Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 20, Issue 12, Pages 3688-3691Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.04.086
Keywords
Melphalan; Anticancer agents; Blood-brain barrier; Large neutral amino acid transporter
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Funding
- Department of Defense [W81XWH-062-0033]
- NIH/NINDS [R01 NS052484]
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Regiospecific and conformationally restrained analogs of melphalan and DL-2-NAM-7 have been synthesized and their affinities for the large neutral amino acid transporter (LAT1) of the blood-brain barrier have been determined to assess their potential for accessing the CNS via facilitated transport. Several analogs had K-i values in the range 2.1-8.5 mu M with greater affinities than that of either L-phenylalanine (K-i = 11 mu M) or melphalan (K-i = 55 mu M), but lower than DL-2-NAM-7 (K-i = 0.08 mu M). The results indicate that regiospecific positioning of the mustard moiety on the aromatic ring in these analogs is very important for optimal affinity for the large neutral amino acid transporter, and that conformational restriction of the DL-2-NAM-7 molecule in benzonorbornane and indane analogs leads to 25- to 60-fold loss, respectively, in affinity. (C) 2010 Elsevier Ltd. All rights reserved.
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