Design and synthesis of novel derivatives of all-trans retinoic acid demonstrate the combined importance of acid moiety and conjugated double bonds in its binding to PMLRAR-α oncogene in acute promyelocytic leukemia

Carolina Schinke, Swati Goel, Tushar D. Bhagat, Li Zhou, Yongkai Mo, Robert Gallagher, George W. Kabalka, Leonidas C. Platanias, Amit K. Verma, Bhaskar Das

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The binding of all-trans retinoic acid (ATRA) to retinoid receptor-α (RAR-α) relieves transcriptional repression induced by the promyelocytic leukemiaretinoic acid receptor (PMLRAR) oncoprotein. The ATRA molecule contains a cyclohexenyl ring, a polyene chain containing conjugated double alkene bonds, and a terminal carboxyl group. To determine the contributions of these structural components of ATRA to its clinical efficacy, we synthesized three novel retinoids. These consisted of either a modified conjugated alkene backbone with an intact acid moiety (13a) or a modified conjugated alkene backbone and conversion of the acid group to either an ester (13b) or an aromatic amide (13c). Reporter assays demonstrated that compound 13a successfully relieved transcriptional repression by RAR-α, while 13b and 13c could not, demonstrating the critical role of the acid moiety in this binding. However, only ATRA was able to significantly inhibit the proliferation of APL cells while 13a, 13b, or 13c was not. Furthermore, only 13a led to partial non-significant differentiation of NB4 cells, demonstrating the importance of C9C10 double bonds in differentiation induced CD11 expression. Our results demonstrate that both the acid moiety and conjugated double bonds present in the ATRA molecule are important for its biological activity in APL and have important implications for the design of future novel retinoids.

Original languageEnglish (US)
Pages (from-to)1108-1114
Number of pages7
JournalLeukemia and Lymphoma
Volume51
Issue number6
DOIs
StatePublished - 2010

Fingerprint

Acute Promyelocytic Leukemia
Tretinoin
Oncogenes
Retinoids
Alkenes
Acids
Polyenes
Oncogene Proteins
Amides
Cell Differentiation
Esters
Cell Proliferation

Keywords

  • Acute promyelocytic leukemia (APL)
  • All-trans retinoic acid (ATRA)
  • Retinoids

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Design and synthesis of novel derivatives of all-trans retinoic acid demonstrate the combined importance of acid moiety and conjugated double bonds in its binding to PMLRAR-α oncogene in acute promyelocytic leukemia. / Schinke, Carolina; Goel, Swati; Bhagat, Tushar D.; Zhou, Li; Mo, Yongkai; Gallagher, Robert; Kabalka, George W.; Platanias, Leonidas C.; Verma, Amit K.; Das, Bhaskar.

In: Leukemia and Lymphoma, Vol. 51, No. 6, 2010, p. 1108-1114.

Research output: Contribution to journalArticle

Schinke, Carolina ; Goel, Swati ; Bhagat, Tushar D. ; Zhou, Li ; Mo, Yongkai ; Gallagher, Robert ; Kabalka, George W. ; Platanias, Leonidas C. ; Verma, Amit K. ; Das, Bhaskar. / Design and synthesis of novel derivatives of all-trans retinoic acid demonstrate the combined importance of acid moiety and conjugated double bonds in its binding to PMLRAR-α oncogene in acute promyelocytic leukemia. In: Leukemia and Lymphoma. 2010 ; Vol. 51, No. 6. pp. 1108-1114.
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