This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major objective of this proposal is to search for new platinum drugs with improved properties compared to currently used metal based anticancer agents such as cisplatin, carboplatin, etc..., and to discover the molecular basis of their cytotoxicity by studying their reactivity toward biological important molecules (DNA, oligonucleotides) of some of the promising discovered drugs. In order to achieve these goals we plan to determine the better conditions for the synthesis and characterization of two series of platinum(II) complexes. 1.- anionic trihalo complexes of platinum(II) in which either a styrylbenzoheterazole or amide derivatives of important biological active carboxylic acids will be used as ligands. These complexes were designed based on the reported anticancer activity of previously synthesized tribromo anionic complexes of styrylbenzoheterazole which demonstrated a different pattern of cross-linking compared to cisplatin. Although no toxicity studies have been performed on these complexes, we expect to decrease any possible unwanted toxicity by substitution of the bromide ligands by chloride bound to the platinum(II) center on other series of compounds. To study the effect of the ligand on these complexes, the new styrylbenzoheterazole ligands to be used will be modified by placing other substituents (electrondonating and/or electronwithdrawing) on either the benzazolo and/or the styryl moieties, and also by changing the heteroatom (NH, S, O) on the benzazolo part of the ligands. Other ligands to be used for the anionic trihalo complexes include amides derived from reported bioactive carboxylic acids, such as 2-phenylacetic acid, phenylbutyric acid, branched and unbranched saturated fatty acids and unsaturated and polyunsaturated fatty acids. 2.- Neutral platinum(II) complexes in which the one or both of the chloride leaving groups in the parent drugs are substituted by the biological active carboxylic acids mentioned above. The parent drugs involves the use of cisplatin, cis-Pt(DACH)CI2, and cis-Pt(en)CI2, where DACH stands for 1,2-diaminocyclohexane and en for ethylenediamine. The use of these ligands are expected to increase the lipophyllicity and membrane permeability of the new complexes and probably to induce new ways of interactions with the main targets for bioactivity. Also the presence of the carboxylate groups are expected to produce a multifunctional compound in such a way that is known that the leaving groups are realized by the platinum complexes before it is bound to DNA. So, the freed carboxylates should exert their own bioactivity on the cells. All of these compounds will be purified and characterized by elemental analysis, UV-Vis spectroscopy, 1H, 3C, 195Pt and two dimension NMR experiments. They will be also crystallized to obtain crystal good enough for X-Ray Diffraction studies. The biological testing against cancer cell lines will be performed at the Biotesting Laboratory at UPR, Rio Piedras Campus. The long term objectives of the proposed projects is to study the interaction of promising complexes with important biological molecules, such as DNA, which is the main target of known platinum complexes. These interactions will be followed by standard procedures andby NMR spectroscopy and HPLC, and their products characterized. In order to obtain information on the preferred sites of binding of the new complexes, the platinated DNA will be enzymatically digested and their adducts separated chromatographically and identified by 1H NMR spectroscopy.
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