New <i>para</i>–<i>para</i> Stilbenophanes: Synthesis by McMurry Coupling, Conformational Analysis and Inhibition of Tubulin Polymerisation

Álvarez, Raquel; López, Vilmarí; Medarde, Manuel; Peláez, Rafael

doi:10.1002/chem.201002869

Cited by 8 publications

(7 citation statements)

References 102 publications

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“…We have recently prepared a new family of macrocyclic combretastatin analogues that are unable to become converted to the trans isomers, but they display reduced potency, probably owing to steric reasons . With the same aims, but following a different strategy, we have also recently described a new family of combretastatin isomers, which we have called isocombretastatins, and structurally related ketones and oximes, which are potent inhibitors of tubulin polymerization and cytotoxic compounds .…”

Section: Introductionmentioning

confidence: 99%

Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins

et al. 2013

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Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.

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Section: Introductionmentioning

confidence: 99%

Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins

et al. 2013

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“…Combretastatins have attracted great attention due to their advance into clinical trials as antitumor compounds . Stimulated by the anticancer activity of combretastatins, Álvarez et al . prepared indole‐based macrocycles using the McMurry methodology to study the conformational implications on the tubulin polymerization inhibitory activity.…”

Section: Anticancer Activities Of Indole‐based Macrocyclesmentioning

confidence: 99%

Medicinal applications of (benz)imidazole‐ and indole‐based macrocycles

Patil

2017

Chem Biol Drug Des

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Macrocyclic chemistry is one of the emerging research areas in the chemical science.Macrocyclic compounds continue to attract significant attention due to their numerous possible applications particularly in the areas like biology, catalysis and industry.This review article summarizes the developments and advances in synthesis and medicinal applications of macrocyclic compounds derived from (benz)imidazoleand indole-based heterocycles. Important medicinal applications of (benz)imidazoleand indole-based macrocycles include antimicrobial and anticancer activities. The representative lead compounds in each series of macromolecules have been discussed. All these initial lead breakthroughs help validate the great potential of (benz) imidazole-and indole-based macrocyclic compounds as a class of effective medicinal agents. S P E C I A L I S S U E A R T I C L E Medicinal applications of (benz)imidazole-and indole-based macrocyclesA macrocycle is a compound that contains a cyclic structure of at least twelve or more atoms. Macrocyclic compounds are natural or synthetic polydentate compounds, containing their donor atoms either incorporated in or less commonly attached to a cyclic backbone. Macrocyclic compounds having heteroatoms are important compounds with broad spectrum of biological activities [1][2][3][4][5][6][7] apart from their potential applications in supramolecular chemistry, catalysis and new materials. [8,9] Over the last few years, macrocyclic chemistry has attracted lot of interest and has become a growing area of research in inorganic and organic chemistry in view of its biological importance. [1][2][3][4] Compared to linear peptide macromolecules, cyclic macromolecules provide improved stability and membrane permeability. These factors were clearly demonstrated in the development of hepatitis C virus (HCV) NS3 protease inhibitor, BILN2061. To optimize multiparameters such as aqueous solubility, microsomal stability and lipophilicity, Zapf et al. used the twelve-membered macrocycles as a promising platform to generate potent Hsp90 inhibitors. Their detailed study revealed that as ring size increased aqueous solubility and microsome stability were decreased whereas lipophilicity increased with increasing ring size.[ [10][11][12][13][14] Within different classes of macrocycles, (benz)imidazoleand indole-based macrocycles have received a great deal attention in drug discovery. These compounds exhibit biological activity as antimicrobial and anticancer agents because of their specific structures. Presently, the syntheses of (benz)imidazole-and indole-based macrocycles have received an increasing attention to synthetic (inorganic and organic) chemists and biologists. Therefore, the newly emerging interest in the antimicrobial and anticancer applications of (benz)imidazole-and indole-based macrocycles led us to examine the few accounts available in the recent literature dealing with this area of research. In this review article, we focus on the synthesis and biological applications such as antimicrobial and a...

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“…A set of four other tethered dialdehydes ( 75 a ‐ d ) was reacted under McMurry conditions as part of a study aimed at the synthesis of macrocyclic analogs of deoxycombrestatin A‐4 (Scheme ) 48. With the exception of 75 b , these highly oxygenated systems did not afford decent yields of the corresponding [7.2]paracyclophanes 76 a – d .…”

Section: The Mcmurry and Related Reactionsmentioning

confidence: 99%

“…Chiral macrocyclic indolophane 105 c was also synthesized using this approach. Very recently, two (1,5)indolophanes ( 107 a and 107 b ) appeared in the literature 48. These were synthesized from dialdehydes 106 a and 106 b in modest yield (Scheme ).…”

Section: The Mcmurry and Related Reactionsmentioning

confidence: 99%

Olefination Reactions in the Synthesis of Cyclophanes

Bodwell

Nandaluru

2012

Israel Journal of Chemistry

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A survey of olefination reactions that have been used in the synthesis of cyclophanes is presented. This covers the Ramberg-Bäcklund reaction, the Wittig and related reactions, the McMurry and related reactions, ring-closing metathesis (alkenes, alkynes and ene-ynes), aldol condensations and Siegrist reactions, as well as miscellaneous reactions. The McMurry reaction and ring-closing metathesis have enjoyed the greatest popularity in recent years, but they are typically used for complementary purposes. In virtually all cases, the McMurry reaction is used to install a twocarbon (1,2-ethenylene) bridge, whereas ring-closing metathesis is used to construct bridges that are at least fourmembered, but usually considerably longer. Some wellknown olefinations have seen little or no use in the field of cyclophane chemistry.The Ramberg-Bäcklund reaction [9] is the final step in a two-to three-step thioether-to-alkene conversion. As such, it appears to be well-suited for the synthesis of alkene-containing cyclophanes. Even though it applies to pre-existing cyclophanes, it warrants attention in the context of this review because both bonds of the newly formed alkene are generated during the reaction. Within the broader scope of organic synthesis, the Ramberg-Bäcklund reaction has been exploited frequently to introduce a double bond into large rings, [10] small rings [11] and more exotic ring systems such as cyclic enediynes. [12] However, it has not performed well in the synthesis of cyclophanes.The first cyclophanes to be synthesized using the Ramberg-Bäcklund reaction were the isomeric biphenylophanes (Z,Z)-7 and (E,E)-7 (Scheme 3). [13] As expected from mechanistic considerations, [14] they were formed stereospecifically in good yield (both 65 %) from the diastereomeric sulfones meso-6 and (AE)-6, respectively. Interestingly, the report of these very good results came shortly after Boekelheide wrote that "the Ramberg-Bäcklund reaction is unsatisfactory when applied to 2,11-dithia-[3.3]cyclophanes". [15] Prior to Boekelheides comment on the Ramberg-Bäcklund reaction, Martel reported that a Ramberg-Prof. Graham Bodwell obtained his B.Sc. and M.Sc. from the University of Victoria, Canada, working with Prof. Reginald Mitchell on cyclophanes. He then moved to Braunschweig, Germany, where he joined the group of Prof. Dr. Henning Hopf as a "Doktorand". Cyclophanes were also the focus of his doctoral research. He then took a break from cyclophanes and worked in the field of asymmetric synthesis as a post-doctoral fellow with Prof. Steve Davies at Oxford University. He then accepted a faculty position at Memorial University, where he now holds the rank of Professor. Cyclophanes have always been one of his core research interests.Penchal Reddy Nandaluru obtained his B.Sc. and M.Sc. from Sri Venkateswara University, India, and then worked as a chemist with AVRA Laboratories in India before joining the group of Prof. Graham Bodwell at Memorial University in St. John's, NL, Canada. The main theme of his doctoral research is the appli...

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New para–para Stilbenophanes: Synthesis by McMurry Coupling, Conformational Analysis and Inhibition of Tubulin Polymerisation

Cited by 8 publications

References 102 publications

Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins

Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins

Medicinal applications of (benz)imidazole‐ and indole‐based macrocycles

Olefination Reactions in the Synthesis of Cyclophanes

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