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 snythesize a focused set of SAP and SDAP analogs. We have found that the synthesis of these compounds can he prepared in a shorter sequence and in better yield using our new sythetic scheme. 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. Our most recent compounds are based on the thiazolidinones (2) and the thiazolidine (3) analogs. We have utilized new synthetic schemes for these new compounds and have 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 alphatic chain is optimum at C-14 while with the new compounds it appears to be C-l8 on DU-145 and PC-3 cell lines. In a few instances we have discovered a new set of 2-arylthiazolidine-4-carboxylic acid amides that show sub micromolar anticancer activity in the cell lines described above. We have designated this set of compounds as 2-arylthiazolidine-4-caroxylic acid amides (ATCAAs).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2005
- Accession Number
- ADA447581
Entities
People
- Duane D Miller
Organizations
- University of Tennessee