Phe-Tyr-OH

The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC-TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed.

To assess the degree to which more perturbative, but widely used "tag" species (Ar, H2, Ne) affect the intrinsic band patterns of the isolated ions, we describe the extension of mass-selective, cryogenic ion vibrational spectroscopy to the very weakly interacting helium complexes of three archetypal ions: the dipeptide SarGlyH(+) and the small protonated water clusters: H(+)(H2O)(2,3), including the H5O2(+) "Zundel" ion. He adducts were generated in a 4.5 K octopole ion trap interfaced to a double-focusing, tandem time-of-flight photofragmentation mass spectrometer to record mass-selected vibrational predissociation spectra. The H2 tag-induced shift (relative to that by He) on the tag-bound NH stretch of the SarGlyH(+) spectrum is quite small (12 cm(-1)), while the effect on the floppy H5O2(+) ion is more dramatic (125 cm(-1)) in going from Ar (or H2) to Ne. The shifts from Ne to He, on the other hand, while quantitatively significant (maximum of 10 cm(-1)), display the same basic H5O2(+) band structure, indicating that the He-tagged H5O2(+) spectrum accurately represents the delocalized nature of the vibrational zero-point level. Interestingly, the He-tagged spectrum of H(+)(H2O)3 reveals the location of the non-bonded OH group on the central H3O(+) ion to fall between the collective non-bonded OH stretches on the flanking water molecules in a position typically associated with a neutral OH group.

The use of mass spectrometry in macromolecular analysis is an incredibly important technique and has allowed efficient identification of secondary and tertiary protein structures. Over 20 years ago, Chemistry Nobelist John Fenn and co-workers revolutionized mass spectrometry by developing ways to non-destructively extract large molecules directly from solution into the gas phase. This advance, in turn, enabled rapid sequencing of biopolymers through tandem mass spectrometry at the heart of the burgeoning field of proteomics. In this Account, we discuss how cryogenic cooling, mass selection, and reactive processing together provide a powerful way to characterize ion structures as well as rationally synthesize labile reaction intermediates. This is accomplished by first cooling the ions close to 10 K and condensing onto them weakly bound, chemically inert small molecules or rare gas atoms. This assembly can then be used as a medium in which to quench reactive encounters by rapid evaporation of the adducts, as well as provide a universal means for acquiring highly resolved vibrational action spectra of the embedded species by photoinduced mass loss. Moreover, the spectroscopic measurements can be obtained with readily available, broadly tunable pulsed infrared lasers because absorption of a single photon is sufficient to induce evaporation. We discuss the implementation of these methods with a new type of hybrid photofragmentation mass spectrometer involving two stages of mass selection with two laser excitation regions interfaced to the cryogenic ion source. We illustrate several capabilities of the cryogenic ion spectrometer by presenting recent applications to peptides, a biomimetic catalyst, a large antibiotic molecule (vancomycin), and reaction intermediates pertinent to the chemistry of the ionosphere. First, we demonstrate how site-specific isotopic substitution can be used to identify bands due to local functional groups in a protonated tripeptide designed to stereoselectively catalyze bromination of biaryl substrates. This procedure directly reveals the particular H-bond donor and acceptor groups that enforce the folded structure of the bare ion as well as provide contact points for noncovalent interaction with substrates. We then show how photochemical hole-burning involving only vibrational excitations can be used in a double-resonance mode to systematically disentangle overlapping spectra that arise when several conformers of a dipeptide are prepared in the ion source. Finally, we highlight our ability to systematically capture reaction intermediates and spectroscopically characterize their structures. Through this method, we can identify the pathway for water-network-mediated, proton-coupled transformation of nitrosonium, NO(+) to HONO, a key reaction controlling the cations present in the ionosphere. Through this work, we reveal the critical role played by water molecules occupying the second solvation shell around the ion, where they stabilize the emergent product ion in a fashion reminiscent of the solvent coordinate responsible for the barrier to charge transfer in solution. Looking to the future, we predict that the capture and characterization of fleeting intermediate complexes in the homogeneous catalytic activation of small molecules like water, alkanes, and CO2 is a likely avenue rich with opportunity.