0000000000143150
AUTHOR
Eva Falomir
Stereoselective Synthesis of Microcarpalide
The first total synthesis of the naturally occurring nonenolide, microcarpalide, is described. The key step in the synthesis was the ring-closing metathesis of a dienic ester prepared in turn by coupling an acid and an alcohol stereoselectively synthesized from (S,S)-tartaric acid and (R)-glycidol, respectively. [structure: see text]
Synthesis and biological evaluation of cyclic derivatives of combretastatin A-4 containing group 14 elements
Several tricyclic compounds inspired by the structure of combretastatin A-4 and bearing group 14 elements have been synthesized by homocoupling lithiated aryl fragments followed by ring-closing metathesis. These tricyclic compounds and their diolefin precursors were evaluated for their antiproliferative action on the tumor cell lines HT-29, MCF-7, HeLa and A-549 and on the non-tumor cell line HEK-293. In addition, their effects on the cell cycle were also measured. The tricyclic compounds show antiproliferative activity similar to that of combretastatin A-4, even though they are not so active in arresting the cell cycle. However, some diolefin precursors are able to cause accumulation of ce…
Stereoselective synthesis of the naturally occurring 2-pyranone dodoneine
The first total synthesis of the naturally occurring dihydropyranone dodoneine is reported. Asymmetric allylation reactions were used for the stereoselective generation of the two stereogenic centers. The pyranone ring was created by ring-closing metathesis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
ChemInform Abstract: Stereoselective Synthesis of syn-α-Methyl-β-hydroxy Esters.
Abstract Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2- syn /1,3- syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O -formylated syn -α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.
Aldol Reactions with Erythrulose Derivatives: Stereoselective Synthesis of Differentially Protected syn -α,β-Dihydroxy Esters
Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-α,β-dihydroxy esters with either hydroxyl group differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate equivalent.
Boron aldol additions with erythrulose derivatives: dependence of stereoselectivity on the type of protecting group
Abstract Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.
ChemInform Abstract: Aldol Reactions with Erythrulose Derivatives: Stereoselective Synthesis of Differentially Protected syn-α,β-Dihydroxy Esters.
Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-α,β-dihydroxy esters with either hydroxyl group differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate equivalent.
Arylpyridines, arylpyrimidines and related compounds as potential modulator agents of the VEGF, hTERT and c-Myc oncogenes.
Twenty-four derivatives structurally related to honokiol have been synthesized and biologically evaluated. IC50 values were determined towards the HT-29, MCF-7 and HEK-293 cell lines. Some of these derivatives exhibited comparable or lower IC50 values than honokiol towards the HT-29 and MCF-7 cell lines or else higher selectivity indexes than the natural product. Twelve selected derivatives were evaluated for their ability to inhibit the expression of the VEGFA, hTERT and c-Myc genes and also to inhibit the production of total c-Myc protein and the secretion of the VEGF protein. One of the most promising compounds, 3-(2,4-dimethoxyphenyl)pyridine, may be a good candidate for further studies…
Stereoselective synthesis and determination of the cytotoxic properties of spicigerolide and three of its stereoisomers.
Stereoselective syntheses of the naturally occurring, cytotoxic lactone spicigerolide and three nonnatural stereoisomers thereof are described. The commercially available sugar l-rhamnose was in all cases the chiral starting material. Key steps in each of these syntheses were asymmetric Brown allylations and ring-closing metatheses. The cytotoxic activities of the four lactones against a range of tumoral lines were then determined.
Stereoselective synthesis of syn-α-methyl-β-hydroxy esters
Abstract Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2- syn /1,3- syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O -formylated syn -α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.
ChemInform Abstract: Boron Aldol Additions with Erythrulose Derivatives: Dependence of Stereoselectivity on the Type of Protecting Group.
Abstract Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.
Synthesis and Biological Evaluation of α-Tubulin-Binding Pironetin Analogues with Enhanced Lipophilicity
Financial support has been granted to M. C. by the Spanish Ministry of Education and Science (project numbers CTQ2008-02800 and CTQ2011-27560), by the Conselleria d'Empresa, Universitat i Ciencia de la Generalitat Valenciana (ACOMP09/113) and by the BANCAJA-UJI Foundation (P1-1B2002-06, P1-1B-2008-14 and PI-1B2011-37). The biological work has been supported in part by grants from the Spanish Ministry of Education and Science (grant number BIO2010-16351) and from the Comunidad de Madrid (grant number S2010/BMD-2457 BIPEDD2-CM), both to J. F. D. We further thank the Matadero Municipal Vicente de Lucas in Segovia for providing the calf brains, which were the source of tubulin.
Stereoselective Syntheses of Naturally Occurring 5,6-Dihydropyran-2-ones
The published syntheses of naturally occurring 5,6-dihydropyran-2-ones are reviewed. Figure options Download full-size image Download as PowerPoint slide
Synthesis of Combretastatin A-4 and 3′-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression
Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3&prime
Enantioselective synthesis and absolute configurations of aculeatins A, B, D, and 6-epi-aculeatin D
The three naturally occurring, bioactive spiroacetals aculeatins A, B, and D, as well as the non-natural 6-epi-aculeatin D have been synthesized for the first time in enantiopure form using an asymmetric allylation as the only chirality source. A further key step was a stereoselective aldol reaction with remote induction. The absolute configurations of the natural products have been established and an erroneous structural assignment has been corrected.
Synthesis of honokiol analogues and evaluation of their modulating action on VEGF protein secretion and telomerase-related gene expressions
A group of 36 biphenyl derivatives structurally related to honokiol were synthesized by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT, and c-Myc genes; the two latter involved in the activation of telomerase in tumoral cells. Some of the synthetized derivatives showed promising pharmacological features as they exhibited IC50 values in low micromolar range, good therapeutic margins, and a multiple mode of action on tumor cells based on the inhibition of VEGF and, at the same time, of the…
Design and synthesis of pironetin analogue/colchicine hybrids and study of their cytotoxic activity and mechanisms of interaction with tubulin
We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an ester-amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated. Relations between the structure and activity are discussed. Since the spacer is not long enough to permit a simultaneous binding of the hybrid molecules to the colchicine and pironetin sites on tubulin, a further feature investigated was whether these molecules would interact with the latter through the pironetin end (irreversible covalent binding) or through the colchicine end (…
Synthesis of N-acyl Derivatives of Aminocombretastatin A-4 and Study of their Interaction with Tubulin and Downregulation of c-Myc.
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