Preparation of Tetracationic Metalloporphyrin−Spermine Conjugates

Abstract

The preparation of tetracationic metalloporphyrin precursors for the attachement to DNA binding molecules is reported. Based on a D 4 h tetrapyridylporphyrin, such precursors are more accessible than the classical tailored tricationic porphyrin derivatives used as DNA cleavers. meso-Tetrapyridylporphyrin was reacted with ethyl bromopentanoate and methyl iodide to afford a monofunctionalized ester derivative of 1 which was hydrolyzed to the corresponding acid 5. This acid was reacted with spermine and BOP to yield conjugates containing one (6) or two (7) porphyrin units that were metalated with Mn(II) salts to afford the metalloporphyrins 6−Mn and 7−Mn. Furthermore, 6−Mn was linked to 5 to yield a spermine conjugate 8 containing two porphyrin moieties, one of which was metalated. The DNA cleavage activity of these different metalloporphyrins was studied in the presence of KHSO5 with double-stranded ΦX174 DNA. Conjugate 5−Mn, the spermine containing compound 6−Mn, and compound 7−Mn which contained two porphyrin moieties showed cleavage activities similar to that of the parent DNA cleaver 1−Mn. The porphyrin conjugate 8 which contained one metalated and one nonmetalated porphyrin had half the efficiency of 1−Mn. None of the synthesized compounds were able to induce direct double-strand breaks in the experimental conditions used.

Thermodynamic investigation of a new water-soluble porphyrin with calf thymus DNA

“…Porphyrins were prepared and purified according to literature methods [43,44]. 5,10,15,20-tetrapyridyl porphyrin (TPyP) (Fluka), 5-bromopentanoate, methyl iodide (Acros chemicals) were used as received.…”

New Porphyrin-Nucleobase Hybrid Compounds and Their Interaction with Nucleosides and Nucleic Acids

“…[7] Generally, however, the yield of the final product does not exceed 5Ϫ7% if the ''mixed aldehyde'' procedure involving Little's adaptation [8] of AdlerϪLongo [9] conditions is used at the first step. A better approach has recently been devised by Meunier et al, [10] the symmetrical T4PyP being monoalkylated with the linker and converted into the hybrid molecule, with subsequent quaternization of the remaining pyridyl fragments, giving fairly high yields based on commercially available T4PyP.…”

“…The formation of the water-soluble derivative takes place in the last step, through methylation of pyridyl fragments, [7,10,12] but substitution at the N-1 adenine position also takes place under these conditions (MeI/DMF, room temp.). [11] This problem cannot be overcome by changing the reaction conditions, but only through a change of the synthetic strategy.…”

“…Synthetic pathways via the mono-phenoxy porphyrin derivative 1 T4PyP with Br-(CH 2 ) 6 -thymine under conditions as given in ref. [10] and further methylation were also unsuccessful. It is known that alkylation of the pyridyl group in T4PyP by iodo-or bromoalkyl derivatives is a clean reaction in various solvents (DMF, DMSO, MeCN, MeNO 2 , etc).…”

“…This approach may be considered as a complementary method to the Meunier technique mentioned above. [10] Several conditions for preparation of fully alkylated pyridylporphyrins have been reported, [6] but the partially methylated T4PyP had not been described until now, [19] although there are a few reports on other partially alkylated derivatives. [20] We examined several systems (methyl p-toluenesulfonate (MTS)/DMF; MTS/MeNO 2 ; MeI/DMF) and have found conditions under which 5,10,15-tris(1-methylpyridinium-4-yl)-20-pyridin-4-ylporphyrin 9 [Tri(MPy)PyP] could be obtained with yields of about 35% (Scheme 3).…”