The objective of the proposed research is to synthesize acyl, carbamyl and carbonate derivatives of demethypenclomedine (DM-PEN), the antitumor active, non-neurotoxic metabolite of penclomedine (PEN), a clinically- evaluated drug whose development was terminated because of clinical neurotoxicity. The three series of novel agents will be evaluated in a human breast tumor xenograft (MX-1) and in a human CNS tumor xenograft (U251) implanted subcutaneously (sc) or intracerebrally (ic), respectively, to provide data for selection of a clinical candidate for proposed further development in Phase II of this fast track application. PEN, DM-PEN and the acetyl derivative of DM-PEN were all active against ic-implanted MX-1 tumor, and PEN and DM-PEN were active against a series of human brain tumor xenografts (gliomas, ependymonas) implanted sc. The primary goal of this project is to evaluate derivatives of DM-PEN in the clinical treatment of brain tumors since the former and its acetyl derivative have been shown to be active against ic-implanted MX-1 tumor, and PEN and DM-PEN were active against a series of human gliomas and ependymomas implanted sc.

Proposed Commercial Applications

The potential commercial application of this research is the synthesis of a novel derivative of DM-PEN that may be of clinical benefit for the treatment of brain tumors or other types of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44CA085021-03
Application #
6514358
Study Section
Special Emphasis Panel (ZRG1-SSS-1 (02))
Program Officer
Lees, Robert G
Project Start
2000-05-01
Project End
2004-04-30
Budget Start
2002-06-14
Budget End
2003-04-30
Support Year
3
Fiscal Year
2002
Total Cost
$122,592
Indirect Cost
Name
Dekk-Tec, Inc.
Department
Type
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70124
Strong, Michael J; Rosenlof, Trevor; Padmanabha, Siddhartha et al. (2015) Treatment of recurrent metastatic uterine leiomyosarcoma of the spine: a multimodality approach using resection, radiosurgery, and chemotherapy. J Neurosurg Spine 23:607-612
Morgan, Lee Roy; Struck, Robert F; Waud, William R et al. (2009) Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents. Cancer Chemother Pharmacol 64:829-35
Tiwari, Anita; Riordan, James M; Waud, William R et al. (2002) Synthesis and antitumor activity of several new analogues of penclomedine and its metabolites. J Med Chem 45:1079-85
Struck, R F; Tiwari, A; Friedman, H S et al. (2001) Acyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine. Cancer Chemother Pharmacol 48:47-52