TY - JOUR
T1 - Design and synthesis of 4-HPR derivatives for rhabdoid tumors
AU - Das, Bhaskar C.
AU - Smith, Melissa E.
AU - Kalpana, Ganjam V.
N1 - Funding Information:
These studies were supported by funding from American Cancer Society (RSG CCG-10493) and Philanthropic funding (Amini foundation) to G.V.K.; Institutional training Grant (NIGMS T32 GM 007491) to M.E.S.; and AECOM start up fund to B.D. G.V.K. is a Mark Trauner faculty scholar and a recipient of the Irma T. Hirschl Career Scientist Award.
PY - 2008/7/1
Y1 - 2008/7/1
N2 - 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.
AB - 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.
KW - 4-HPR
KW - Cyclin D1
KW - Rhabdoid tumor
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U2 - 10.1016/j.bmcl.2008.05.021
DO - 10.1016/j.bmcl.2008.05.021
M3 - Article
C2 - 18515102
AN - SCOPUS:44849137194
SN - 0960-894X
VL - 18
SP - 3805
EP - 3808
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 13
ER -