Photosynthesis in different types of transgenic tobacco plants with elevated cytokinin content

Photosynthetic parameters were compared in three types of transgenic tobacco plants: ipt-transgenic plants with slightly elevated endogenous cytokinin (CK) content, Pssu-ipt-transgenic plants with markedly increased CK content, and zmp-transgenic plants with slightly elevated CK content accompanied by elevated auxin content. Slightly increased CK content promoted net photosynthetic rate (P_N) in both ipt- and zmp-transgenic plants, and chlorophyll (Chl) and carotenoid contents in zmp-transgenic plants. Morphology, growth characteristics, stomatal conductance, and parameters of Chl a fluorescence kinetics were similar in control and transgenic plants with slightly higher CK content. No significant effect of increased level of endogenous auxin (indole-3-acetic acid) on development of zmp-transgenic plants and measured parameters was found. Pssu-ipt-transgenic plants with highly increased CK content revealed suppressed root development, wilting of plants, and depression of P_N and stomatal conductance; however, Chl content was slightly increased and parameters of Chl a fluorescence kinetics did not indicate damage to photosynthetic apparatus. This revised version was published online in July 2006 with corrections to the Cover Date.     

Structure of synthetic peptide analogues of an eggshell protein of Schistosoma mansoni.

The peptide (Gly-L-Tyr-L-Asp-L-Lys-L-Tyr)6, referred to as F4-6, was synthesized as a model for a schistosome eggshell protein in which the Gly-Tyr-Asp-Lys-Tyr consensus sequence is repeated over 40 times. Analysis by CD, Fourier transform infrared spectroscopy, potentiometric and spectrophotomertric titrations, NMR, and molecular modeling suggests that F4-6 forms some type of left-handed structure. A likely possibility appears to be a left-handed alpha-helix stabilized by Lysi-Aspi +4 salt bridges and possibly Aspi-Tyri +4 hydrogen bonding and Tyr-Tyr interactions. Spectroscopic studies of a number of F4-6 analogues support this conclusion. For example, substitution of D-Ala for Gly produces a peptide with enhanced left-handed helical spectral characteristics, whereas an L-Ala substitution results in a peptide with minimal structure. These studies suggest that the F4 protein from Schistosoma mansoni may be the first example of a naturally occurring protein devoid of proline and carbohydrate that forms a left-handed helix composed of L-amino acids, although alternative forms of other left-handed structures have yet to be rigorously excluded.     

Exploration of ring size in a series of cyclic vicinal diamines with σ(1) receptor affinity

Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl-N'-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ(1) receptors. The imidazolidines possessed nanomolar σ(1) affinities (K(i)=6.45-53.5nM), and relatively low levels of subtype selectivity (σ(2)/σ(1)=58-237). However, the piperazines and diazepanes achieved picomolar σ(1) interactions, with K(i) ranges of 0.05-10.28 and 0.10-0.194nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ(2) receptor, with σ(1) selectivities of 143-16140 and 220-11542, respectively.     

Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.     

An investigation into the structure-activity relationships associated with the systematic modification of the β(2)-adrenoceptor agonist indacaterol

The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the β(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical β(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.