ABSTRACT The photosensitizing and chemosensitizing properties of porphyrins or metalloporphyrins have long been of interest to researchers designing photodynamic therapy or chemotherapy of cancers and tumors. Chemical modification or construction of super hybrid molecules with porphyrins and other functional molecules is a continuous theme in diverse research areas. It is known, but not yet well understood, that porphyrin molecules tend to localize in tumor cells. However, the porphyrin units must be located in a particular structural environment in order to render their specific functions. This review will focus on the DNA reactive porphyrin compounds, including design, synthesis, structure-activity studies, and biomedical application. Naturally occurring porphyrins, such as chlorophylls and haemoglobin, differ in the kind of groups that substitute on the pyrrole rings. In synthetic porphyrins, substitution can be introduced at either meso positions or on pyrroles of porphyrins. Derivatization on pyrrole rings or meso positions of the porphyrin peripheral and/or metallation of the porphyrin core produces a large variety of bio-active porphyrin molecules; these include porphyrinyl nucleosides, nucleotides, and oligonucleotides, which have been the research focus in our laboratory. Structural parameters are closely related to porphyrin derivatives‘ antitumor and antibacterial activities. Porphyrinyl nucleosides have porphyrins and sugar moieties connected through different bonds, such as C-C, C-O, and C-N. The first porphyrinyl-C-glycosides were found in a microalgae, a cyanophyte isolated from a soil sample. The porphyrinyl-N-glycosides synthesized in our lab (U. of I.) represent the first real nucleoside analogs in which a nucleobase is replaced by a porphyrin unit. Porphyrinyl nucleosides with free 3‘ and 5‘ hydroxyl groups have the possibility for elongation and incorporation into nucleic acid sequences. Molecules with porphyrins connected to nucleosides through 3‘ or 5‘ hydroxyl groups may only be incorporated at the terminals of nucleic acids. Porphyrinyl oligonucleotide conjugates have been widely studied as a new direction in antisense and antigene drug research. Synthesis of these conjugates is still a challenging subject. Synthesis in solution phase has been studied in particular by several French and Russian groups. A solid phase strategy was developed in our lab to conjugate porphyrin units with a given oligonucleotide sequence and it offers a cleaner and more efficient conjugation than the solution phase methodology. The introduction of free porphyrins or metalloporphyrins into oligonucleotides not only improves the cellular up-take, nuclease resistance, and DNA/RNA binding affinity of an antisense drug, but also produces photosensitizing or chemosensitizing groups. These can be considered as ribozyme mimics which function to “bind and bite” target molecules.
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