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Structure−Activity Relationship Studies for the Peptide Portion of the Bladder Epithelial Cell Antiproliferative Factor from Interstitial Cystitis Patients

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Piotr Kaczmarek^†, Susan K. Keay*^‡^§, Gillian M. Tocci^†, Kristopher R. Koch^‡, Chen-Ou Zhang^‡, Joseph J. Barchi, Jr., David Grkovic^‡, Li Guo^‡ and Christopher J. Michejda^†

Molecular Aspects of Drug Design Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, Research Service, Veterans Administration Maryland Health Care System, Baltimore, Maryland 21201, and Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702

J. Med. Chem., 2008, 51 (19), pp 5974–5983

DOI: 10.1021/jm8002763

Publication Date (Web): September 13, 2008

* To whom correspondence should be addressed. Address: Research Division, Room 3B-184, Baltimore Veterans Affairs Medical Center, 10 North Greene Street, Baltimore, MD 21201. Phone: 410-605-7000, extension 6450. Fax: 410-605-7837. E-mail: skeay@medicine.umaryland.edu., †

Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute at Frederick.

, ‡

University of Maryland School of Medicine.

, §

Veterans Administration Maryland Health Care System.

Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick.

Section:

Pharmacology

Abstract

We performed comprehensive structure−activity relationship (SAR) studies on the peptide portion of antiproliferative factor (APF), a sialylated frizzled-8 related glycopeptide that inhibits normal bladder epithelial and urothelial carcinoma cell proliferation. Glycopeptide derivatives were synthesized by solid-phase methods using standard Fmoc chemistry and purified by RP-HPLC; all intermediate and final products were verified by HPLC-MS and NMR analyses. Antiproliferative activity of each derivative was determined by inhibition of ³H-thymidine incorporation in primary normal human bladder epithelial cells. Structural components of the peptide segment of APF that proved to be important for biological activity included the presence of at least eight of the nine N-terminal amino acids, a negative charge in the C-terminal amino acid, a free amino group at the N-terminus, maintenance of a specific amino acid sequence in the C-terminal tail, and trans conformation for the peptide bonds. These data provide critical guidelines for optimization of structure in design of APF analogues as potential therapeutic agents.

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This article has been cited by 1 ACS Journal articles (1 most recent appear below).

Structure−Activity Studies on Antiproliferative Factor (APF) Glycooctapeptide Derivatives
Piotr Kaczmarek, Gillian M. Tocci, Susan K. Keay, Kristie M. Adams, Chen-Ou Zhang, Kristopher R. Koch, David Grkovic, Li Guo, Christopher J. Michejda, and Joseph J. Barchi, Jr.
ACS Medicinal Chemistry Letters2010 1 (8), 390-394
- Structure−Activity Studies on Antiproliferative Factor (APF) Glycooctapeptide Derivatives
  Piotr Kaczmarek, Gillian M. Tocci, Susan K. Keay, Kristie M. Adams, Chen-Ou Zhang, Kristopher R. Koch, David Grkovic, Li Guo, Christopher J. Michejda, and Joseph J. Barchi, Jr.
  ACS Medicinal Chemistry Letters2010 1 (8), 390-394
  Antiproliferative factor (APF), a sialylated glycopeptide secreted by explanted bladder epithelial cells from interstitial cystitis/painful bladder syndrome (IC/PBS) patients, and its unsialylated analogue (as-APF) significantly decrease proliferation of ...
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