- Evolution of concise and flexible synthetic strategies for trichostatic acid and the potent histone deacetylase inhibitor trichostatin A
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(R)-(+)-Trichostatic acid and (R)-(+)-trichostatin A (TSA) are natural products that have attracted considerable attention in the field of epigenetic therapies. TSA in particular is a naturally occurring hydroxamic acid having potent activity as a histone deacetylase inhibitor (HDACi) and having significant potential for treatment of a myriad of genetically based diseases. Development of TSA and other trichostatic acid derivatives into useful small-molecule therapies has been hindered by the low natural abundance and high cost associated with these compounds. We report herein our collective efforts towards the development of concise and scalable routes for the synthesis of trichostatic acid and TSA in both racemic and enantioenriched forms. Three independent synthetic pathways were developed with varying degrees of efficiency and convergency. In the first synthesis, the key step was a vinylogous Horner-Wadsworth-Emmons condensation. A Marshall propargylation reaction was used as the key step in the second synthesis, and Pd-catalyzed α-alkenylation of a ketone zinc enolate by using various functionalized alkenyl or dienyl halides was developed for the third synthesis. The second pathway proved to be readily amenable to an enantioselective modification, and both the second and third pathways were straightforwardly adapted for the facile preparation of new analogues of trichostatic acid and TSA. Three synthetic strategies have been developed for trichostatic acid and trichostatin A. Each strategy has a different key bond-forming step; a vinylogous Horner-Wadsworth-Emmons condensation, a Marshall propargylation, and coupling of a ketone enolate with various alkenyl halides. Two of the syntheses were efficient and able to produce analogues. Two of the syntheses were enantioselective. Copyright
- Cosner, Casey C.,Bhaskara Reddy Iska, Vijaya,Chatterjee, Anamitra,Markiewicz, John T.,Corden, Steven J.,Loefstedt, Joakim,Ankner, Tobias,Richer, Joshua,Hulett, Tyler,Schauer, Douglas J.,Wiest, Olaf,Helquist, Paul
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p. 162 - 172
(2013/02/23)
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- SYNTHESIS OF HDAC INHIBITORS: TRICHOSTATIN A AND ANALOGUES
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Embodiments herein relate to histone deacetylaces (HDACs) and HDAC inhibitors, such as trichostatin A (TSA) and TSA analogues. Embodiments provide simple methods of synthesizing TSA and TSA analogues. These methods provide routes of synthesis of TSA and TSA analogues that enable the production of the HDAC inhibitors at lower cost and in greater quantities than previously were available.
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Page/Page column 4
(2011/10/12)
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- OCULAR HYPOTENSIVE AGENT COMPRISING COMPOUND CAPABLE OF INHIBITING HISTONE DEACETYLASE AS ACTIVE INGREDIENT
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An object of the present invention is to find a novel pharmacological effect of a compound having an HDAC inhibitory effect. The compound having an HDAC inhibitory effect of the invention has an excellent effect of cell morphological change on trabecular meshwork cells and/or effect of intraocular pressure reduction, and is therefore useful as a preventive and/or therapeutic agent for a disease considered to be associated with aqueous humor circulation and/or intraocular pressure, particularly as a preventive and/or therapeutic agent for glaucoma or ocular hypertension.
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- Processes and compounds for preparing histone deacetylase inhibitors and intermediates thereof
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Processes for preparing unsaturated esters useful as intermediates for HDAC inhibitors, by reacting an aldehyde or ketone with compounds having the following formula XX: wherein R8 is an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group; R9 and R10 are each independently hydrogen, an aliphatic group, an aromatic group, a combined aliphatic and aromatic group, or R10 forms a double bond with L2 or X3; R11 and R12 are each independently an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group; L2 is an aliphatic linking group, an aromatic linking group, or a combined aliphatic and aromatic linking group; A is P or As; L2 being selected so that the number of carbon atoms directly in the carbon chain between the R8 and R9 groups is at least 4, X1 and X2 are each independently O or a single bond, and X3 is O or forms R13 and double bond with R10, wherein R13 is an aliphatic group, an aromatic group, or a combined aliphatic and aromatic group.
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Page/Page column title page; 12
(2010/11/25)
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- Efficient, enantioselective organocatalytic synthesis of trichostatin A
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An efficient, highly stereocontrolled total synthesis of trichostatin A (1) has been achieved in 9 steps with 17.4% overall yield and >99% optical purity from readily available achiral starting materials. The key features of this synthesis include the L-proline-promoted, highly enantioselective cross-aldol reaction as a crucial step for the construction of the C-6 chiral center and the minimization of racemization by final step oxidation of the OH group to a ketone at position 7.
- Zhang, Shilei,Duan, Wenhu,Wang, Wei
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p. 1228 - 1234
(2007/10/03)
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- Anti-cocaine catalytic antibody
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Disclosed are catalytic antibodies and polypeptides capable of degrading cocaine. Said catalytic antibodies and polypeptides are characterized by the amino acid sequence of their complementary determining regions and framework regions. The present invention also discloses a pharmaceutical composition and a method for decreasing the concentration and a method for decreasing the concentration of cocaine of a subject. Finally, the invention discloses pharmaceutical compositions and methods for treating cocaine overdose and addiction in subjects.
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- SYNTHESIS OF TRICHOSTATIN A, A POTENT DIFFERENTIATION INDUCER OF FRIEND LEUKEMIC CELLS, AND ITS ANTIPODE
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Both the enantiomers of trichostatin acid (1, 98percent e.e.) and trichostatin A (2, 93percent e.e.) were synthesized employing methyl (R)- or (S)-3-hydroxy-2-methyl-propanoate as a starting material.
- Mori, Kenji,Koseki, Koshi
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p. 6013 - 6020
(2007/10/02)
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