To address two fundamental and unsolved problems in optical imaging (nonspecific uptake of near‐infrared fluorophores by normal tissues and organs and incomplete elimination of unbound targeted fluorophores from the body), novel zwitterionic near‐infrared fluorophores (e.g., ZW800‐1) were synthesized and their performance compared in vivo to conventional molecules (e.g., ICG) as a function of charge, charge distribution, and hydrophobicity (see picture).
A longstanding problem in the field of image-guided surgery is the development of ideal near-infrared (NIR) fluorophores. The heptamethine NIR fluorophore indocyanine green (ICG) has been used extensively for image-guided surgery because of its clinical availability and safety. [1][2][3] However, ICG is far from ideal because it exhibits high uptake in the liver, contaminates the gastrointestinal (GI) tract, provides moderate optical properties, [4] is unstable in aqueous media, [3,5] and is unable to conjugate covalently to targeting ligands. [2] Although several classes of novel molecules have been described, [6][7][8][9][10][11][12][13] none to date exhibit simultaneous low background binding, bifunctionality, excellent optical properties, low protein binding, and high serum stability. Although it is intuitive that physicochemical properties, that is, positive/ negative charge density, hydrophilicity/lipophilicity, and charge distribution, will impact in vivo performance, chemical structures that exhibit ideal characteristics have not yet been defined.Previously, our group showed that rigid spherical nanoparticles, such as quantum dots, with a hydrodynamic diameter (HD) 5.5 nm could be rapidly cleared by the kidneys, and exhibit low background binding to normal tissues and organs, but only when the surface charge was neutral, geometrically balanced, and polyionic (referred to herein as zwitterionic for simplicity). [14][15][16][17][18][19] In this study, we explored the hypothesis that NIR fluorescent small molecules would exhibit improved in vitro and in vivo performance if synthesized with zwitterionic charges that are evenly spaced over the molecule to shield the underlying hydrophobicity of the relatively large heptamethine core.We describe two complementary molecules, termed ZW800 AE i where AE i is the charge of the conjugated targeting ligand that will render the final molecule with a net charge of zero (i.e., zwitterionic). ZW800-1 has a net charge = 0 prior to targeting ligand conjugation, and a net charge = 0 after conjugation to a targeting ligand that has a net charge of À1 (that is, a targeting ligand with a net charge of 0 prior to conjugation). ZW800-3a has a net charge = + 2 prior to conjugation, and a net charge = 0 after conjugation to a targeting ligand that has a net charge of À3 (that is, a targeting ligand with a net charge of À2 prior to conjugation). ZW800-1 and ZW800-3a were engineered for high hydrophilicity, with logD (distribution coefficient) at pH 7.4 of À3.56 and À6.95, respectively. Importantly, these molecules have also been engineered with sulfonate groups to impart negative charge and quaternary ammonium cations (quats) to impart positive charge because preliminary results showed that the weaker, more common natural analogues (carboxylic acids and primary amines, respectively) did not exhibit the desired properties.As depicted in Figure 1 a, chloro-substituted NIR fluorophores 8 and 9 were synthesized by employing quats and/or sulfonates (5 or 6) on the indocyanine backbone...
Design and optimization of quadruplex-specific small molecules is developing into an attractive strategy for anti-cancer therapeutics with some promising candidates in clinical trials. A number of therapeutically favorable features of cyanine molecules can be effectively exploited to develop them as promising quadruplex-targeting agents. Herein, the design, synthesis and evaluation of a series of dimethylindoliene cyanine dyes with varying halogen substitutions are reported. Their interactions with telomeric and c-myc quadruplexes as well as a reference duplex sequence have been evaluated using thermal melting, biosensor-surface plasmon resonance, circular dichroism, isothermal titration calorimetry and mass spectrometry. Thermal melting analysis indicates that these ligands exhibit significant quadruplex stabilization and a very low duplex binding, with the dimethyl incorporation of paramount importance for decreased duplex affinity. Circular dichroism studies showed that the interaction of cyanines with quadruplex structures are primarily through stacking at one or both ends of the terminal tetrads with the two (trimethylammonium)propyl groups interacting in the accessible quadruplex grooves. Surface plasmon resonance and mass spectral studies shows the formation of an initial strong 1:1 complex followed by a significantly weaker secondary binding. Isothermal calorimetry studies show that the interaction of cyanines is predominantly entropy driven. In line with the design principles, this work provides new insights for further developing potent, highly selective cyanines as promising quadruplex-specific agents.
Biodegradable scaffolds have been extensively used in the field of tissue engineering and regenerative medicine. However, noninvasive monitoring of in vivo scaffold degradation is still lacking. In order to develop a real-time trafficking technique, a series of meso-brominated near-infrared (NIR) fluorophores were synthesized and conjugated to biodegradable gelatin scaffolds. Since the pentamethine cyanine core is highly lipophilic, the side chain of each fluorophore was modified with either quaternary ammonium salts or sulfonate groups. The physicochemical properties such as lipophilicity and net charge of fluorophores played a key role in the fate of NIR-conjugated scaffolds in vivo after biodegradation. The positively charged fluorophore-conjugated scaffold fragments were found in salivary glands, lymph nodes, and most of the hepatobiliary excretion route. However, halogenated fluorophores intensively accumulated into lymph nodes and the liver. Interestingly, balanced-charged gelatin scaffolds were degraded into urine in a short period of time. These results demonstrate that the noninvasive optical imaging using NIR fluorophores can be useful for the translation of biodegradable scaffolds into the clinic.
This publication continues the series of reviews devoted to the current state of gold catalysis in organic chemistry. The second review addresses Au-catalyzed reactions of alkynes, giving rise to carbon – carbon bonds. Most of the described reactions are addition reactions involving the triple bond of alkynes. The review covers both intramolecular reactions, including cyclization of various substrates (enynes, diynes, enediynes, etc.) and enyne isomerization without ring formation, and intermolecular reactions, including alkyne reactions with alkenes, other alkynes, heteroaromatic compounds, etc., in particular, tandem reactions. A special part is devoted to dual gold catalysis involving the intermediate formation of binuclear complexes with σ- and π-coordinated metal atoms. The last part of the review deals with the carbon – carbon bond formation reactions in which the alkyne triple bond is retained. The bibliography includes 369 references.
This publication is a continuation of the series of reviews devoted to the state of the art of gold catalysis in organic chemistry. The third review covers gold-catalyzed reactions of compounds containing double bonds. The reactions of alkenes, cumulated and conjugated dienes and enynes with different types of nucleophiles, including those with heteroatoms (oxygen, nitrogen and sulfur), are considered. The bibliography includes 355 references.
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