Synthesis and cellular studies of polyamine conjugates of a mercaptomethyl–carboranylporphyrin

Abstract

Seven polyamine conjugates of a tri(p-carboranylmethylthio)tetrafluorophenylporphyrin were prepared in high yields by sequential substitution of the p-phenyl fluoride of tetrakis(pentafluorophenyl)porphyrin (TPPF), and investigated as boron delivery agents for boron neutron capture therapy (BNCT). The polyamines used were derivatives of the natural-occurring spermine with different lengths of the carbon chains, terminal primary amine groups and, in two of the conjugates, additional aminoethyl moieties. A tri(polyethylene glycol) conjugate was also synthesized for comparison purposes. The polyamine conjugates showed low dark cytotoxicity (IC50 > 400 μM) and low phototoxicity (IC50 > 40 μM at 1.5 J/cm2). All polyamine conjugates, with one exception, showed higher uptake into human glioma T98G cells (up to 12-fold) than the PEG conjugate, and localized preferentially in the cell ER, Golgi and the lysosomes. Our results show that spermine derivatives can serve as effective carriers of boronated porphyrins for the BNCT of tumors.

Synthesis and Transformations of 5‐Chloro‐2,2′‐Dipyrrins and Their Boron Complexes, 8‐Chloro‐BODIPYs

“…Two sulfur nucleophiles were also reacted with BODIPY 4a , in THF and in the presence of K 2 CO 3 as the base (Scheme 4). 2-Mercaptobenzothiazole gave BODIPY 16 in 56% yield, whereas 1-mercaptomethyl- p -carborane [27] gave 17 in 92% yield. BODIPYs 16 and 17 showed redshifted UV/Vis absorptions at 539 and 529 nm, respectively.…”

Synthesis and in Vitro Evaluation of BBB Permeability, Tumor Cell Uptake, and Cytotoxicity of a Series of Carboranylporphyrin Conjugates

“…We have reported the synthesis and investigation of promising dual sensitizers for application in combined PDT and BNCT treatment, H 2 TCP 14,15 and TPFC, 16 that show efficient photosensitizing activity against melanotic melanomas. We have also demonstrated that conjugation of a boron-containing porphyrin to polyamines (Figure 1) 17 or to a cell-penetrating peptide sequence 18 significantly increases their cellular uptake by approximately 12-fold. Herein, we report the synthesis and conjugation of a fluorinated p -carbonylmethylthioporphyrin to linear and branched polyamines, glucose, arginine, and Tyr- d -Arg-Phe-β-Ala (YRFA) peptide.…”

“…The carboxyl-terminated tri(ethylene glycol)porphyrin 6 (17) was conjugated in solution phase to l -arginine, using HATU and DIEA, to produce conjugate 7 in 89% yield and in solid phase to YRFA, using DEPBT, HOBt, and DIEA, to produce 8 in 65% yield after HPLC purifications.…”

Influence of N atom number and form on the photodynamic activities of zinc phthalocyanines

“…4. The results showed that all phthalocyanine derivatives studied produce singlet oxygen, as showed in Table 2, the exact reaction rate constant (k) followed the order k ZnPcB (0.11627) > k ZnPcA (0.05294); k ZnPcB1 (0.14648) > k ZnPcA1 (0.08478); k ZnPcB2 (0.16023) > k ZnPcA2 (0.11282), depending on the number of amine groups [21]. For non-ionic ZnPcA and ZnPcB, the larger number of amine groups and the carbon skeleton might increase steric hindrance, besides, non-ionic ZnPcB probably involvement in hydrogen-bonding to aqueous solution.…”

“…As shown in Table 3, significant difference in cellular uptake efficiency was obtained from the three groups of phthalocyanine, the uptake of these ZnPcs follow the order ZnPcB > ZnPcA, ZnPcB1 > ZnPcA1, ZnPcB2 > ZnPcA2. For ZnPcB might be attributable to it larger number of nitrogens; such derivatives may accumulate in cells via the polyamine transportsystem [23]. In addition, the quaternization and protonation of polyamines demonstrated that positive charge densities at peripheral parts of substituent of ZnPc molecules were responsible for their binding to negatively charged membranes on the cell surface [24], which can efficiently promote the uptake of ZnPcs.…”