- Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers
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(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.
- Atigadda, Venkatram R.,Xia, Gang,Deshpande, Anil,Wu, Lizhi,Kedishvili, Natalia,Smith, Craig D.,Krontiras, Helen,Bland, Kirby I.,Grubbs, Clinton J.,Brouillette, Wayne J.,Muccio, Donald D.
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p. 7763 - 7774
(2015/10/20)
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- METHOD FOR MANUFACTURING PHOSPHONOCROTONIC ACID DERIVATIVE
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Provided is a method of manufacturing a high quality phosphonocrotonic acid derivative. The present invention is a method of manufacturing a compound represented by the following Formula (3) by reacting a compound represented by the following Formula (1) with a compound represented by the following Formula (2), which comprises a treatment process using an acid or base. [in the formula, R1 represents a C1-6 linear or branched alkyl group that may be substituted by a C6-10 aryl group, a C2-6 linear or branched alkenyl group that may be substituted by a C6-10 aryl group, a C2-6 linear or branched alkynyl group that may be substituted by a C6-10 aryl group, or a C6-10 aryl group, R2 represents a hydrogen atom, or a C1-6 linear or branched alkyl group that may be substituted by a C6-10 aryl group, R3 represents a C1-6 linear or branched alkyl group, a C6-10 aryl group, or a halogen atom, and X represents a halogen atom, and multiple R1s may be the same or different].
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Paragraph 0143-0145
(2014/03/24)
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