Phosphoramidite derivatives of texaphyrins

The invention is directed to a method of incorporating expanded porphyrins, and particularly of incorporating a sapphyrin or a texaphyrin, before, during, or after chemical synthesis of an oligomer to form an expanded porphyrin-oligonucleotide conjugate, and particularly a sapphyrin- or texaphyrin-oligonucleotide conjugate. This method includes reacting derivatized nucleotides and a sapphyrin or a texaphyrin in a desired order in an automated or manual DNA synthesizer having a solid support to form a sapphyrin- or a texaphyrin-oligonucleotide conjugate.Board of Regents, University of Texas Syste

Aspects of cyclodextrin host-guest complexes in mass spectrometry

Cancer is a widely spread disease leading to uncontrolled cellular replication that caused 9.6 million deaths worldwide in 2018. One approach in cancer treatment is inhibiting the replication process by the administration of organometallic compounds that bind to DNA. Cisplatin is one of the most prominent organometallic compounds that reached clinical approval. However, it suffers from severe side effects (e.g., nephrotoxicity) and causes the development of resistance. Various other metallorganic drugs have been evaluated for their potential in cancer treatment. Thereof, titanocene dichloride had entered clinical trials, but showed only low patient effcacy. Titanocene dichloride is a representative of the class of the bent metallocene dihalides that comprise a tetrahedral structure with two cyclopentadienyl and two halogenide ligands and a metal ion as central atom. Hydrolysis of the halogenide ligands is a crucial step in the activation of the metallocene, allowing for the interaction with its biological target. Unfortunately, extensive hydrolysis of the halogenide and the cyclopentadienyl ligands is detected for titanocene in aqueous environment at physiological conditions, leading to its inactivation. One approach for increasing the hydrolytic stability of titanocene is its inclusion within the cavity of a macrocyclic host structure. Cyclodextrins are such macrocyclic compounds composed of six to eight 1,4-linked α-D-glucopyranose units that are considered nontoxic upon oral administration. Therefore, several aspects of cyclodextrin host-guest complexes in mass spectrometry have been investigated and are discussed in this thesis. In the first section, the mass spectrometric behavior of cyclodextrins is discussed. The central part of this project was the elucidation of the fragmentation mechanism underlying the decomposition of protonated cyclodextrins. Linearization of the macrocyclic structure upon charge-induced cleavage of a glycosidic bond has been revealed as the initial dissociation step. Further decomposition of the linearized structure is characterized by neutral loss of glucose subunits. This dissociation step has been stated to occur upon charge-remote cleavage of other glycosidic bonds, leading to the elimination of a zwitterionic moiety which is potentially internally rearranged. In the second section, the focus is laid on the interaction between titanocene and cyclodextrins elucidated from mass spectrometric experiments. The obtained data indicated the formation of covalent bonds between titanium and the hydroxy groups at the rim of cyclodextrins rather than the formation of an inclusion complex. Consequently, improvement of the hydrolytic stability of titanocene at physiological pH was not obtained by the interaction of titanocene with cyclodextrins. In-source fragmentation has been found to contribute considerably to the ions detected in full scan mass spectrometry. Therefore, the effect of instrumental parameters on the quality of the obtained full scan mass spectra has been evaluated. While the capillary voltage showed only minor effects, proper adjustment of the capillary temperature and the tube lens voltage signifcantly improved the quality of the obtained data. In conclusion, diverse aspects of cyclodextrin host-guest complexes have been successfully investigated using mass spectrometry showing the potential of this analytical technique for various applications

Phosphoramidite derivatives of macrocycles

The invention is directed to phosphoramidite derivatives of macrocycles, such as porphyrins and expanded porphyrins, including sapphyrins and texaphyrins. The phosphoramidite derivatives are useful as intermediates in the preparation of macrocycle-oligonucleotide conjugates.Board of Regents, University of Texas Syste

Review on abyssomicins:Inhibitors of the chorismate pathway and folate biosynthesis

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure–activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure–activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop-o-benzyl-desmethylabyssomicin C constitute promising candidates for such programs

Structure and Dynamics of Viral Substrate Recognition and Drug Resistance: A Dissertation

Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles. The native substrates adopt a consensus volume when bound to the enzyme, the substrate envelope. The most severe resistance mutations occur at protease residues that are contacted by the inhibitors outside the substrate envelope. To guide the design of robust inhibitors, we investigate the shared and varied properties of substrates with the protein dynamics taken into account to define the dynamic substrate envelope of both viral proteases. The NS3/4A dynamic substrate envelope is compared with inhibitors to detect the structural and dynamic basis of resistance mutation patterns. Comparative analyses of substrates and inhibitors result in a solid list of structural and dynamic features of substrates that are not shared by inhibitors. This study can help guiding the development of novel inhibitors by paying attention to the subtle differences between the binding properties of substrates versus inhibitors

Mechanisms of Porphyrinoid and Carotenoid Spectral Tuning Revealed with Quantum Chemistry

Continued advances in a myriad of biomedical and technological fields require the rational design of molecules or supramolecular architectures with specific photophysical properties. Central to this endeavor is a mechanistic understanding of optical property modulation as a function of molecular structure, conformation, and environment. Natural pigments and protein-pigment complexes constitute a ‘solutions manual’ to challenges in electronic (optical) engineering that has been refined over a few billion years of evolution, and from which design principles can be deduced. In this thesis, unique mechanisms for modulating the optical properties of natural or synthetic porphyrinoid and carotenoid pigments are elucidated with quantum chemical methods. Our investigations add a new conformational mechanism, as well as design principles for regioisomer-dependent electronic substituent effects to the cannon of structural tools for regulating the optical properties of pyrrole-modified porphyrins. The lessons learned provide insight into analogous spectral tuning mechanisms found in nature. We also delineate the molecular factors optimally regulating light harvesting in a natural photosynthetic antenna complex. These discoveries have advanced the fundamental understanding and practical utilization of structure-optical property modulation mechanisms, and may aid the design of next-generation photonic-based technologies

Euphorbia characias: Phytochemistry and Biological Activities

The aim of this review is to summarize all the compounds identified and characterized from Euphorbia characias, along with the biological activities reported for this plant. Euphorbia is one of the greatest genera in the spurge family of Euphorbiaceae and includes different kinds of plants characterized by the presence of milky latex. Among them, the species Euphorbia characias L. is an evergreen perennial shrub widely distributed in Mediterranean countries. E. characias latex and extracts from different parts of the plant have been extensively studied, leading to the identification of several chemical components such as terpenoids, sterol hydrocarbons, saturated and unsaturated fatty acids, cerebrosides and phenolic and carboxylic acids. The biological properties range between antioxidant activities, antimicrobial, antiviral and pesticidal activities, wound-healing properties, anti-aging and hypoglycemic properties and inhibitory activities toward target enzymes related to different diseases, such as cholinesterases and xanthine oxidase. The information available in this review allows us to consider the plant E. characias as a potential source of compounds for biomedical research

Studies on transition metal tetraaza macrocyclic complexes

CHAPTER 1 An introduction to the work in the thesis is given. A survey of the literature describes general methods of synthesis of transition metal macrocycles and porphyrins and their relevance to substrate binding and activation. The aims of this study are introduced.CHAPTER 2 The synthesis and characterization of four neutral 14- membered tetraaza 2 ,6 -pyridyl macrocycles L 1- ! 1* with varying carbon and nitrogen alkylation is described. Extensive 1H and 1 3C n.m.r. studies in combination with a single X-ray crystal structure of the free ligand I^.E^O were undertaken. The free ligand was found to adopt a puckered arrangement in order to minimise nitrogen donor lone pair interactions.CHAPTER 3 The insertion of the platinum metals Ru(II), Rh(III), Ir(III), Pd(II), and Pt(II) into the tetraaza macrocyclic ligands L¹ - L⁴ is described. All new compounds were fully characterized by n.m.r., infrared and mass spectral techniques and by the X-ray crystal structures of cis [RuL³ (CO) Cl] BPh₄, trans [RhL² Cl₂„ ] PF₆, cis[IrL⁴(H)Cl]PF₆, and [PdL¹](BPh₄)₂. The Rh(III) and Pd(II) structures both show the macrocyclic ligands bound to four equatorial sites around each metal centre. In contrast the Ir(III) and Ru(II) complexes display folded ligand structures with one nitrogen donor, N(7), bent away to occupy an apical position to give a-is coordination of the remaining two ligands. 1H and ¹³C n.m.r. studies indicated that in most cases several ligand isomers were present in solution.CHAPTER 4 The X-ray crystal structure of the square planar [Pd (TMC) ] cation shows the macrocycle to adopt the R.S.R.S. conformation.The complex shows a fully reversible one electron reduction process in acetonitrile at E,= -1.45V vs. A g / A g+, ΔEp=65mV at Pt electrodes. Controlled potential electrolysis of [Pd(TMC)]²+ at -1.50V in acetonitrile afforded a reduction product which was assigned as a d⁹, Pd(I) complex [Pd(TMC)]+, (g₁₁ = 2.302, g₁=2.076) with coupling to ¹⁰⁵Pd (22.2%, I = 5/2), A₁₁= 53 , A₁=40G. From an investigation of TMC and six other tetraaza macrocyclic complexes, the Pd(II)/(I) redox couple was found to occur at potentials on average 300mV more cathodic than the corresponding Ni(II)/(I) couples. No Pd(II)/(III) redox process was observed within the anodic range of the acetonitrile solvent; this contrasts with the corresponding nickel macrocyclic complexes which all show Ni(II)/(III) redox couples in the range +0.68—»+1.33V.CHAPTER 5 A comparison of the redox chemistry of the square planar nickel diiminopyridyl macrocyclic complexes [Ni(n₃X)]²⁺ was investigated. (X = n,p where n₄, n₃p are respective tetraaza and triazaphosphorus donor sets) . Both complexes show two reversible one electron reductions. Characterization of the first reduction product by e.s.r. spectroscopy shows the reduction of [Ni(n₄)]²⁺ to be ligand based, whereas for [Ni (n₃p)]²⁺the reduction was found to be metal based. The binding of CO, phosphines and related ligands to the mono ­ valent complex is described. The single crystal X-ray structure of [Ni(n₃p)] (PF₆)₂ was determined confirming the square planar nickel geometry.A structural investigation of the monohalo derivatives [Ni(n₃X)Cl]+, (X = p,s, where n^s is a triazathia donor set) was u n d e r t a k e n . [Ni (n₃p)Cl]+ shows a 5 coordinate square based pyramidal geometry around Ni(II) analogous to the previously reported [Ni(n4)Br]+ complex. In contrast a dimeric structure with dichloro bridges between octahedral nickel(II) centres is found for the sulphur analogue [Ni(n₃s)Cl]₂²+•CHAPTER 6 Parallel studies were instigated into the isoelectronic reactions of [NiL]+ with dioxygen and [NiL]²+ with superoxide ion in acetonitrile at 230K (L = TMC, C-rac HMC).The product of the reactions was a reactive paramagnetic pale green solution with an anisotropic e.s.r. signal, g₁=2.195, g₁₁=2.056. ⁶¹Ni labelling experiments confirmed the predominantly metal based radical nature of the species of proposed stoichiometry [NiL(O₂)]+ . A respective one or two electron transfer from nickel to superoxide or dioxygen is proposed to form a reactive, formal nickel(III) - peroxo complex. A rhombic e.s.r. signal from a paramagnetic green solution for L=TMC is also assigned as a nickel (III) - peroxo species

Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature

This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the \u3e20 distinct compound classes is also reviewed, and commonalities are discussed