- Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure
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Aqueous solubility is a key requirement for many functional molecules, e. g., drug candidates. Decrease of the partition coefficient (log P) by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical strategy for improving aqueous solubility. We have been investigating alternative strategies for improving the aqueous solubility of pharmaceutical compounds by disrupting intermolecular interactions. Here, we show that introducing a bend into the molecular structure of retinoic acid receptor (RAR) agonists by changing the substitution pattern from para to meta or ortho dramatically enhances aqueous solubility by up to 890-fold. We found that meta analogs exhibit similar hydrophobicity to the parent para compound, and have lower melting points, supporting the idea that the increase of aqueous solubility was due to decreased intermolecular interactions in the solid state as a result of the structural changes.
- Hiramatsu, Michiaki,Ichikawa, Yuki,Tomoshige, Shusuke,Makishima, Makoto,Muranaka, Atsuya,Uchiyama, Masanobu,Yamaguchi, Takao,Hashimoto, Yuichi,Ishikawa, Minoru
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- Liposomal formulation of retinoids designed for enzyme triggered release
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The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A2 IIA and have potential in liposomal drug delivery targeting tumors. We have synthesized four different retinoid phospholipid prodrugs and shown that they form particles in the liposome size region with average diameters of 94-118 nm. Upon subjection to phospholipase A2, the lipid prodrugs were hydrolyzed, releasing cytotoxic retinoids and lysolipids. The formulated lipid prodrugs displayed IC50 values in the range of 3-19 μM toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A 2, while no significant cell death was observed in the absence of the enzyme.
- Pedersen, Palle J.,Adolph, Sidsel K.,Subramanian, Arun K.,Arouri, Ahmad,Andresen, Thomas L.,Mouritsen, Ole G.,Madsen, Robert,Madsen, Mogens W.,Peters, Günther H.,Clausen, Mads H.
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supporting information; experimental part
p. 3782 - 3792
(2010/08/06)
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- COMPOUNDS WITH ACTIVITY AT RETINOIC ACID RECEPTORS
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Disclosed herein are novel compounds with activity at RARβ 2 receptors. Further disclosed are the use of such compounds for treatment of or to alleviate symptoms of cancer, neurological disorders such as memory deficits and schizophrenia, neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, inflammatory disorders such as psoriasis and rheumatoid arthritis, eye disorders and depression.
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Page/Page column 59
(2008/06/13)
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