SYNTHESIS OF PRO-APOPTOTIC ANALOGS OF GOSSYPOL

 

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Gossypol, the main pigment of cotton seed, is a synthetic target of choice for organic chemists because of its multiple pharmacological applications: male oral contraceptive, treatment of bronchitis, total inhibitor of the replication of HIV 1, in vitro antiviral activity against herpes type 2 virus, influenza virus, anticancer treatment. These are its anti-cancer properties which generate in the recent time the most interest. Recent work (≥ 2000) shows that gossypol is a very good ligand of the protein family Bcl-2 which is a major point of control for regulation of apoptosis. This work provides new substance analogues of gossypol. The original chemical pathways developed allow the replacement of the isopropyl and methyl groups of gossypol by groups structurally similar (ethyl, n-propyl, n-butyl, etc.).
The first general method of preparation of veratric acid derivatives substituted in position C2 by ortho-lithiation was developed. The commercially available veratric acid is metalated effectively in the position C2 by LTMP. 3,4-Dimethoxy-2-methylbenzoic acids obtained by this reaction is in turn metalated laterally by LDA. It was also demonstrated that the position C3 of 8-isopropyl-4,6,7-trimethoxynaphtalen-2-carboxylic acid is metalated by LTMP. When C8 is occupied by a methyl, metalation takes place exclusively in this position with LTMP. 2.3-Dimethoxybenzoic acids substituted in the position C2 by various groups lead after Stobbe condensation to naphthalenic compounds themselves precursors — after oxidative dimerization — to the binaphthalene backbone of gossypol and apogossypol. Racemic 5,5′-didesisopropyl-5,5′-dimethylgossypol and 5-desisopropyl-5-methylhemigossypol were thus prepared according to these methods.

See:

“Racemic total synthesis of structural analogues of gossypol and apogossypol involving reactions of aromatic metalation”

J. Mortier*, A.-S. Castanet, N. T. T. Chau Gossypol and apogossypol derivatives, preparation thereof and use thereof” US Patent US8455540B2 (2013)

T. T. Le, N. T. T. Chau, T. T. Nguyen, J. Brien, T. T. Thai, A. Nourry, A.-S. Castanet, K. P. Phung Nguyen, J. Mortier*[Université du Maine]Evidence for a Trianion Intermediate in the Metalation of 4-Hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic Acid. Methodology and Application to Racemic 5,5’-Didesisopropyl-5,5’-dialkylapogossypol Derivatives“  J. Org. Chem. 201176, 601  Supporting Information

The metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (8) affording trianion 6 is presented and applied to the regioselective efficient construction of a series of 5,5′-didesisopropyl-5,5′-dialkylapogossypol derivatives 3 that are potent pan-active inhibitors of antiapoptotic Bcl-2 family proteins.

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J. Mortier*, A.-S. Castanet, N. T. T. Chau [Université du Maine]Gossypol and apogossypol derivatives of general formula (1), preparation thereof and use thereof.” US Patent US20100331398A1 (2010)

J. Mortier*, A.-S. Castanet, N. T. T. Chau [Université du Maine]Gossypol and Apogossypol Derivatives, Preparation Thereof and Uses ThereofWorld Patent WO2009080949, 2009

N. T. T. Chau, T.-H. Nguyen, A.-S. Castanet, K. P. P. Nguyen, and J. Mortier*[Université du Maine] Competition of Substituents for Ortho Direction of Metalation of Veratric AcidTetrahedron 2008, 64, 10552.

J. Mortier*, A.-S. Castanet, N. T. T. Chau [Université du Maine]Dérivés du gossypol et de l’apogossypol, leurs préparations et leurs applicationsFrench Patent FR 0708518 (2007)

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