Expanding the scope of aromatic polyketides by combinatorial biosynthesis

Combinatorial biosynthesis is a technology for mixing genes responsible for the biosynthesis of secondary metabolites, in order to generate products for compound libraries serendipitously or to cause desired modifications to natural products. Both of these approaches are extremely useful in drug discovery. Streptomyces and related species are abundant in bioactive secondary metabolites and were therefore the first microbes to be used for combinatorial biosynthesis. Polyketides are the most abundant medicinal agents among natural products. Structural diversity and a wide scope of bioactivities are typical of the group. However, the common feature of polyketides is a biosynthetic process from simple carboxylic acid residues. In molecular genetics, polyketides are sub-classified as types I and II, called modular and aromatic polyketides respectively. The best-known bioactivities of aromatic polyketides are their antibacterial and antitumor effects. Genetic analysis of aromatic polyketides has resulted in almost 30 cloned and identified biosynthetic gene clusters. Several biosynthetic enzymes are flexible enough to allow their use in combinatorial biosynthesis to create high diversity compound libraries. This review describes the state of the art of combinatorial biosynthesis, giving anthracyclines as examples. Contiguous DNA sequences for antibiotics, cloned from four different anthracycline producers, provide tools for rapid lead optimization or other structural modification processes, and not only for anthracyclines. Two gene cassettes enabling fast and flexible structural modification of polyketides are introduced in this paper.     

How Fast can a Subharmonic Function Decay Along a Ray?

Much is known about the connection between the growth and decayof subharmonic functions. The results indicate that there isa general principle: asubharmonic function cannot decay ‘toofast’ relative to its growth.Three theorems are provedwhich, together with work previously published elsewhere, givea fairly complete account of how this principle works out fora subharmonic function having extremal decay along a ray. 1991Mathematics Subject Classification: 30D20, 31A05.     

Analogy between unconventional superconductivity and unconventional states of liquid crystals

An analogy is stressed between the order-parameter symmetries of the two-dimensional d-pairing wave superconductors and of liquid-crystal mesophases formed from achiral bent-shaped molecules. It leads to a definition of a class of liquid-crystal states which are the analogs of the unconventional superconducting states, and are characterized by a loss of discrete symmetry operations of the parent state.     

Experimental and quantum-chemical determination of the (2)H quadrupole coupling tensor in deuterated benzenes

Deuterium Quadrupole Coupling Constant (DQCC) in benzene was determined both experimentally by Nuclear Magnetic Resonance spectroscopy in Liquid Crystalline solutions (LC NMR) and theoretically by ab initio electronic structure calculations. DQCCs were measured for benzene-d(1) and 1,3,5-benzene-d(3) using several different liquid crystalline solvents and taking vibrational and deformational corrections into account in the analysis of experimental dipolar couplings, used to determine the orientational order parameter of the dissolved benzene. The experimental DQCC results for the isotopomers benzene-d(1) and 1,3,5-benzene-d(3) are found to be 187.7 kHz and 187.3 kHz, respectively, which are essentially equal within the experimental accuracy (+/-0.4 kHz). Theoretical results were obtained at different C-D bond lengths, and by applying corrections for electron correlation and rovibrational motion on top of large-basis-set Hartree-Fock results. The computations give a consistent DQCC of ca. 189 kHz for three different isotopomers; benzene-d(1), 1,3,5-benzene-d(3), and benzene-d(6), revealing that isotope effects are not detectable within the present experimental accuracy. Calculations carried out using a continuum solvation model to account for intermolecular interaction effects result in very small changes as compared to the data obtained in vacuo. The comparison of theoretical and experimental results points out the selection of the underlying molecular geometry as the most likely source of the remaining discrepancy of less than 2 kHz. Such an agreement between the calculated and the experimental DQCC results can only be achieved if rovibrational effects are considered on one hand in the experimental direct dipolar coupling data, and on the other hand in the theoretical property calculation, as is done presently.     

Field-induced alignment of the nematic director: studies of nuclear magnetic resonance spectral oscillations in the limit of fast director rotation

Time-resolved NMR spectroscopy is a powerful method to investigate field-induced rotation of the director in a nematic liquid crystal. The method requires that the director does not rotate significantly during the acquisition of the free induction decay and hence the NMR spectrum. We have extended the method to systems where this is not the case and the observed NMR spectra are now found to contain novel oscillatory features. To understand these oscillations, we have developed a model combining both director and spin dynamics. In addition to increasing the information content of the time-resolved NMR spectra, it also proves possible to determine the field-induced relaxation time from a single spectrum.