Guillermo Moyna

cis-peptide bond mimetic tetrazole analogs of the insect kinins identify the active conformation

The insect kinin neuropeptides have been implicated in the regulation of water balance, digestive organ contraction, and energy mobilization in a number of insect species. A previous solution conformation study of an active, restricted-conformation cyclic analog, identified two possible turn conformations as the likely active conformation adopted by the insect kinins at the receptor site. These were a cisPro type VI beta-turn over C-terminal pentapeptide core residues 1-4 and a transPro type I-like beta-turn over core residues 2-5, present in a ratio of 60:40. Synthesis and evaluation of the diuretic activity of insect kinin analogs incorporating a tetrazole moiety, which mimics a cis peptide bond, identifies the active conformation as the former. The discovery of a receptor interaction model can lead to the development of potent agonist and antagonist analogs of the insect kinins. Indeed, in this study a tetrazole analog with D stereochemistry has been shown to demonstrate partial antagonism of the diuretic activity of natural insect kinins, providing a lead for more potent and effective antagonists of this critical neuropeptide family. The future development of mimetic agonists and antagonists of insect kinin neuropeptides will provide important tools to neuroendocrinologists studying the mechanisms by which they operate and to researchers developing new, environmentally friendly pest insect control strategies.

Comparison of active conformations of the insectatachykinin/tachykinin and insect kinin/Tyr-W-MIF-1 neuropeptide family pairs.

Abstract: A comparison of solution conformations of active, restricted‐conformation analogues of two sequence‐similar insect/vertebrate neuropeptide family pairs shed light on the potential existence of molecular evolutionary relationships. Analogues of the locustatachykinins and the mammalian tachykinin substance P, containing a sterically hindered Aib‐NMePhe/Tyr residue block, share similar low‐energy turn conformations incorporating a cis peptide bond. Conversely, restricted conformation analogues of the insect kinins and the mammalian opiate peptide Tyr‐W‐MIF‐1, with near identical C‐terminal tetrapeptide sequences, adopt different conformations. The insect kinins adopt a cisPro 1‐4 β‐turn, in which the Phe1 is critical for bioactivity. Tyr‐W‐MIF‐1 prefers a transPro 2‐5 turn, and an additional N‐terminal Phe severely inhibits μ‐opiate receptor binding. Comparisons of the chemical/conformational requirements for receptor interaction are consistent with a distant evolutionary relationship between the insectatachykinins and tachykinins, but not between the insect kinins and Tyr‐W‐MIF‐1. Therefore, analogues of the insect kinins with pest control potential can be readily designed to avoid mammalian interactions.

Conformation in solution and dynamics of a structurally constrained linear insect kinin pentapeptide analogue.

The preferred conformations of the active diuretic insect kinin pentapeptide analogue Phe-Phe-Aib-Trp-Gly-NH2 were studied using nmr spectroscopy and molecular modeling. Structure sets consistent with rotating frame nuclear Overhauser effect spectroscopy distance constraints obtained by restrained simulated annealing in vacuo indicate a predominant population of a type II beta-turn involving the Phe1-Trp4 region. An equilibrium between this type II and a type I beta-turn formed by residues Phe2 and Gly5 was observed in a 5 ns restrained molecular dynamics simulation using the implicit generalized Born solvent accessible surface area (GB/SA) solvation model. When subjected to 500 ps dynamics with explicit water both beta-turn folds were conserved throughout the simulations. The results obtained with implicit and explicit solvation models are compared, and their consistency with the nmr observations is discussed. The behavior of the linear pentapeptide in this study is in agreement with an earlier report on the consensus conformation of the insect kinin active core derived from analysis of cyclic active analogues.

Synthesis, biological activity, and conformational studies of insect allatostatin neuropeptide analogues incorporating turn-promoting moieties

Allatostatins are 6-18 amino acid peptides synthezed by insects to control production of juvenile hormones, which in turn regulate functions including metamorphosis and egg production. Four insect allatostatin neuropeptide analogues incorporating turn-promoting pseudopeptide moieties in the region responsible for biological activity were prepared by solid phase peptide synthetic methods. Bioassay indicated that activities approached those of the natural neuropeptides, and molecular models based on NMR data showed similar conformations and the presence of a beta-turn in the active core region for the four analogues. Differences in activity are believed to be due to differences in bulk and relative position of atoms in the unnatural portion of the analogues, and their differing degrees of conformational freedom. The studies support the feasibility of development of neuropeptide-based insect control agents resistant to peptidase deactivation.

Diversity in cyclic sesquiterpene production by Gossypium hirsutum

Major sesquiterpene components of oil of Texas Race Stock 810 of Gossypium hirsutum were alpha- and beta-selinene. This is the seventh cyclic terpene type found to date in this genus. Both alpha- and beta-selinene, along with aromadendrene, were found but only as minor components of extracts of several domestic cultivars of G. hirsutum.

COMPARISON OF RING CURRENT METHODS FOR USE IN MOLECULAR MODELING REFINEMENT OF NMR DERIVED THREE-DIMENSIONAL STRUCTURES

A comparison between three different methods commonly used to estimate ring current effects on chemical shifts is presented. Haigh-Mallion, Johnson-Bovey, and classical point-dipole approximations were used to estimate the ring current contribution to chemical shifts for protons in several proteins for which both detailed X-ray crystal structures and chemical shift assignments were available. For the classical point-dipole model, new proportionality constants were calculated by fitting to ring current estimations from both the quantum-mechanical Haigh-Mallion and semiclassical Johnson-Bovey methods and compared with the previously used point-dipole constant of Perkins and Dwek. Statistical analysis of the predictions obtained by all methods indicates that the point-dipole approximation parametrized against quantum-mechanical data is superior to the previously used classical model, comparable to Johnson-Bovey calculations, and slightly poorer than predictions from the Haigh-Mallion theory. The implementation of a pseudoenergy penalty term for use in structure refinement from chemical shift data based on the classical point-dipole model is described, and its usefulness in cases where other NMR information is limited is discussed with a specific example.

Preparation of aminated taxol side chain precursors. A Simple Approach to 2,3-Diamond Acids Using the β-Lactam Synthon Method.

Abstract Coupling-ready aminated side chain analog precursors of the anticancer drug taxol were prepared through the β-lactam synthon method. The procedure described represents an easy connection between β-lactams and 2,3-diamino acids, is highly stereospecific, and causes no racemization due to vicinal group participation.

An Improved Procedure for the Epoxidation of Methyl Cinnamate Derivatives and Production of Acid Sensitive Epoxides

Abstract By using a biphasic epoxidation system, unreactive methyl cinnamate derivatives were epoxidized at higher rates, and epoxides that decomposed in the presence of m-chlorobenzoic acid (mCBA) to diol ester opening products under standard conditions were obtained in fair to excellent yields.

A simple algorithm for superimposing sets of NMR derived structures: its application to the conformational study of cephalomannine in lipophobic and lipophilic solution.

A simple iterative method for superimposing sets of NMR derived structures and calculation of the root mean square deviation (RMSD) of the sets is described. It was compared to the commonly used algorithm involving pairwise best fitting in the conformational study of the taxoid anticancer drug cephalomannine in lipophobic and lipophilic solvents. Lower RMSD values were obtained, indicating a better superposition of the structures in the sets. The conformations of cephalomannine in the two solvent systems reported are in good agreement with earlier conformational studies on other active taxoids.

β-Caryophyllene Derivatives from the Wild Cottons

Abstract 12-Hydroxy-β-caryophyllene (1), 12-hydroxy-β-caryophyllene acetate (2), and 12-hydroxy-β-caryophyllene-4,5-oxide acetate (3) were purified from the essential oil of the wild cottons Gossypium armourianum Kearn., G. harknessii Brandg., and G. turneri Fryx. by preparative gas chromatography and identified using NMR and mass spectroscopy. In chloroform solution, the first two compounds exist as two slowly interconverting conformers as does β-caryophyllene.