Biological evaluation of cryptophycin 52 fragment A analogues: effect of the multidrug resistance ATP binding cassette transporters on antitumor activity.
Cryptophycin 52 (LY355703) is a potent antiproliferative analogue of the marine natural product cryptophycin 1. It has been shown to have a broad range of antitumor activity against human tumor xenografts and murine tumors including tumors resistant to Taxol and Adriamycin. Its mechanism of action involves arresting cells in the G2-M phase of the cell cycle by binding to microtubules and suppressing their dynamics. This 16-membered depsipeptide can be divided into four major subunits or fragments (A-D). We reported previously on our synthetic efforts around fragment A and discovered that this region of the molecule was amenable to a structure-activity relationship study that resulted in highly active antiproliferative agents when evaluated in the CEM leukemia cell line. The synthetic analogues were designed to help improve the efficacy and aqueous solubility of the parent compound; therefore, many in this series contained ionizable functional groups such as an amino group, a hydroxy group, or a carboxylic acid. Although several of these analogues showed improvements in potency over cryptophycin 52 in drug-sensitive tumor xenograft models, many lost their activity against Adriamycin-resistant tumor lines. It was discovered on additional in vitro evaluation that these analogues became good substrates of the multidrug resistance transporter P-glycoprotein.
Al-Awar
Rima S
RS
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Al-awar_Rima_S@Lilly.com
Corbett
Thomas H
TH
Ray
James E
JE
Polin
Lisa
L
Kennedy
Joseph H
JH
Wagner
Margaret M
MM
Williams
Daniel C
DC
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; C114033:cryptophycin 52