Phosphatase inhibitors—III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase

Beers, Scott A.; Schwender, Charles F.; Malloy, Elizabeth A.; Demarest, Keith; Jordan, Jerold

doi:10.1016/0968-0896(96)00186-1

Cited by 86 publications

(49 citation statements)

References 13 publications

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“…BABPA is also a potent PAP inhibitor (IC 50 , 4 nmol/L; refs. 17,23), and the predicted (calculated) binding constant of IQ 2-P with PAP can be compared with the predicted and experimentally determined binding constant of BABPA. In addition, the conformation of the PAP active site originating from the PAP-BABPA complex (which during the simulation remains rigid)…”

Section: Resultsmentioning

confidence: 99%

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

et al. 2007

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We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2 ¶-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ 2-P ) was docked in silico into the X-ray structure of PAP. The data indicate that IQ 2-P docked into the PAP active site with a calculated inhibition constant (K i ) more favorable than that of the PAP inhibitor A-benzylaminobenzylphosphonic acid. When 125 IQ 2-P , the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2 ¶-hydroxyphenyl)-6-[125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-OH ). Similarly, the incubation of IQ 2-P with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ 2-OH crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with 125 IQ 2-P showed accumulation of radioactive grains ( 125 IQ 2-OH ) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases. [Cancer Res 2007;67(5):2197-205]

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Section: Resultsmentioning

confidence: 99%

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

et al. 2007

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“…Me 3 SiBr/A C H T U N G T R E N N U N G (allyl)SiMe 3 . When the Boc group was replaced by the diethoxyphosphinyl group, the a-aminobenzyllithium intermediate partially enantiomerised even at À78 8C and rearranged to yield an a-aminophosphonate with 50 % ee (ee = enantiomeric excess).…”

Section: Introductionmentioning

confidence: 99%

“…[2] N-Benzyl a-aminobenzylphosphonic acids were found to be potent inhibitors of human prostatic acid phosphatase. [3] (R)-Phosphatyrosine (the phosphonic acid analogue of l-tyrosine) is a component of naturally occurring hypotensive tripeptides. [4] Not surprisingly, the widespread interest in aminophosphonic acids gave rise to the development of many methods for their asymmetric preparation, but a limited number for quaternary ones.…”

Section: Introductionmentioning

confidence: 99%

Preparation of α‐Aminobenzylphosphonic Acids with a Stereogenic Quaternary Carbon Atom via Microscopically Configurationally Stable α‐Aminobenzyllithiums

Kuliszewska

Hanbauer

Hammerschmidt

2008

Chemistry A European J

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The enantiomers of 1-phenylethylamine were phosphorylated with diethyl chlorophosphate/Et(3)N and then Boc-protected (Boc=tert-butoxycarbonyl) at the nitrogen atom. These phosphoramidates were metalated by using sBuLi/N,N,N',N'-tetramethylethylenediamine (TMEDA) to give alpha-aminobenzyllithiums that isomerised to alpha-aminophosphonates in yields of up to 80 % with retention of the configuration at the carbon atom. The intermediate tertiary organolithiums were found to be microscopically configurationally stable from -78 to 0 degrees C in Et(2)O. The protected alpha-aminophosphonates were deblocked by using boiling 6 M HCl or preferably Me(3)SiBr/(allyl)SiMe(3). When the Boc group was replaced by the diethoxyphosphinyl group, the alpha-aminobenzyllithium intermediate partially enantiomerised even at -78 degrees C and rearranged to yield an alpha-aminophosphonate with 50 % ee (ee=enantiomeric excess). Similarly, N-Boc-protected phosphoramidates derived from racemates and/or enantiomers of 1-(1-naphthyl)ethyl-, 1-indanyl- and 1,2,3,4-tetrahydro-1-naphthylamine or 1-azidoindan- and 1-azido-1,2,3,4-tetrahydronaphthalene were converted to aminophosphonates in good yields. Deblocking gave alpha-aminophosphonic acids of excellent enantiomeric excess (97-99 %), as determined by means of HPLC on a chiral ion-exchange stationary phase based on quinine carbamate. When racemic Boc-protected diethyl phosphoramidate derived from 1,2,3,4-tetrahydro-1-naphthylamine was metalated with LiTMP/TMEDA (TMP=2,2,6,6-tetramethylpiperidine), 1-hydroxyethylphosphonamidates resulted. The configuration of the main isomer was determined by means of a single-crystal X-ray structure analysis.

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“…By analogy to aminocarboxylic acids, the introduction of fluorine atoms into the molecule of aminophosphonic acids can extend the spectrum of their biological activity and make possible the application of 19 F NMR spectroscopy to study the metabolism of these substances. [15] Some ring-substituted a-aminobenzylphosphonic acids were found to exhibit antifungal activity, [16] to be potent inhibitors of phenylalanine ammonia-lyase, [17] human prostatic acid phosphatase, [18] as well as promising structural units for the design of antithrombotic tripeptides. [19] Optically active a-aminobenzylphosphonic acids are of special interest.…”

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confidence: 99%

Catalytic Hydrogenation of α‐Iminophosphonates as a Method for the Synthesis of Racemic and Optically Active α‐Aminophosphonates

et al. 2008

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Phosphatase inhibitors—III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase

Cited by 86 publications

References 13 publications

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

Preparation of α‐Aminobenzylphosphonic Acids with a Stereogenic Quaternary Carbon Atom via Microscopically Configurationally Stable α‐Aminobenzyllithiums

Catalytic Hydrogenation of α‐Iminophosphonates as a Method for the Synthesis of Racemic and Optically Active α‐Aminophosphonates

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