Utilizing linear dichroism (LD), circular dichroism (CD), and fluorescence energy transfer, the binding geometries of a series of Co(3+)-porphyrins and their free ligands were examined. The compounds studied were Co-meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (CoTMPyP) and its free ligand (H2-TMPyP), Co-meso-tetrakis(N-n-butylpyridinium-4-yl)porphyrin (CoTBPyP) and its free ligand (H2TBPyP), and Co-meso-tetrakis(N-n-octylpyridinium-4-yl)porphyrin (CoTOPyP). The two non-metalloporphyrins exhibit negative LD, having angles of roughly 75 degrees relative to the DNA helix axis. They also display negative CD and a significant contact energy transfer from the DNA bases. On the other hand, the three metalloporphyrins display orientation angles of roughly 45 degrees between the porphyrin plane and the helix axis of DNA. Furthermore, they exhibit positive CD and no contact energy transfer from DNA bases. These observations show that the metalloporphyrins are not intercalated whereas non-metalloporphyrins having four freely rotating meso-aryl groups intercalate between the base pairs of DNA. In the presence of KHSO5, the cobalt porphyrins cleave closed circular PM2 DNA in a single strand manner, i.e., a single activation event on the porphyrin leads to a break in one of the DNA strands. A kinetic analysis of the cleavage data revealed that cleavage rates are in the order CoTMPyP > CoTBPyP > CoTOPyP with the difference being due to different DNA affinities rather than differences in cleavage rate-constants. Based on these and earlier observations, the metalloporphyrins appear bound to a partially melted region of DNA.
The complex cis,trans,cis-[PtCl(2)(OAc)(2)NH(3)(c-C(6)H(11)NH(2))] (JM-216) is currently undergoing clinical evaluation as an antitumor agent. In support of characterization and analysis of this complex a study of its isomers and other complexes [PtCl(m)()(OAc)((4)(-)(m)()())NH(3)(c-C(6)H(11)NH(2))] (m = 0-4) has been undertaken. The complexes have been obtained by a variety of synthetic routes which now extend the scope for the preparation of platinum(IV) antitumor complexes. As platinum(IV) complexes are very stable to substitution in the absence of catalysis, use has been made of both light and base catalysis to promote substitution. Oxidative addition to platinum(II) using hypervalent iodine reagents has also been used. The stereochemistry of the complexes has been confirmed by spectroscopic studies, primarily NMR including natural abundance (15)N NMR spectroscopy.
The ability of two platinum(IV) antitumor agents, cis,cis,trans-PtIV[(CH3)2CHNH2]2Cl2(OH)2 (2) and cis,cis,trans-PtIV(NH3)2Cl2(OH)2 (4), to interact with PM2 DNA was examined. Analysis using gel electrophoresis showed that neither compound is able to alter the electrophoretic mobilities of the three forms of PM2 DNA in the gel. However, incubation of 2 and 4 with 2 equiv of Fe(ClO4)2 X 6H2O or 1 equiv of ascorbic acid results in reduction to yield the divalent complexes cis-PtII(NH3)2Cl2 (1) and cis-PtII-[(CH3)2CHNH2]2Cl2 (3). The structures of the reduction products were characterized by using elemental analysis as well as infrared and 195Pt NMR spectroscopies. Both 1 and 3 were found to bind to and unwind supercoiled form I PM2 DNA. The aforementioned observations support the suggestion that reduction is a means of activating the antitumor properties of 2 and 4.
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