Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors

Bhaskar C. Das, Melissa E. Smith, Ganjam V. Kalpana

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Rhabdoid tumors (RTs) are an extremely aggressive pediatric malignancy that results from loss of the INI1/hSNF5 tumor suppressor gene. Loss of INI1 results in aberrant expression of Cyclin D1, which supports rhabdoid tumorigenesis and survival. 4-HPR, a synthetic retinoid that down-modulates Cyclin D1, has shown promise in treating various tumors including RTs. In this study, we have generated a chemical library of peptidomimetic derivatives of 4-HPR in an attempt to create a more biologically active compound for use as a therapeutic agent against RTs and other tumors. We have synthesized novel peptidomimetic compound by substituting alkene backbone with a ring structure that retains the biological activity in cell culture models of rhabdoid tumors. We further identified derivative of peptidomimetic compound (11d, IC50 ∼ 3 μM) with approximately five times higher potency than 4-HPR (1, IC50 ∼ 15 μM) based on a survival assay against rhabdoid tumor cells. These studies indicate that peptidomimetic derivatives that retain the cytotoxic activity are promising novel chemotherapeutic agents against RTs and other tumors.

Original languageEnglish (US)
Pages (from-to)4177-4180
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number14
DOIs
StatePublished - Jul 15 2008

Fingerprint

Fenretinide
Rhabdoid Tumor
Peptidomimetics
Tumors
Derivatives
Cyclin D1
Inhibitory Concentration 50
Neoplasms
Small Molecule Libraries
Retinoids
Alkenes
Tumor Suppressor Genes
Carcinogenesis
Cell Culture Techniques
Pediatrics
Bioactivity
Cell culture
Assays
Genes

Keywords

  • 4-HPR
  • Cyclin D1
  • Retinoid
  • Rhabdoid tumor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors. / Das, Bhaskar C.; Smith, Melissa E.; Kalpana, Ganjam V.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 14, 15.07.2008, p. 4177-4180.

Research output: Contribution to journalArticle

@article{d69568394cb14b928c04f5998beeb686,
title = "Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors",
abstract = "Rhabdoid tumors (RTs) are an extremely aggressive pediatric malignancy that results from loss of the INI1/hSNF5 tumor suppressor gene. Loss of INI1 results in aberrant expression of Cyclin D1, which supports rhabdoid tumorigenesis and survival. 4-HPR, a synthetic retinoid that down-modulates Cyclin D1, has shown promise in treating various tumors including RTs. In this study, we have generated a chemical library of peptidomimetic derivatives of 4-HPR in an attempt to create a more biologically active compound for use as a therapeutic agent against RTs and other tumors. We have synthesized novel peptidomimetic compound by substituting alkene backbone with a ring structure that retains the biological activity in cell culture models of rhabdoid tumors. We further identified derivative of peptidomimetic compound (11d, IC50 ∼ 3 μM) with approximately five times higher potency than 4-HPR (1, IC50 ∼ 15 μM) based on a survival assay against rhabdoid tumor cells. These studies indicate that peptidomimetic derivatives that retain the cytotoxic activity are promising novel chemotherapeutic agents against RTs and other tumors.",
keywords = "4-HPR, Cyclin D1, Retinoid, Rhabdoid tumor",
author = "Das, {Bhaskar C.} and Smith, {Melissa E.} and Kalpana, {Ganjam V.}",
year = "2008",
month = "7",
day = "15",
doi = "10.1016/j.bmcl.2008.05.097",
language = "English (US)",
volume = "18",
pages = "4177--4180",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "14",

}

TY - JOUR

T1 - Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors

AU - Das, Bhaskar C.

AU - Smith, Melissa E.

AU - Kalpana, Ganjam V.

PY - 2008/7/15

Y1 - 2008/7/15

N2 - Rhabdoid tumors (RTs) are an extremely aggressive pediatric malignancy that results from loss of the INI1/hSNF5 tumor suppressor gene. Loss of INI1 results in aberrant expression of Cyclin D1, which supports rhabdoid tumorigenesis and survival. 4-HPR, a synthetic retinoid that down-modulates Cyclin D1, has shown promise in treating various tumors including RTs. In this study, we have generated a chemical library of peptidomimetic derivatives of 4-HPR in an attempt to create a more biologically active compound for use as a therapeutic agent against RTs and other tumors. We have synthesized novel peptidomimetic compound by substituting alkene backbone with a ring structure that retains the biological activity in cell culture models of rhabdoid tumors. We further identified derivative of peptidomimetic compound (11d, IC50 ∼ 3 μM) with approximately five times higher potency than 4-HPR (1, IC50 ∼ 15 μM) based on a survival assay against rhabdoid tumor cells. These studies indicate that peptidomimetic derivatives that retain the cytotoxic activity are promising novel chemotherapeutic agents against RTs and other tumors.

AB - Rhabdoid tumors (RTs) are an extremely aggressive pediatric malignancy that results from loss of the INI1/hSNF5 tumor suppressor gene. Loss of INI1 results in aberrant expression of Cyclin D1, which supports rhabdoid tumorigenesis and survival. 4-HPR, a synthetic retinoid that down-modulates Cyclin D1, has shown promise in treating various tumors including RTs. In this study, we have generated a chemical library of peptidomimetic derivatives of 4-HPR in an attempt to create a more biologically active compound for use as a therapeutic agent against RTs and other tumors. We have synthesized novel peptidomimetic compound by substituting alkene backbone with a ring structure that retains the biological activity in cell culture models of rhabdoid tumors. We further identified derivative of peptidomimetic compound (11d, IC50 ∼ 3 μM) with approximately five times higher potency than 4-HPR (1, IC50 ∼ 15 μM) based on a survival assay against rhabdoid tumor cells. These studies indicate that peptidomimetic derivatives that retain the cytotoxic activity are promising novel chemotherapeutic agents against RTs and other tumors.

KW - 4-HPR

KW - Cyclin D1

KW - Retinoid

KW - Rhabdoid tumor

UR - http://www.scopus.com/inward/record.url?scp=47149102333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=47149102333&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2008.05.097

DO - 10.1016/j.bmcl.2008.05.097

M3 - Article

VL - 18

SP - 4177

EP - 4180

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 14

ER -