Design and synthesis of 4-HPR derivatives for rhabdoid tumors

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis that arise due to loss of the hSNF5/INI1 tumor suppressor. Molecular studies indicate that cyclin D1, a downstream effector of INI1 is up regulated in RT, and is essential for this tumor formation. Previously we demonstrated that 4-HPR, a synthetic retinoid that targets Cyclin D1, is a potential chemotherapeutic agent for RT. To facilitate further chemical development of this retinoid, and to determine its active moiety, we synthesized small chemical libraries of 4-HPR and tested their cytotoxic effect on RT cells. We synthesized 4-HPR (1) and the derivatives (5a-5n) starting from retinoic acid. First, retinoic acid was converted to acid chloride derivatives, then in the presence of DMF, base, and aniline derivatives, we synthesized the corresponding 4-hydroxy phenyl amine derivatives (5a-5n). This procedure gave 70-90% yield. Then, the 4-HPR derivatives were tested for their ability to inhibit RT cells using an in vitro cell survival assay. We found that the 4-hydroxy group at para-position is essential for cytotoxic activity against RT cells. Furthermore, we identified a few derivatives of 4-HPR with higher cytotoxic potencies than 4-HPR. In addition, we demonstrate that either chloro, fluoro or iodo derivatives at meta-position of phenyl ring retain the cytotoxic activity. Interestingly, substitution of iodo-moiety at meta-position (5j) substantially increased the efficacy (IC50 ∼ 3 μM, Fig. 1D). These results indicate that chemical modification of 4-HPR may result in derivatives with increased therapeutic potential for RTs and that halogen substituted 4-HPR that retain the activity can be synthesized for further therapeutic and diagnostic use.

Original languageEnglish (US)
Pages (from-to)3805-3808
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number13
DOIs
StatePublished - Jul 1 2008

Fingerprint

Fenretinide
Rhabdoid Tumor
Tumors
Derivatives
Cyclin D1
Retinoids
Tretinoin
Small Molecule Libraries
Neoplasms
Halogens
Pediatrics
Therapeutic Uses
Chemical modification
Inhibitory Concentration 50
Amines
Chlorides
Cell Survival
Assays
Substitution reactions
Cells

Keywords

  • 4-HPR
  • Cyclin D1
  • Rhabdoid tumor

ASJC Scopus subject areas

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

Cite this

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 13, 01.07.2008, p. 3805-3808.

Research output: Contribution to journalArticle

Das, Bhaskar C. ; Smith, Melissa E. ; Kalpana, Ganjam V. / Design and synthesis of 4-HPR derivatives for rhabdoid tumors. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 13. pp. 3805-3808.
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