Dionisios Vourloumis

The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century.

A new millenium has begun-grounds enough to question the present state of the total synthesis of natural products. In this review we answer this question by tracing the evolution of this fine art and science from its birth to the present time. This retrospective on total synthesis should serve to demonstrate how far we have come, yet show that the science of total synthesis is still in its infancy.

Chemical Biology of Epothilones

Only a few months after the disclosure of the absolute configuration of epothilones A (R=H, see picture on the right) and B (R=Me) the first total syntheses of these natural products were reported. Interest intensified with the realization of their potential as anticancer agents with a taxol-like mechanism of action. In addition to describing the most important total syntheses and biological properties of the naturally occurring epothilones A-E, this review also provides a systematic overview of numerous epothilone analogues that have been modified in the A-D regions in order to obtain information about structure-activity relationships.

Dietary flavonoids in cancer therapy and prevention: Substrates and inhibitors of cytochrome P450 CYP1 enzymes

Flavonoids are polyphenolic compounds that have attracted the attention of the scientific community as the hallmark molecules responsible for cancer prevention by a plethora of different mechanisms. One of their most important characteristics, responsible for their cancer preventive properties, is their interaction with cytochrome P450 CYP1 enzymes. Flavonoids have traditionally been described as CYP1 inhibitors due to the inhibition of carcinogenic product formation and consequent blockage of the initiation stage of carcinogenesis. However, mounting evidence indicate that flavonoids are also capable of acting as CYP1 substrates, undergoing bioactivation to more antiproliferative agents within cancer cells. In this review, a comprehensive summary of the two models is presented. Structural features responsible for CYP1 inhibition or substrate turnover are discussed and limitations as well as discrepancies between procarcinogen-activating and 7-ethoxyresorufin-inhibition assay systems are further explored in vitro and in vivo. Moreover, a thorough investigation of the substrate specificity of flavonoids for the active site of CYP1 enzymes is undertaken. Finally, issues concerning the bioavailability and metabolic fate of these compounds in vivo are addressed. Ultimately, the mode of flavonoid action, in terms of CYP1 inhibition or CYP1-mediated bioactivation, is dependent on the lipophilicity or hydrophilicity of each compound. The degree of hydroxylation or methoxylation of the A and B rings is the major factor which determines the accessibility to the tumor site, in terms of hepatic and intestinal metabolism, and the introduction of the molecules to the CYP1 active site, respectively.

Der Stand der Totalsynthese zu Beginn des 21. Jahrhunderts

Ein neues Jahrtausend hat begonnen – Grund genug, sich die Frage zu stellen, welchen Stand die Totalsynthese von Naturstoffen erreicht hat. Dieser Aufsatz mochte eine Antwort geben, indem er die Entwicklung dieser chemischen Disziplin, die Aspekte von exakter Wissenschaft und schoner Kunst in sich vereint, von Anbeginn bis in die heutige Zeit beschreibt; es wird geschildert, wie viel wir in der Wissenschaft der Totalsynthese schon erreicht haben, aber auch, dass dieses Forschungsgebiet den Kinderschuhen gerade erst entschlupft.

Total synthesis of Epothilone E and related side-chain modified analogues via a stille coupling based strategy

A Stille coupling strategy has been utilized to complete a total synthesis of epothilone E from vinyl iodide 7 and thiazole-stannane 8h. The central core fragment 7 and its trans-isomer 11 were prepared from triene 15 using ring-closing metathesis (RCM), and were subsequently coupled to a variety of alternative stannanes to provide a library of epothilone analogues 18a-o and 19a-o. The Stille coupling approach was then used to prepare epothilone B analogues from the key macrolactone intermediate 24 which was itself synthesized by a macrolactonization based strategy.

Synthesis and biological properties of C12,13-cyclopropylepothilone A and related epothilones

BACKGROUND The epothilones are natural substances that are potently cytotoxic, having an almost identical mode of action to Taxoltrade mark as tubulin-polymerization and microtubule-stabilizing agents. The development of detailed structure-activity relationships for these compounds and the further elucidation of their mechanism of action is of high priority. RESULTS The chemical synthesis of the C12,13-cyclopropyl analog of epothilone A and its C12,13-trans-diastereoisomer has been accomplished. These compounds and several other epothilone analogs have been screened for their ability to induce tubulin polymerization and death of a number of tumor cells. Several interesting structure-activity trends within this family of compounds were identified. CONCLUSIONS The results of the biological tests conducted in this study have demonstrated that, although a number of positions on the epothilone skeleton are amenable to modification without significant loss of biological activity, the replacement of the epoxide moiety of epothilone A with a cyclopropyl group leads to total loss of activity.

Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides

ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play critical roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N-terminally extended precursors of antigenic peptides in order to generate the correct length epitopes for binding on to MHC class I molecules. The specificity of these peptidases can affect antigenic peptide selection, but has not yet been investigated in detail. In the present study we utilized a collection of 82 fluorigenic substrates to define a detailed selectivity profile for each of the three enzymes and to probe structural and functional features of the S1 (primary specificity) pocket. Molecular modelling of the three S1 pockets reveals substrate-enzyme interactions that are critical determinants for specificity. The substrate selectivity profiles suggest that IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with its proposed biological function. IRAP, however, does not achieve this dual specificity by simply combining structural features of ERAP1 and ERAP2, but rather by an unique amino acid change at position 541. The results of the present study provide insights on antigenic peptide selection and may prove valuable in designing selective inhibitors or activity markers for this class of enzymes.

Solid-phase synthesis of benzimidazole libraries biased for RNA targets

Abstract An efficient and highly versatile synthesis of two libraries 1(x,y) and 2-Ar(x,y,z) or 2-R 2 (x,y,w) based on the privileged benzimidazole scaffold is described. Our design is aimed at obtaining molecules, biased for binding to RNA targets, by incorporating functionalities, which are frequently found in natural RNA-ligands. The library construction was realized with the use of SPOS in high average yields and purity. Monitoring and quantitation of intermediates and final products were performed by the use of NMR spectroscopy using DMFu as an internal standard.

Synthesis and Biological Activity of Sarcodictyins

A new class of potential antitumor agents with a taxol-like mechanism of action is presented by the sarcodictyins 1. Modification of the reported syntheses of sarcodictyins permitted the preparation of additional derivatives, the biological properties of which are highly dependent upon the structure.

Novel 2,5-Dideoxystreptamine Derivatives Targeting the Ribosomal Decoding Site RNA

The ribosomal decoding site is the target of aminoglycoside antibiotics that specifically recognize an internal loop RNA structure. We synthesized RNA-targeted 2,5-dideoxystreptamine-4-amides in which a sugar moiety in natural aminoglycosides is replaced by heterocycles.