Ulf Pindur

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalating or alkylating activity are described and evaluated for prospective applications. Furthermore there exists DNA minor groove binder with different basic structures which does not possess the typical polyamide chain, including dimeric intercalating chromophores. Finally new results about peptide nucleic acids and related nucleic acid bases linked with polyamides are reported. In pronounced examples the structural chemistry, synthesis, DNA binding with several biophysical methods, molecular aspects, structure activity relationship, topoisomerase inhibition, antitumour and antibacterial effects are discussed in detail.

Chemistry and biology of new marine alkaloids from the indole and annelated indole series.

Chemistry and biology of marine natural products from the indole and annelated indole series have become an attractive research field for development of new pharmacological lead substances. In the past years some of the isolated natural organic compounds were synthesized by chemists and evaluated with great enthusiasm to find new lead natural compounds against different diseases. In this review the latest results for new compounds including isolation, biological evaluation, synthetic pathways and some retrosynthetic analyses are summarized.

Advances in marine natural products of the indole and annelated indole series: chemical and biological aspects.

Marine natural products, form a field of scientific endeavour, that has recently grown considerably. The isolation, biological evaluation, chemical properties and synthetic elaborations of products of marine organisms have attracted the attention of organic chemists, medicinal chemists, biologists and pharmacists. In this context a structurally and biologically highly interesting class is represented by the marine natural products containing an indole moiety in a pure substituted form or in an anellated form. The present review summarizes primarily the actual results concerning these products as new pharmacologically attractive lead compounds for drug design. The chemistry, biological evaluation and synthetic aspects are discussed. The spectrum of compounds represented comprises simply substituted indoles, peptidic products, dimeric indoles, anellated indoles and a variety of carbazoles. Most of them exhibit significant cytotoxicities.

N-benzoylindole-2,3-quinodimethane: Diels-Alder reactivity and synthetic applications for [b]annellated indoles

Abstract The Diels-Alder reactivity of in situ generated N -benzoylindole-2,3-quinodimethane has been expanded considerably to include reactions with carbon- and hetero-dienophiles which furnish a variety of [ b ]annellated indoles as well as functionalized and annellated carbazoles. The frontier molecular orbital theory was found to be a useful model for the prediction of the experimental results under consideration of reactivity aspects.

Photochemical electrocyclisation of 3-vinylindoles to pyrido[2,3-a]-, pyrido[4,3-a]- and thieno[2,3-a]-carbazoles: design, synthesis, DNA binding and antitumor cell cytotoxicity.

In the context of the design and synthesis of DNA ligands, some new hetarene annelated carbazoles were synthesized. As lead structure the intercalating tetracyclic systems pyrido[2,3-a]- and pyrido[4,3-a]-carbazoles and in one case a thieno[2,3-a]-carbazole were taken into account. A dialkyl amino amidic chain was introduced to the planar chromophoric system with the intent to generate minor groove binding properties. The cytotoxicity of some compounds was examined by the NCI antitumor screening. Furthermore, biophysical as well as biochemical studies were performed in order to get some information about the DNA-binding properties and inhibition of DNA related functional enzymes of this new series of molecules.

Cycloadditions of vinylindoles with chiral carbodienophiles: the first asymmetric Diels-Alder reactions in the vinylhetarane series

Abstract The first asymmetric Diels-Alder reactions of some 3- and 2-vinylindoles with ( N -propenoyl)bornane-10,2-sultam are described. With one exception, the experimental results are indicative of a high π-facial diastereoselectivity. Following a related procedure, 3-vinylindoles were also allowed to react with a racemic bis(naphthylsulfonyl)-dienophile to furnish tetrahydrocarbazoles with endo -diastereoselectivity.

Molecular modeling of intercalation complexes of antitumor active 9-aminoacridine and a [d, e]-anellated isoquinoline derivative with base paired deoxytetranucleotides

SummaryIntercalators are molecules capable of sliding between DNA base pairs without breaking up the hydrogen bonds between the DNA bases. On the basis of molecular mechanics calculations structural, models of B-DNA tetranucleotide intercalation complexes of some cytostatic active 9-aminoacridines and of a [d, e]-anellated isoquinoline derivative are presented. The drug complexes are stabilized by energetically favouredvan der Waals interactions and by selective hydrogen bonds between the side chains of the drugs and the DNA bases. Semiempirical quantum chemistry calculations revealed that the chromophoric system of the intercalators is able to form π,π-charge-transfer interactions with the purine bases of the base paired deoxytetranucleotides. The theoretical findings are of interest for a more specific drug design of cytostatically active agents.ZusammenfassungInterkalatoren sind Moleküle, die in der Lage sind, sich zwischen DNA-Basenpaare einzulagern, ohne die Wasserstoffbrücken zwischen den DNA-Basen aufzubrechen. Auf der Basis von molekülmechanischen Rechnungen werden Tetranukleotid-Interkalationskomplexe von verschiedenen zytostatisch aktiven 9-Aminoacridinen und von einem [d, e]-anellierten Isochinolinderivat präsentiert. Die Komplexe werden durch energetisch günstigevan der Waals-Interaktionen sowie durch selektive Wasserstoffbrückenbindungen zwischen den Seitenketten der Wirkstoffe und den DNA-Basen stabilisiert. Semiempirische quantenchemische Rechnungen ergaben, daß der Chromophor der Interkalatoren in der Lage ist, π,π-charge-transfer Wechselwirkungen mit den Purinbasen der basengepaarten Desoxytetranukleotide auszubilden. Die theoretischen Ergebnisse sind für ein spezifischeres Wirkstoffdesign zytostatisch aktiver Verbindungen von Interesse.

A new access to 2′-amino-substituted vinylindoles as donor-activated heterocyclic dienes and their first diels-alder reactions

Abstract Reactions of the 3-acylindoles 5, 10 , and 15 with α-amino-α′-diphenylphosphinoyl-substituted carbanions gave rise to the 2′-amino-substituted 3− and 2-vinylindoles 7, 12 , and 17 by way of the isolable carbinols 6 , 11 , and 16 . The heterocyclic dienes 7 , 12 , and 17 readily underwent Diels-Alder reactions with N -phenylmaleimide.

First cycloaddition of 2-vinylindoles with dimethyl, 1,2,4,5-tetrazine-3,6-dicarboxylate: Diels-Alder reactions with inverse electron demand to new substituted and annelated pyridazines

Abstract 2-Vinylindole 1a and its donor-/acceptor-substituted ( E )-derivatives 1b–1e react with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate to form new indolyl-1,4-dihydropyridazines 3a , 7 and annelated pyridazines 3b–d , 5 , 6 . The reactions proceed under steric control with high locoselectivities.

New structural aspects of 3-vinyl-1H-indoles for predicting the outcome of Diels-Alder reactions

SummarySome selected 3-vinyl-1H-indoles have been synthesised and the first13C-NMR studies performed; in addition He(Iα) photoelectron spectra and the results of perturbation MO calculations of some examples of this class of compounds are presented. The molecular characteristics obtained thereby can be used to predict the results of [π4s+π2s]-cycloaddition reactions with 3-vinylindoles.ZusammenfassungAn selektiv synthetisierten 3-Vinyl-1H-indolen werden erstmals13C-NMR-spektroskopische Studien durchgeführt und exemplarisch an einigen Vertretern dieser Strukturklasse He(Iα)-Photoelektronenspektren sowie Ergebnisse von Störungs-MO-Rechnungen vorgestellt. Die daraus gewonnenen Moleküleigenschaften können zur Vorhersage des Reaktionsausganges von [π4s+π2s]-Cycloadditionen mit 3-Vinylindolen verwendent werden.