TY - JOUR
T1 - 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
AU - Schinke, Carolina
AU - Goel, Swati
AU - Bhagat, Tushar D.
AU - Zhou, Li
AU - Mo, Yongkai
AU - Gallagher, Robert
AU - Kabalka, George W.
AU - Platanias, Leonidas C.
AU - Verma, Amit
AU - Das, Bhaskar
N1 - Funding Information:
Declaration of interest: This study was supported by NIH 1R01HL082946-01, Gabrielle Angel Foundation, Hershaft Family Foundation, and American Cancer Society grants (A.V.); Immunooncology Training Program T32 CA009173 grant and MDS foundation award (L.Z.); and NIH grant CA121192 and a Merit Review grant from the Department of Veterans Affairs (L.C.P.).
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Acute promyelocytic leukemia (APL)
KW - All-trans retinoic acid (ATRA)
KW - Retinoids
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U2 - 10.3109/10428191003786766
DO - 10.3109/10428191003786766
M3 - Article
C2 - 20536349
AN - SCOPUS:77953530664
SN - 1042-8194
VL - 51
SP - 1108
EP - 1114
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 6
ER -