Selective Cytotoxic Phospholipids for Prostate Cancer
Abstract
The goal of this project is to build upon our discovery of two phospholipid lead compounds, serine amide phosphate (SAP) and serine diamide phosphate (SDAP), that have been shown to he selective in their cytotoxic actions in PC-3 and DU-145 prostate caner cells respectively. These agents were originally designed as part of a series of compounds to inhibit lysophosphatidic acid (LPA), a phospholid growth factor. After discovering the antiproliferation activity of SAP and SDAP in prostate cancer cell lines we propose to synthesize a focused set of SAP and SDAP analog We have found that the synthesis of these compounds can be prepared in a shorter sequence and in better yield our new synthetic process outlined in Scheme 3. We have tested for the affinity of the synthesized compounds in PC-3, DU-145, and LNCaP cell lines as we proposed earlier. In addition to these cell lines we have also tested for affinity of these compounds in two additional PPC-1 and TSU cell lines (data shown in Table 1). These new analogs have provided valuable insight as to the importance of chirality, lipid solubility, spatial orientation, and important functional groups of the pharamcophore and for the optimization of the antiproliferative actions of this new set of drugs. One of the key factors is that the Serine Amides and the N-BOC-Serine Amide alcohol series which lack a phosphate show higher activity with longer aliphatic chains. We have not found the optimum length of the aliphatic chain in these two series. In earlier studies it appeared in our Serine Amide Phosphate (SAP) series that the aliphatic chain is optimum at C-14 on DU-145 and PC-3 cell lines. However, the pure isomers do not show any large differences and the activity is different from earlier tests run on the racemic mixtures. We have observed that one of the isomers of the SAP series with the aliphatic chain being C-18 does have moderate activity against all of the cancer cell lines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2002
- Accession Number
- ADA412138
Entities
People
- Duane D Miller
Organizations
- University of Tennessee