Two-dimensionally extended, polycyclic heteroaromatic molecules (heterocyclic nanographenes) are a highly versatile class of organic materials, applicable as functional chromophores and organic semiconductors. In this Review, we discuss the rich chemistry of large heteroaromatics, focusing on their synthesis, electronic properties, and applications in materials science. This Review summarizes the historical development and current state of the art in this rapidly expanding field of research, which has become one of the key exploration areas of modern heterocyclic chemistry.

Heterocyclic Nanographenes and Other Polycyclic Heteroaromatic Compounds: Synthetic Routes, Properties, and Applications

The marine environment is a seemingly inexhaustible treasury of organisms whose secondary metabolites bear witness to the lavishness and inventiveness with which nature is able to manipulate molecular architecture. But to what purpose are these diverse and often grotesque compounds produced? This review is founded on the premise that some of them may be involved in the uptake and transport of metal ions present in the aquatic milieu. Many metabolites produced by terrestrial organisms are known to act as ionophores, but the case for similar behavior by their marine counterparts is far hazier. Notwithstanding the relative abundance of certain metal ions in the oceans, and of metabolite structures possessing features that should facilitate the chelation of metal ions, few attempts to establish a connection between these two phenomena have been reported. We have whittled down the voluminous literature of natural products derived from marine sources to expose a core of observations and speculations germane to our premise. These facts and fantasies are evaluated in this review. A mere handful of metal-containing complexes has actually been isolated; furthermore, attempts to prepare such complexes in vitro are rare, and spectroscopic evidence for metal–metabolite interactions, whether in vivo or in vitro, is not common. Only with the vanadium-sequestering tunichromes does a logical (but by no means complete) picture begin to emerge. In several other cases, the plausibility of metal chelation, though mooted by authors, remains unsupported by experimental evidence. However, continuing efforts to obtain structural, and particularly conformational, information on the metabolites by means of X-ray crystallography, nuclear magnetic resonance spectroscopy, and molecular mechanics calculations would seem to provide the key to a rational approach to this neglected topic. On the basis of recent studies dealing with such structural aspects, we present a selection of candidate compounds, some of which are the targets of our own synthetic attentions, whose potential for binding to metal cations merits further research.

Marine Metabolites and Metal Ion Chelation: The Facts and the Fantasies

This review describes the use of shaped pulses for frequency-selective excitation, refocusing and/or mixing. The selectivity of different pulse shapes is described. Selective excitation can be used to transform 2D experiments into 1D analogues or to restrict the size in higher dimensional spectra. Soft excitation also can be used to apply techniques in homonuclear spectroscopy which are otherwise only possible in heteronuclear spectroscopy.

Multi‐dimensional NMR experiments using selective pulses

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can...

Structure−Activity Relationships of the Didemnins1,2

The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

Natural products as probes of cell biology: 20 years of didemnin research.

We present the application of several homo- and heteronuclear 1D- and 2D-NMR techniques to assign the 1H-NMR chemical shifts of the dominant conformation of didemnin B (2; three different conformations in (D6)DMSO solution in the ratio 8:1:1) and its conformational analysis, as well as the solution conformation of didemnin A (1). The conformations were refined by restrained molecular-dynamics calculations using the GROMOS program and by MOMO, a novel personal-computer-based interactive molecular-graphics and molecular-mechanics package, using experimental distances (via a H…H pseudo potential function) as restraints. The solution structures of 1 and 2 obtained by GROMOS and MOMO calculations were compared with each other and related to the recently solved crystal structure of 2. Focusing on the main conformer, the two kinds of the distance-restrained conformational calculations for 2 yielded a ‘solution structure’ close to the crystal structure. Almost all of the 40 restrained H…H distances coincided (within the estimated standard deviations) with those observed in the crystal structure. One more hydrogen bond was detected in solution involving the lactoyl OH group (disordered in the crystal structure) and the dimethyltyrosine (Me2Tyr5) carbonyl O-atom. The macrocyclic ring system in the modeled solution structure of 1 exhibited a topology close to those of the solution and crystal structures of 2. The main difference between 1 and 2 could be traced back to a significant change in the Ψ angle of the N-methyl-D-leucine (MeLeu7) residue. In 1, the N-methyl moiety of MeLeu7 points inward within the macrocyclic ring toward the 1st and Hip region. We also tested the suitability of structures obtained from NMR data as ‘search fragments’ in the ‘Patterson search approach’ of crystal-structure analysis. It proved possible to resolve the crystal structure of 2 a posteriori with the Patterson search program PATSEE, in this way.

Holger Beck

Papers

Conformational Analysis of Didemnins. A multidisciplinary approach by means of X-Ray, NMR, molecular-dynamics, and molecular-mechanics techniques

Stereoselective synthesis of functionalized, tetra- and penta-substituted 1,3-butadienes by allene Claisen rearrangement

Zur Struktur cyclotrimerer 1,4-Chinone