Synthesis and Studies of Core-Modified Tellura Dithiasapphyrins.

Four different aromatic meso-substituted tellurophene-containing dithiasapphyrins were synthesized by acid-catalyzed [3+2] condensation of 16-telluratripyrrane with bithiophene diol in 22-23% yields. The structural, spectral, and electrochemical properties of tellura dithiasapphyrins were studied and compared with those of previously reported aza (pyrrole)- and other heterocycle (furan, thiophene, and selenophene)-containing dithiasapphyrins. Nuclear magnetic resonance studies indicated that the tellurophene ring in tellura dithiasapphyrins is in the normal conformation, facing toward the inner core, but flips in diprotonated derivatives to an inverted conformation, facing away from the macrocyclic core, unlike aza- and other heterocycle-containing dithiasapphyrins in which pyrrole and the corresponding heterocycle ring always prefer to be in inverted conformation in their neutral and protonated forms. The crystal structure obtained for one of the tellura dithiasapphyrins showed that the macrocycle is highly planar and the tellurophene ring is in the normal conformation. The absorption spectra of tellura dithiasapphyrins exhibited slight hypsochromic shifts compared to those of pyrrole- and other heterocycle-containing dithiasapphyrins. The redox studies indicated that the tellura dithiasapphyrins are electron deficient and readily undergoes reductions. Density functional theory and nuclear independent chemical shift studies indicated that the macrocycles are aromatic, and the computational results closely matched the experimental observations.

Tellurophene-Containing Core-Modified Pentaphyrin(2.1.1.1.1)s.

Various core-modified tellurophene-containing pentaphyrin(2.1.1.1.1)s were synthesized via (3 + 2) condensation of 16-telluratripyrrane with different heterodiols under mild acid catalyzed conditions in 5-12% yields. The formation of pentaphyrin (2.1.1.1.1) with a N2O2Te core was not successful due to its inherent instability. The new pentaphyrins were characterized and studied by HR-MS, 1D and 2D NMR, X-ray crystallography for one of the pentaphyrins, absorption and DFT/TD-DFT techniques. The NMR studies indicated their nonaromatic nature. The X-ray structure obtained for pentaphyrin(2.1.1.1.1) with N4Te core revealed that the macrocycle exists in a highly distorted nonplanar structure. The DFT studies showed that the macrocycles are nonaromatic and exists in highly distorted nonplanar geometry. Furthermore, as the core heterocyclic groups at ethene moiety were changed from pyrrole to furan to thiophene to benzene, the macrocycles tended toward more planar structures. The absorption spectra of pentaphyrins showed one strong sharp band in the region of 450-540 nm along with a broad band in the region of 700-800 nm. The pentaphyrin(2.1.1.1.1) with N4Te core upon protonation showed distinct color change in solution and large bathochromic shifts in absorption bands with an absorption in the NIR region.

Crowned Macrocycles Containing Two Pyrrolo[1,2-a] Indoles Created By Intramolecular Fusion.

Heterocyclic fused-ring systems are of utmost importance because of their presence in many natural products with biological activity. Pyrroloindoles are tricyclic heterocycles that are present in various bioactive and medicinally valuable compounds. Herein, we report the synthesis of phenylene-bridged bis-pyrrolo[1,2-a]indole crowned macrocycles 1-3 in which the pyrrolo[1,2-a]indole moieties were formed via intramolecular fusion. The macrocycles were thoroughly characterized by 1D and 2D NMR, HRMS and X-ray crystallographic studies. The X-ray structure revealed that the two pyrrolo[1,2-a]indole moieties were parallel to each other, and one pyrrolo[1,2-a]indole unit was deviated by an angle of 9.54° while the other pyrrolo[1,2-a]indole unit was deviated by an angle of 12.0° from the mean plane defined by 28 core atoms. The macrocycles 1-3 absorb in the visible region and readily undergo oxidations because of their electron rich nature. The macrocycles 1-3 upon treatment with trifluoroacetic acid (TFA) generates the corresponding cation radicals 1-3.+ which were stable in the open air for a week. The cation radicals 1-3.+ absorb strongly in the NIR region and the experimental observations on crowned macrocycles 1-3 were corroborated by DFT and TD-DFT studies.

Cell-Penetrating Peptide-Conjugated BF2 -Oxasmaragdyrins as NIRF Imaging and Photothermal Agents.

Cell-penetrating peptides (CPPs) are excellent cell internalizing agents for hydrophobic drug/dye moieties. We exploited this property of CPPs for the cell internalization of BF2 -oxasmaragdyrin by constructing covalent conjugates of BF2 -oxasmaragdyrin with CPPs (CRGDK and polyarginine (R9 )) using a solid-phase peptide synthesis (SPPS) methodology. The CPP-conjugated BF2 -oxasmaragdyrins were purified by reversed-phase HPLC and characterized by mass spectrometry. The CPP-conjugated BF2 -oxasmaragdyrins were found to be photostable, absorb in the visible-NIR region (400-700 nm), emit in the NIR-I region (∼715-720 nm) with moderate quantum yields, and be biocompatible, with excellent cellular imaging potential in breast cancer cells (MDA-MB-231). The R9 conjugate, being the first water-soluble BF2 -oxasmaragdyrin, also possesses excellent photothermal transduction efficacy with 750 nm laser irradiation and is a potential theranostic agent.

BF2-Oxasmaragdyrin Nanoparticles: A Non-toxic, Photostable, Enhanced Non-radiative Decay-Assisted Efficient Photothermal Cancer Theragnostic Agent.

Photothermal therapy (PTT), a simple and minimally invasive procedure, is an attractive option for cancer therapy. To date, inorganic agents have been widely employed as photothermal agents; however, organic molecules may provide a solution to rapid metabolic/in vivo clearance. Herein, we prepared lipid (S 75)-stabilized meso-tritolyl-BF2-oxasmaragdyrin nanoparticles (TBSNPs) using thin-film hydration and homogenization. Assessment of the physicochemical properties of the TBSNPs reveals the formation of particles of size <12 nm stabilized within the lipid matrix. The TBSNPs exhibit near infrared fluorescence (NIRF) being accompanied by an increase in non-radiative decay, leading to excellent photothermal properties. In vitro studies demonstrate excellent biocompatibility, hemocompatibility, cellular internalization, and photothermal efficacy (p = 0.0004). Extensive in vivo assessment of TBSNPs also highlights the non-toxic nature of the material and passive tumor homing. The strong NIRF exhibited by the material is exploited for whole-body imaging in the rodent model. The novel material also shows excellent photothermal efficacy (p = 0.0002) in a 4T1 xenograft mice model. The organic nature of the material coupled with its small size and strong NIRF provides an advantage for bio-elimination and potential clinical image-guided therapy over the inorganic counterparts.

Antiaromatic Carbaporphyrinoids: Fluorene as a Fused Motif toward the Synthesis of meso-Fused Heterobenziporphyrins.

meso-Tetraphenyl meta-benziporphyrins are nonaromatic macrocycles which can be changed to antiaromatic by fusing the core benzene ring with one of the adjacent meso-phenyl groups, as demonstrated here by adopting a premodification method. We used a fluorene moiety in place of the m-phenylene ring as a premodified fused aromatic motif to synthesize fused heterobenziporphyrins. Spectral and X-ray data indicated that the macrocycles are antiaromatic, which was supported by DFT, ACID, and NICS calculations. These macrocycles formed organopalladium complexes.