 7.0 and 37 degrees C. However, only two analogues 6a and 6c, both with a benzylic oxygen in the phosphorinane ring para to the nitro group, showed a modest 33-36-fold enhanced cytotoxicity in E. coli nitroreductase-expressing cells. These results suggest that good substrate activity and the para benzylic oxygen are required for activation by E. coli nitroreductase. Compounds 6a and 6c represent a new structure type for reductive activation and a lead for further modification in the development of better analogues with improved selective toxicity to be used in gene-directed enzyme prodrug therapy.

A facile synthesis of 2-oxazolidinones via Hofmann rearrangement mediated by bis(trifluoroacetoxy)iodobenzene

Abstract A mild and efficient synthesis of 2-oxazolidinones from β-hydroxypropionamides via Hofmann rearrangement was achieved in 96% to quantitative yield using bis(trifluoroacetoxy)iodobenzene (BTI) in acetonitrile. The method should be useful in both solution- and solid-phase construction of 2-oxazolidinone libraries.

Synthesis and stereochemical preference of peptide 4-aminocyclophosphamide conjugates as potential prodrugs of phosphoramide mustard for activation by prostate-specific antigen (PSA)

In an effort to develop proteolytically activated prodrugs of phosphoramide mustard by prostate-specific antigen (PSA), a series of tetrapeptide (Cbz-Ser-Ser-Phe-Tyr)-conjugated 4-aminocyclophosphamide (4-NH(2)-CPA) isomers were synthesized and evaluated as substrates of PSA. The cleavage of the conjugates by PSA were found to be stereoselective as only the two isomers with 4R-configuration were efficiently cleaved by PSA. The cis-(2R,4R)-isomer was the best substrate of PSA with a half-life of 12min. LC/MS analysis of the incubation solution of this isomer with PSA suggests that 4-NH(2)-CPA is released upon proteolysis and quickly degrades to cytotoxic phosphoramide mustard. These results clarified the stereochemical requirements of PSA on the peptide conjugates of 4-NH(2)-CPA and demonstrated the potential of these conjugates as potential PSA-activated prodrugs targeting prostate cancer.

N-(2,2-Dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide as a potential bioreductively activated prodrug of phosphoramide mustard

N-(2,2-Dimethyl-2-(2-nitrophenyl)acetyl)-4-aminocyclophosphamide isomers (DMNA-NH-CPA, 4) were synthesized stereospecifically from Boc-L-Hse(OBn)-OH and the degradation of the corresponding reduced amine 5a was investigated by UV/vis spectroscopy and LC/MS. The rate of cyclization of 5a was found to increase with decreasing pH, with half-lives ranging from 3.2 to 54 min at pH 4-7.4, suggesting that the cyclization is catalyzed by the hydronium ions. LC/MS analysis of the degradation products of 5a indicates that 4-aminocyclophosphamide is rapidly released from 4 upon reductive activation under acidic conditions and further decomposes into the cytotoxic phosphoramide mustard. These results validated 4-aminocyclophosphamide as a prodrug form of phosphoramide mustard and suggest that compound 4 can potentially be used as a prodrug of phosphoramide mustard for bioreductive activation.

2,2-dimethyl-2-(o-nitrophenyl)acetyl (DMNA) as an assisted cleavage protecting group for amines

Abstract 2,2-Dimethyl-2-( o -nitrophenyl)acetyl group (DMNA) was explored as an assisted cleavage protecting group for amines and a one-step deprotection condition was developed for its efficient removal using hydrogenation in the presence of Pd–C or PtO 2 catalyst and 10% HOAc in MeOH. DMNA was found to be especially useful for the synthesis of gem -diamino compounds using Hofmann rearrangement.

Peptide conjugates of 4-aminocyclophosphamide as prodrugs of phosphoramide mustard for selective activation by prostate-specific antigen (PSA)

In our continued effort to develop prodrugs of phosphoramide mustard, conjugates of 4-aminocyclophosphamide (4-NH2-CPA) with three PSA-specific peptides were synthesized and evaluated as substrates of PSA. These include conjugates of cis-(2R,4R)-4-NH2-CPA with a tetrapeptide Succinyl-Ser-Lys-Leu-Gln-OH, a hexapeptide Succinyl-His-Ser-Ser-Lys-Leu-Gln-OH, and a pentapeptide Glutaryl-Hyp-Ala-Ser-Chg-Gln-OH. These conjugates were cleaved by PSA efficiently and exclusively after the expected glutamine residue to release 4-NH2-CPA, the activated prodrug form of phosphoramide mustard. The cleavage was most efficient for the pentapeptide conjugate 3 (Glutaryl-Hyp-Ala-Ser-Chg-Gln-NH-CPA), which showed a half-life of 55 min with PSA, followed by the hexapeptide conjugate 2 (Succinyl-His-Ser-Ser-Lys-Leu-Gln-NH-CPA) and the tertrapeptide conjugate 1 (Succinyl-Ser-Lys-Leu-Gln-NH-CPA) with half-lives of 6.5 and 12h, respectively. These results indicate a potential of the conjugate 3 as an anticancer prodrug of phosphoramide mustard for selective PSA activation.

Facile synthesis and cleavage of imidazolidines in a novel protection strategy for the preparation of peptides containing a reduced amide bioisostere

Abstract Unsymmetrical imidazolidines were obtained in 75–91% yield by treating monoalkoxycarbonyl vicinal diamines at room temperature with aqueous 37% formaldehyde in the presence of Montmorillonite KSF as a solid catalyst. The imidazolidines were shown to be useful intermediates in a novel protection strategy for the synthesis of peptide analogues containing a reduced glycine amide bioisostere. The imidazolidine intermediate was cleaved conveniently and efficiently by 50% TFA in methylene chloride.