Bioorganic and bioinorganic chemistry

The interdisciplinary projects in bioinorganic and bioorganic chemistry of the Department of Chemistry, University of Basel led to the preparation of new systems that mimic biologically important processes and to the discovery of compounds from natural sources which are very promising with respect to medical applications. The advances in these areas are reported here.     

Directed Biosynthesis of Phytotoxic Alkaloids in the Cyanobacterium Nostoc 78–12A

Out of the green! Precursor‐directed biosynthesis allowed for the production of new nostocarboline derivatives that display phytotoxic and algicidal properties—in a phototrophic organism. The mechanism of action includes downregulation of photosynthesis, as demonstrated by chlorophyll‐a fluorescence imaging.

     

Synthesis and catalysis

Research projects of the Department of Chemistry, University of Basel are reviewed ranging from the synthesis of complex natural products to the development of metalorganic catalysts and organocatalysts.     

Use of G-CSF (Neupogen) in multimodal treatment in radiotherapy

BACKGROUND: Therapy-induced leukopenias with corresponding consequences repeatedly occur in radiotherapy using combined modalities treatment. In radiotherapy, where G-CSF (granulocyte-colony-stimulating-factor) is not licensed, G-CSF has been used successfully under individual circumstances. These results were confirmed in several studies with small patient groups. The aim of this study was to check former results in a larger patient group, to verify postulated side effects and specially to define a cost-effective schedule in the treatment with G-CSF (Neupogen).PATIENTS AND METHODS: In this surveillance trial 50, partially previously treated patients with different malignant tumors were treated with G-CSF. According to the probability of a leucocytosis lower than 1000/mm3, G-CSF (Neuropogen) was already given at leukocyte values lower than 2500/mm3 (500/mm3 bis 2450/mm3). It administered subcutaneously every other day, based on body weight until reaching normal leucocyte levels. RESULTS:In 92% of the patients the increase of leucocytes occurred in the first 24 hours. On average G-CSF was given 4.9 times per patient. Patients without prior therapies or less complex therapies needed less G-CSF applications (3.5 to 5.8 applications). Due to individually varying leucocyte courses the G-CSF therapy was started with leucocyte values between 500/mm3 and 2450/mm3. Patients who were treated with up to 3 G-CSF applications had higher leucocyte levels than those with 4 or more applications (1620/mm3 to 1250/mm3). Leucopenia related infections, therapy interruptions or break-offs did not occur. Besides light "flu like" symptoms in 14% of the patients, no side effects were observed. CONCLUSIONS: When a decrease of leucocyte values lower than 1000/mm3 is expected, the most cost-effective treatment is given when starting the interventional G-CSF administration already at leucocyte values around 1600/mm3. Leucopenias can be treated effectively, with little side effects and in a cost-effective way when G-CSF is given on time.     

Scheduling vehicles in automated transportation systems Algorithms and case study

One of the major planning issues in large scale automated transportation systems is so-called empty vehicle management, the timely supply of vehicles to terminals in order to reduce cargo waiting times. Motivated by a Dutch pilot project on an underground cargo transportation system using Automated Guided Vehicles (AGVs), we developed several rules and algorithms for empty vehicle management, varying from trivial First-Come, First-Served (FCFS) via look-ahead rules to integral planning. For our application, we focus on attaining customer service levels in the presence of varying order priorities, taking into account resource capacities and the relation to other planning decisions, such as terminal management. We show how the various rules are embedded in a framework for logistics control of automated transportation networks. Using simulation, the planning options are evaluated on their performance in terms of customer service levels, AGV requirements and empty travel distances. Based on our experiments, we conclude that look-ahead rules have significant advantages above FCFS. A more advanced so-called serial scheduling method outperforms the look-ahead rules if the peak demand quickly moves amongst routes in the system. Received: June 21, 2000 / Accepted: January 22, 2001     

Mechanistic studies on the tyrosinase-catalyzed formation of the anachelin chromophore

The complex secondary metabolite anachelin, isolated from the freshwater cyanobacterium Anabaena cylindrica, is believed to act as siderophore, facilitating iron uptake. Its structure is characterized by a fascinating blend of polyketide, peptide, and alkaloid fragments. In particular, the tetrahydroquinolinium-derived chromophore is unique among natural products, and its biosynthesis is unknown. We propose a hypothesis for the biogenesis of the anachelin chromophore starting from a C-terminally bound L-Tyr residue. It is proposed that this amino acid is reductively aminated, methylated, and hydroxylated. Oxidation of this catechol diamine substrate by a tyrosinase would lead to an o-quinone, which would react by intramolecular aza-annulation and tautomerization to give the anachelin chromophore. In order to evaluate this hypothesis, a model substrate related to the proposed biogenetic precursor was prepared. It was shown that the enzyme tyrosinase is able to transform this substrate into an anachelin chromophore derivative, which corroborates the biogenetic hypothesis. In order to gain further insight into the mechanism of this transformation, we performed spectrophotometric reaction monitoring, allowing the formation of the expected product to be observed. In addition, a rise in absorption at around 250 nm might be due to the presence of a spiro five-membered ring intermediate resulting from an alternative 1,4-addition to the o-quinone. Lastly, we were able to show that the action of tyrosinase on this substrate follows Michaelis-Menten kinetics (k(cat)=123 s(-1) and K(m)=8.66 mM). Interestingly, the catalytic efficiency is decreased only by a factor of 30 relative to the natural substrate L-DOPA.     

Spatial isolation favours the divergence in microcystin net production by Microcystis in Ugandan freshwater lakes

It is generally agreed that the hepatotoxic microcystins (MCs) are the most abundant toxins produced by cyanobacteria in freshwater. In various freshwater lakes in East Africa MC-producing Microcystis has been reported to dominate the phytoplankton, however the regulation of MC production is poorly understood. From May 2007 to April 2008 the Microcystis abundance, the absolute and relative abundance of the mcyB genotype indicative of MC production and the MC concentrations were recorded monthly in five freshwater lakes in Uganda: (1) in a crater lake (Lake Saka), (2) in three shallow lakes (Lake Mburo, George, Edward), (3) in Lake Victoria (Murchison Bay, Napoleon Gulf). During the whole study period Microcystis was abundant or dominated the phytoplankton. In all samples mcyB-containing cells of Microcystis were found and on average comprised 20 ± 2% (SE) of the total population. The proportion of the mcyB genotype differed significantly between the sampling sites, and while the highest mcyB proportions were recorded in Lake Saka (37 ± 3%), the lowest proportion was recorded in Lake George (1.4 ± 0.2%). Consequently Microcystis from Lake George had the lowest MC cell quotas (0.03-1.24 fg MC cell⁻¹) and resulted in the lowest MC concentrations (0-0.5 μg L⁻¹) while Microcystis from Lake Saka consistently showed maximum MC cell quotas (14-144 fg cell⁻¹) and the highest MC concentrations (0.5-10.2 μg L⁻¹). Over the whole study period the average MC content per Microcystis cell depended linearly on the proportion of the mcyB genotype of Microcystis. It is concluded that Microcystis populations differ consistently and independently of the season in mcyB genotype proportion between lakes resulting in population-specific differences in the average MC content per cell.     

Linear-programming-based heuristics for project capacity planning

Many multi-project organizations are capacity driven, which means that their operations are constrained by various scarce resources. An important planning aspect in a capacity driven multi-project organization is capacity planning. By capacity planning, we mean the problem of matching demand for resources and availability of resources for the medium term. Capacity planning is a very useful method to support important tactical decisions such as due date quotation and price quotation for new projects, and to gain an insight into capacity requirements for the medium term. We present a capacity planning model in which aspects such as capacity flexibility, precedence relations between work packages, and maximum work content per period can be taken into account. For this model, we discuss several linear-programming-based heuristics. Using a large set of test instances, we compare these heuristics with some results from the literature. It turns out that some of these heuristics are very powerful for solving capacity planning problems.     

Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin

Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA synthetase >100-fold more potent than that of the activity registered against the human enzyme. Despite its compelling activity, cladosporin exhibits poor oral bioavailability; a critical requirement for antimalarial drugs. Thus, the quest to develop metabolically stable cladosporin-derived analogues, while retaining similar selectivity and potency to that of the natural compound, has begun. Chemogenomic profiling of a designed library allowed an entirely innovative structure–activity relationship study to be initiated; this shed light on structural evidence of a privileged scaffold with a unique activity against tRNA synthetases.