Synthesis and Nucleic Acid-Binding Properties of Water-Soluble Porphyrins Appending Platinum(II) Complexes.

Abstract

There has been considerable interest in understanding the binding of the antitumor drug cis-dichlorodiammine platinum(II) (CDDP) and its analogs to their putative target DNA in cancer cells.1) Platinum complexes can bind rapidly to nucleic acids (including DNA) in aqueous solution and therefore are useful as a functional group to design artificial receptors for DNA. The anti-cancer activity of CDDP arises from its ability to damage DNA by forming a major adduct with intrastrand d(GpG) and d(ApG) crosslinks.2) These crosslinks of CDDP to d(GpG) and d(ApG) bend and unwind the duplex, and then the altered structure attracts high-mobility-group (HMG) domain proteins.3) This binding of HMGdomain proteins to CDDP-modified DNA has been postulated to mediate the antitumor properties of the drugs. 4)Studies on the binding of cationic porphyrins to DNA have been of great significance to those working in cancer research and gene technology. 5) Some cationic porphyrins bearing quaternary ammonium salt units such as ammonium or pyridinium groups can act as binders for DNA. Several researchers have investigated how cationic porphyrins bind to DNA in groove or outside binding on the basis of Coulomb and/or hydrophobic interactions.5a,c,6) We designed and synthesized two water-soluble porphyrins appending platinum(II) complexes and studied their reactions with a variety of DNA and nucleic acids. In the porphyrins, cationic groups of the appended platinum(II) complex solubilize the porphyrins to water and provide coordination ability for binding to DNA. Furthermore, because the cationic porphyrins can also bind to DNA, the platinum(II) complexes appended by the porphyrins are expected to function additively with the porphyrins and then bind strongly to DNA.This report describes the synthesis of two derivatives of 5,15-bis(o-substituted phenyl)porphyrin appending two chlorodiammineplatinum(II) complexes at the ortho position of the two phenyl rings of the porphyrin (see 4a and 4b in Fig. 1). We then studied their reactions with a variety of nucleic acids [disodium adenosine-5Ј-monophosphate (AMP), disodium guanosine-5Ј-monophosphate (GMP), disodium thymine-5Ј-monophosphate (TMP), disodium cytidine-5Ј-monophosphate (CMP), synthetic polymer poly(dG)-poly(dC), poly(dA)-poly(dT)] using 1 H-NMR, UV-vis or FAB-MS spectroscopies. Results and DiscussionSyntheses and Characterization of Water-Soluble Porphyrins Appending Platinum(II) Complexes or Quaternary Ammonium Groups Syntheses of the water-soluble porphyrins with two platinum(II) complexes are outlined in Fig. 1. Condensation of (tetramethyldipyrryl)methane 7) with o-phthalaldehydic acid gave porphyrinogen 1 in a good yield. Oxidation of the porphyrinogen to porphyrin 2 was accomplished by using o-chloranil. Because of the limited solubility of 2, the chromatographic separation of the two atropisomers could not be accomplished; it was achieved after deriving to aminoethylcarbamides 3a and 3b. Compound 3b was hydorolyzed with hydrochloric acid (6 M), and a treatment of the hydrolyzed...

Water-Soluble Porphyrins Appending Platinum(II) Complexes as Binders for Synthetic Nucleic Acid Polymers

“…Comparisons of the spectral changes with those with poly(dA)-poly(dT) suggest that the first step will be the electrostatic association of the porphyrins with GMP. We speculate that the changes in the second step are due to the coordination of GMP to Pt in the porphyrins, 3) because a similar reaction for the binding of CDDP with GMP have been reported. 11,12) Since such binding behavior was not observed for both cases of these porphyrins with poly(dA)-poly(dT) and of porphyrins with quaternary ammonium groups such as TMPyPs, 1,3) the coordinative interaction seems to dominate over or to eclipse the Coulomb interaction.…”

“…Thus the presence of the porphyrins did not cause significant changes in the melting temperature of poly(dA)-poly(dT), and the reannealing phenomenon was observed. These results indicate that the porphyrins bind to poly(dA)-poly(dT) by Coulomb interaction, 3) similar to the case of cationic porphyrins with quaternary ammonium groups, such as meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (TMPyP). (Fig.…”

“…We have reported 3) the synthesis of water-soluble porphyrins appending two platinum(II) complexes and their binding properties with nucleotides and synthetic nucleic acids polymers are discussed. The binding modes between the porphyrins and synthetic nucleic acid polymers were explained based on coordinative, Coulomb, and hydrophobic interactions.…”

Synthesis of 5-(4-methacrylamidophenyl)-10,15,20-triphenylporphyrin, its copolymerization with acrylamide and EDMA, use of this copolymer in the adsorption of bovine serum albumin

“…The ability of some porphyrins and metalloporphyrins to interact with or aggregate onto biomolecules is well known [9][10][11][12][13][14][15][16][17][18][19][20]. Because porphyrins selectively accumulates in tumorous cells, a great deal amount of research has been devoted to their potential photosensitizing efficacy in photodynamic therapy, magnetic resonance imaging, and transmissible spongiform encepalopathy therapy [21] and binding studies of porphyrins to DNA have been great of significance to those working in cancer research [17,20].…”

“…Because porphyrins selectively accumulates in tumorous cells, a great deal amount of research has been devoted to their potential photosensitizing efficacy in photodynamic therapy, magnetic resonance imaging, and transmissible spongiform encepalopathy therapy [21] and binding studies of porphyrins to DNA have been great of significance to those working in cancer research [17,20]. It was reported that some cationic water-soluble porphyrins bearing quaternary ammonium groups can interact strongly with DNA in aqueous solution [12,22].…”