Sunaina Singh

Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics

for Diagnostics and Therapeutics Sunaina Singh,*,†,∥ Amit Aggarwal,*,†,∥ N. V. S. Dinesh K. Bhupathiraju,*,‡ Gianluca Arianna,‡ Kirran Tiwari,‡ and Charles Michael Drain‡,§ †Department of Natural Sciences, LaGuardia Community College of the City University of New York, Long Island City, New York 11101, United States ‡Department of Chemistry and Biochemistry, Hunter College of the City University of New York, New York, New York 10065, United States The Rockefeller University, New York, New York 10065, United States

Synthesis and photophysical properties of thioglycosylated chlorins, isobacteriochlorins, and bacteriochlorins for bioimaging and diagnostics.

The facile synthesis and photophysical properties of three nonhydrolyzable thioglycosylated porphyrinoids are reported. Starting from meso-perfluorophenylporphyrin, the nonhydrolyzable thioglycosylated porphyrin (PGlc₄), chlorin (CGlc₄), isobacteriochlorin (IGlc₄), and bacteriochlorin (BGlc₄) can be made in 2-3 steps. The ability to append a wide range of targeting agents onto the perfluorophenyl moieties, the chemical stability, and the ability to fine-tune the photophysical properties of the chromophores make this a suitable platform for development of biochemical tags, diagnostics, or as photodynamic therapeutic agents. Compared to the porphyrin in phosphate buffered saline, CGlc₄ has a markedly greater absorbance of red light near 650 nm and a 6-fold increase in fluorescence quantum yield, whereas IGlc₄ has broad Q-bands and a 12-fold increase in fluorescence quantum yield. BGlc₄ has a similar fluorescence quantum yield to PGlc₄ (<10%), but the lowest-energy absorption/emission peaks of BGlc₄ are considerably red-shifted to near 730 nm with a nearly 50-fold greater absorbance, which may allow this conjugate to be an effective PDT agent. The uptake of CGlc₄, IGlc₄, and BGlc₄ derivatives into cells such as human breast cancer cells MDA-MB-231 and K:Molv NIH 3T3 mouse fibroblast cells can be observed at nanomolar concentrations. Photobleaching under these conditions is minimal.

Self-organized nanofibers and nanorods of porphyrins bearing hydrogen bonding motifs

Porphyrins bearing uracyl motifs at the four meso positions self-organize via homo-complementary hydrogen bonds and pi-stacking into nanofibers, nanorods and thin films on mica and glass surfaces depending on deposition conditions.

Photophysics of Glycosylated Derivatives of a Chlorin, Isobacteriochlorin and Bacteriochlorin for Photodynamic Theragnostics: Discovery of a Two‐photon‐absorbing Photosensitizer

The photophysical properties of a chlorin, isobacteriochlorin and bacteriochlorin built on a core tetrapentafluorophenylporphyrin (TPPF20) and the nonhydrolyzable para thioglycosylated conjugates of these chromophores are presented. The photophysical characterization of these compounds was done in three different solvents to correlate with different environments in cells and tissues. Compared with TPPF20 other dyes have greater absorption in the red region of the visible spectrum and greater fluorescence quantum yields. The excited state lifetimes are from 3 to 11 ns. The radiative and nonradiative rate constants for deactivation of the excited state were estimated from the fluorescence quantum yield and excited state lifetime. The data indicate that the bacteriochlorin has strong absorption bands near 730 nm and efficiently enters the triplet manifold. The isobacteriochlorin has a 40–70% fluorescence quantum yield depending on solvent, so it may be a good fluorescent tag. The isobacteriochlorins also display enhanced two‐photon absorption, thereby allowing the use of 860 nm light to excite the compound. While the two‐photon cross section of 25 GM units is not large, excitation of low chromophore concentrations can induce apoptosis. The glycosylated compounds accumulate in cancer cells and a head and neck squamous carcinoma xenograft tumor model in mice. These compounds are robust to photobleaching.

Adaptive Organic Nanoparticles of a Teflon-Coated Iron (III) Porphyrin Catalytically Activate Dioxygen for Cyclohexene Oxidation

Self-organized organic nanoparticles (ONP) are adaptive to the environmental reaction conditions. ONP of fluorous alkyl iron(III) porphyrin catalytically oxidize cyclohexene to the allylic oxidation products. In contrast, the solvated metalloporphyrin yields both allylic oxidation and epoxidation products. The ONP system facilitates a greener reaction because about 89% reaction medium is water, molecular oxygen is used in place of synthetic oxidants, and the ambient reaction conditions used require less energy. The enhanced catalytic activity of these ONP is unexpected because the metalloporphyrins in the nanoaggregates are in the close proximity and the TON should diminish by self-oxidative degradation. The fluorous alkyl chain stabilizes the ONP toward self-oxidative degradation.

Synthesis and cell phototoxicity of a triply bridged fused diporphyrin appended with six thioglucose units

A triply bridged fused diporphyrin appended with six thioglucose units is reported. This new, chemically and photochemically stable amphiphilic compound is taken up by breast cancer cells and causes cell death upon light exposure. Photophysical studies reveal absorption bands in the near IR region, and photosensitized formation of singlet oxygen in high quantum yields.

Nanoaggregates of Mn(III)tetraperfluorophenylporphyrin: a greener approach for allylic oxidation of olefins

Organic nanoparticles of metalloporphyrins can be a versatile catalyst for the selective oxidation of alkenes and other hydrocarbons. The catalytic activity of the metalloporphyrin depends on the nature of the central metal atom, peripheral groups, and the architecture of the porphyrin macrocycle. Herein, we report the catalytic activity of organic nanoparticles of 5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorophenyl)porphyrinato manganese(III), Mn(III)TPPF20, for the oxidation of cyclohexene using molecular oxygen as an oxidant in aqueous solvent under ambient conditions. While the solvated metalloporphyrins catalytically oxidize alkenes to the corresponding epoxide with a modest turn-over numbers, ca. 30 nm organic nanoparticles of Mn(III)TPPF20 have enhanced catalytic activity with up to a two-fold greater turn-over number and yields only allylic oxidation products. The activity of organic nanoparticles is slow compared to the solvated metalloporphyrins. These organic nanoparticles catalytic systems facilitate a greener reaction since ca. 89% of the reaction medium is water, molecular oxygen is used in place of man-made oxidants, and the ambient reaction conditions require less energy. This organic nanoparticle catalytic system also avoids using halogenated solvents commonly used in solution phase reactions. The enhanced catalytic activity of these organic nanoparticles is unexpected because the metalloporphyrins in the nanoaggregates are in the close proximity and the turn-over number should diminish by self-oxidative degradation.

New porphyrin glyco-conjugates

Porphyrins bearing sugars and other motifs are proposed for a variety of therapeutic applications. Non-hydrolysable glyco conjugates of porphyrins can be formed in rapid, room temperature reacting in greater than 90% yields from tetraperfluorophenyporphyrin. Additional functional groups can be appended using the same chemistry but different stoichiometries of the reagents. Thus sugars, amines, peptides, and cationic moieties designed to target cancer cells or other diseased or disease-causing cells are made rapidly and cleanly. These compounds can then be rapidly screened for cell uptake, or selected from combinatorial libraries by cell uptake assays using a combination of fluorescence microscopy and mass spectrometry. Modifications of the macrocycle allow fine-tuning of the photonic properties for specific medical, imaging, or biochemical applications.

A structural model of nitro-porphyrin dyes based on spectroscopy and density functional theory

Nitro‐porphyrins are an important class of commercial dyes with a range of potential applications. The nitro group is known to dramatically affect the photophysics of the porphyrin, but there are few systematic investigations of the contributing factors. To address this deficiency, we present spectroscopic studies of a series of nitro‐porphyrins, accompanied by density functional theory calculations to elucidate their structures. In particular, we explore how the positions of the substituents affect the energy levels and nuclear geometry. As expected, nitro groups on the meso‐phenyl rings cause small changes to the orbital energies by induction, while those at the β‐pyrrole positions more strongly conjugate into the aromatic system. In addition, however, we find evidence that β‐pyrrole nitro groups distort the porphyrin, creating two non‐planar conformations with distinct properties. This unexpected result helps explain the anomalous photophysics of nitro‐porphyrins reported throughout the literature, including inhomogeneous line broadening and biexponential fluorescence decay.

Compromising the plasma membrane as a secondary target in photodynamic therapy-induced necrosis

Photodynamic therapy (PDT) is a non-invasive treatment widely applied to different cancers. The goal of PDT is the photo-induced destruction of cancer cells by the activation of different cell death mechanisms, including apoptosis and/or necrosis. Recent efforts focusing on understanding the mechanisms of cell death activated by PDT find that it depends on the type of photosensitizer (PS), targeted organelles, and nature of the light used. It is generally accepted that very short incubation times are required to direct the PS to the plasma membrane (PM), while longer periods result in the accumulation of the PS in internal compartments such as the endoplasmic reticulum or mitochondria. Glycosylation of the PS targets cancer via saccharide receptors on the cell surface, and is generally assumed that these compounds rapidly internalize and accumulate, e.g. in the endoplasmic reticulum. Herein we demonstrate that a minor fraction of a glycosylated chlorin compound residing at the PM of cancer cells can activate necrosis upon illumination by compromising the PM independently of the length of the incubation period. The results presented here show that the PM can also be targeted by glycosylated PS designed to accumulate in internal organelles. PS activation to induce necrosis by compromising the plasma membrane has the benefits of fast cell death and shorter irradiation times. The findings described here expand our understanding of the cellular damage induced by phototherapies, presenting the possibility of activating another cell death mechanism based on the incubation time and type of light used.