Journal article
Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates
Bioorganic & medicinal chemistry, Vol.12(18), pp.4969-4979
09/15/2004
Handle:
https://hdl.handle.net/2376/113590
PMID: 15336276
Abstract
A series of phenylalkylphosphonamidate derivatives of glutamic acid were synthesized and evaluated for their inhibitory potencies against PSMA. The greatest inhibitory potency was observed for the inhibitors 1f (n=5) and 1g (n=6) suggesting the presence of a hydrophobic binding register remote from the substrate recognition architecture in the active site of PSMA.
To explore for the existence of an auxiliary hydrophobic binding register remote from the active site of PSMA a series of phenylalkylphosphonamidate derivatives of glutamic acid were synthesized and evaluated for their inhibitory potencies against PSMA. Both the phenyl- and benzylphosphonamidates (1a and 1b) exhibited only modest inhibitory potency against. The phenethyl analog 1c was intermediate in inhibitory potency while inhibitors possessing a longer alkyl tether from the phenyl ring, resulted in markedly improved Ki values. The greatest inhibitory potency was obtained for the inhibitors in which the phenyl ring was extended furthest from the central phosphorus (1f, n=5 and 1g, n=6). The slightly serrated pattern that emerged as the alkyl tether increased from three to six methylene units suggests that inhibitory potency is not simply correlated to increased hydrophobicity imparted by the phenylalkyl chain, but rather that one or more hydrophobic binding registers may exist remote from the substrate recognition architecture in the active site of PSMA.
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Details
- Title
- Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates
- Creators
- Jack Maung - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAJeremy P Mallari - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USATeri A Girtsman - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USALisa Y Wu - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAJennifer A Rowley - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USANicholas M Santiago - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAAlan N Brunelle - SCOLR, Inc., 3625 132nd Ave. SE, suite 300, Bellevue, WA 98006, USAClifford E Berkman - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USA
- Publication Details
- Bioorganic & medicinal chemistry, Vol.12(18), pp.4969-4979
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900548047301842
- Language
- English
- Resource Type
- Journal article