Biomedical subjects

Benjamin J Vesper

Publications and source records attributed to Benjamin J Vesper.

4 recordsLinked to original sources

PubMed2006

Developing a structure-function relationship for anionic porphyrazines exhibiting selective anti-tumor activity.

The porphyrazines (pzs) are a class of porphyrin derivatives being studied for their use as optical imaging agents and photodynamic therapy (PDT) anti-tumor agents. A previous study revealed that the anionic pz, 18--of the form H2[pz(An;B4-n)], where A is [S(CH2)3CO2-], B is a fused beta',beta'-diisopropyloxy benzo group, with n=2 (trans)--selectively killed tumor cells, while analogous neutral and positively charged pzs lacked this property. In this report, we compare the properties of a suite of three H2[pz(An;B4-n)] pzs containing the same A and B groups as 18, but differing in their values of n: pzs 4 (n=4) and 11 (n=3), and 18 (n=2, trans) exhibit a progressive variation in charge due to the carboxylates, balance between hydrophobic/hydrophilic character, as well as a progressive variation in the singlet oxygen quantum yield (PhiDelta): PhiDelta (18)>PhiDelta (11)>PhiDelta (4). The biological activity of the pzs was tested in human lung carcinoma (A549) and SV40 transformed embryonic (WI-38 VA13) cell lines. Pzs 4 and 11 exhibited significant toxicity in both tumor and normal cells, while 18 showed selective anti-tumor cell activity in a dose-dependent manner. As the number of net negative charges decreased, the compounds became less toxic to normal cells, and the killing effect observed with these compounds was light independent. These observations indicate that the toxicity may have little to do with singlet oxygen quantum yields, but rather is more dependent on the net number of negative charges a pz contains. The study reported herein presents an example of how the porphyrazines can be easily modified to vary their biological behavior and specifically suggest that anionic porphyrazines pzs with lower n (fewer carboxylates, larger hydrophobic core) are more specific tumor killers, while those with larger n (increased net negative charge) are more potent tumor killers.

Antineoplastic Agents↗

PubMed2005

Charge dependence of cellular uptake and selective antitumor activity of porphyrazines.

Porphyrazines (pzs), or tetraazaporphyrins, can be viewed as porphyrinic macrocycles in which the porphyrin meso (CH) groups are replaced by nitrogen atoms; as such, it can be anticipated that pzs would show similar biocompatibility and biodistribution to those of porphyrins. However, distinctive chemical and physical features of the pzs differentiate them from either the porphyrins or phthalocyanines, in particular making them excellent candidates as optical imaging/therapeutic agents. The novelty of the pzs requires that we first determine how specific structures selectively alter biological function, leading to the development of "rules" that will be used to predict future biologically functional pzs. In the first of these studies, we present here a correlation of pz charge with biocompatibility for a suite of three pzs-neutral, negative, and positive. Confocal fluorescence microscopy and proliferation/viability measurements disclose that the three pzs differ in their toxicity, uptake, and localization in A549 human lung adenocarcinoma cells and WI-38 VA13 normal cells. Interestingly, the negatively charged pz exhibits selective dark toxicity in pulmonary adenocarcinoma cells.

Antineoplastic Agents↗

PubMed2005

ROM polymerization-capture-release strategy for the chromatography-free synthesis of novel unsymmetrical porphyrazines.

[reaction: see text] Crossover-Linstead macrocyclization reactions of two norbornenyl-tagged diaminomaleonitriles with dipropylmaleonitrile gave access to crude mixtures of porphyrazines containing diamino-hexapropyl-porphyrazine magnesium complexes. The mixtures were subjected to ring-opening metathesis polymerization to yield the insoluble diaminoporphyrazine-functionalized polymers. Acid-mediated cleavage from the polymer backbone followed by acylation of the resultant sensitive macrocyclic diamines gave monoacetyl-, monotrifluoroacetyl-, and ditrifluoroacetyl-substituted porphyrazinediamines. Conversion of these amido-porphyrazines to the corresponding zinc macrocycles and studies of their electronic absorption and emission spectra, electrochemistry, and photophysics are described.

Journal Article↗

PubMed2004

Surface-bound porphyrazines: controlling reduction potentials of self-assembled monolayers through molecular proximity/orientation to a metal surface.

We report the preparation of two novel H2[pz(An;B(4-n))] porphyrazines (pzs) which were designed to position themselves quite differently when attached to a surface: one to form a standard self-assembled monolayer (SAM) roughly perpendicular to a surface, the other to lie horizontally along a surface. As the former, we synthesized a pz, 1, where one pyrrole group is functionalized with two thioethers terminated in mercaptides (SR, R = (CH2)3CONH(CH2)2S-), each protected as a disulfide, and -S-Me is attached to the other pyrrole sites; the latter is a pz, 2, with dialkoxybenzo groups fused to two trans-pyrroles of the pz ring, and SR groups are attached to the other pair of pyrroles. Nanostructures of 1 and 2 were successfully patterned on gold surfaces via dip-pen nanolithography, and the predicted molecular orientation of the resulting structures was confirmed by topographic AFM images. The two pzs exhibit similar reduction potentials in solution. Both show large shifts in potential upon surface binding, with the magnitude of the shift depending on the proximity/orientation of the pz to the surface. The first reduction potential of the "vertically" aligned 1 shifts by ca. +430 mV when incorporated in a binary pz/hexanethiol SAM, while that for 2, which lies flat, shifts by ca. +800 mV; the potential thus shifts by ca. +370 mV upon taking a given pz that stands atop a two-legged insulating "standoff" in a traditional SAM and "laying it down". We suggest these observed effects can be explained by image-charge energetics, and this is supported by a simple model.

Journal Article↗