Though my area of expertise (synthetic organic chemistry) is different from those of Tom Dougherty, we nonetheless managed to actively collaborate on several PDT projects through the intermediacy of Professor Ravi Pandey. This brief talk will concentrate on those projects that we published jointly, and on my memories of Tom, a great scientist, and an even greater friend.
The syntheses and properties of novel water-soluble phthalocyanies are reported, as well as new chemistry of tetrabutanoporphyrins aimed at the preparation of new, functionalizable, tribenzoporphyrin systems. The objective of the study is to provide new second-generation photosensitizing drugs, with long-wavelength absorption, for use in the photodynamic therapy of tumors.
The chlorophyll-a degradation product, purpurin-18 methyl ester (4), was converted into a series of new bacteriochlorins (18)-(20). These stable bacteriochlorins have strong long- wavelength absorptions > 800 nm, and were tested for in vivo photosensitizing activity using the standard screening system of DBA/2 mice bearing transplanted SMT/F tumors. In preliminary screening, among the photosensitizers tested so far, bacteriochlorins (19) and (20) have shown promising anti-tumor activity. Preliminary attempts are described, using photo- Fenton chemistry, to synthesize photosensitizers which display both Type-I and Type-II photochemical behavior.
Photodynamic therapy (PDT) has emerged as a promising modality for the treatment of cancer. We are using newly synthesized and chemically defined and characterized porphyrin photosensitizers that are specifically labeled with deuterium to perform in vivo NMR studies in a murine tumor model. In vivo magnetic resonance offers the potential for repetitive, safe, noninvasive evaluation of photosensitizers, tumor metabolism, and the effect of PDT on the tumor metabolism. In an effort to monitor noninvasively the photosensitizers in an in vivo tumor model, we are synthesizing several deuterium labeled photosensitizers which absorb red light at or above 630 nm. Development of methods to test these photosensitizers directly in humans is not feasible at this time, since these photosensitizers are new and we do not yet understand the side effects. In addition, we do not understand the potential benefits compared with Photofrin II, the widely used photosensitizer. To perform our in vivo deuterium NMR studies on mouse foot tumors, we have constructed a solenoid coil which operates at 30.7 MHz for the deuterium nucleus. We have been able to detect the deuterium labeled photosensitizer in the tumor after a direct intra-tumor injection. The use of <SUP>31</SUP>P NMR to predict the possible outcome of PDT in these tumors is also discussed.
In order to evaluate the effect of substituents in photosensitizing activity, a series of long wavelength absorbing photosensitizers related to pyropheophorbides, bacteriopheophorbides, and benzoporphyrin derivatives were synthesized. Pheophorbide dimers, covalently joining two molecules of pyropheophorbide-a and bacteriopheophorbide-a with lysine as a cross-link were also prepared. The syntheses and spectroscopic properties of these compounds are discussed. Some of these compounds were tested for in vivo photosensitizing activity vis-a-vis Photofrin II<SUP>TM</SUP>, using the standard screening system of DBA/2 mice bearing transplanted SMT/F tumors. The preliminary in vivo results suggest that replacement of substituents at peripheral positions of the macrocycles causes a significant difference in photosensitizing efficacy.
In the first part of this paper, syntheses of water-soluble photosensitizers for use in photodynamic therapy are described. Vinylporphyrins and vinylchlorins react with N.N- dimethylmethyleneammonium iodide (Eschenmoser's reagent) to give 2- (dimethylaminomethyl)vinyl derivatives which can be readily quaternized with methyl iodide to give highly water-soluble quaternary ammonium salts. Deuteroporphyrin-IX dimethyl ester undergoes direct substitution with dimethylaminomethyl at the nuclear 2- and 4-positions. The second part of this report describes the syntheses of bacteriochlorin analogues of natural chlorophyll derivatives; these are obtained by osmium tetraoxide oxidation of chlorins to give vic-dihydroxybacteriochlorins. Acid catalyzed pinacol-pinacolone rearrangements of a number of vic-dihydroxybacterochlorins to given ketobacteriochlorins are described, and the chemistry of the rearrangement is investigated. Biological studies of all sensitizers described will be reported elsewhere.
Syntheses and chemical characterization of a number of new porphyrin-derived sensitizers related to ''benzoporphyrin derivative'' (BPD) are described. The work discussed centers in solving the isomer problem inherent in BPD synthesis from protoporphyrin IX, with regard to the 2- and 4-vinyls and the 6- and 7-propionic acid groups (Fischer nomenclature).
Efficient methods for the syntheses of porphyrin and chlorin dimers joined with variable length carbon units, either at meso positions or at (beta) -pyrrolic positions, are described. The in vivo testing results for some of the dimers are also discussed. The main objective of this work is to understand the structure/activity relationships among carbon-carbon linked dimers of porphyrins and chlorins. It is anticipated that this study will assist the authors in designing photosensitizers with required chemical and photochemical properties.