الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Possibilities for research in the coming decade with new techniques, which follow
the reactions of Pt complexes and nucleic acids and proteins, will allow the detection of
otherwise invisible intermediate products. The need for new platinum antitumor drugs was
underscored by the usefulness of cisplatin and carboplatin in chemotherapy and the
resistance of many tumors to these compounds. Combinatorial chemistry could aid in the
search for cisplatin analogs if fast, high-throughput assays were available. The goal is to
develop rapid cell-based assays suitable for high-throughput screening that accurately
predicts the cytotoxicity of platinum complexes. The next stage in drug design is likely to
be the development of dedicated drugs that comprise the transport (through the
membranes), survival in the cell, binding to the DNA, and eventually, excretion from the
body with minimum side effects. In this process, both metal coordination and hydrogen
bonding will be key factors at the molecular level. Recent advances in medicinal inorganic
chemistry demonstrate significant prospects for the utilization of metal complexes as
drugs, presenting a flourishing arena for inorganic chemistry. Significant progress in
platinum based anticancer agents has been achieved, based in part on a mechanistic
understanding of the DNA-binding and pharmacological effects of cisplatin.
DNAs are the target molecules for most of the metal anticancer agents in human
body. The anticancer nature is the coordination of metal ions with DNA molecules. i.e. the
direct chelation of the metal ions with certain nucleophilic groups in DNA (such as oxygen
sites from phosphates and nitrogen as well as oxygen sites from bases), causing the DNAs’
damage in cancer cells, the DNAs were hindered during the processes of replication or
transcription, the growing and division of the cancer cells were stopped, and resulted in
their death.
When drug molecules (pre-anticancer molecules) enter into an organism, they will
first undergo a series of processes including hydrolysis, transport and membrane-crossing,
and then reach the nearby of the target DNA molecule and form active intermediates which
interact with DNA molecules directly and exert the anticancer activity. These active
intermediates have a general cis-form of two-water-binding transitional state:
[cis-AnM(H2O)2]m+,
where A is stably binding hydrophobic group, n=1, 2 or more and M is metal ion.
The number of water molecules binding to M must not be fewer than two and they
must be lie in the ortho-position of the structure.
The functions of the hydrophobic ligand A are:
(1) caring the whole molecule to cross membranes (including cell membranes and nucleus
membranes), go through the bilipid bilayers.
Introduction
19
(2) making the metal ion to move to the nearby of the base’s cyclic-nitrogen sites and form
covalent bonding.
Metal anticancer complexes are often electrophilic and may react with many cellular
components, such as simple ions and molecules like Cl-,(HPO4)2-,OH- and H2O; amino
acids , peptides and polyphosphates like histidine(His), methionine(Met), cysteine(Cys),
glutathione, metallothionein and ATP. from the view of the coordination chemistry, metal
complexes (including those of Pt ) can bind to several types of possible biomolecules in the
cell. But only the binding on DNA which lead to cell death is considered the most
important. In the case of platinum complexes, it is quite clear that in the cells, after the
relatively slow hydrolysis, cis-Pt have a preference for DNA over proteins and other
molecules. L-methionine increases the rate of reaction of 5’-GMP with cisplatin and that Sbound
L-HMet in the adduct [Pt(dien)(L-HMet-S)]2+ (dien= 1,5-diamino-3-azapentane )
can be replaced by N7 of 5’GMP(177,178). A methionine-contaning protein or peptide could
transport and transfer some platinum to DNA(178).
Thus, in a very simple model, the action process of a metal anticancer agent in an
organism may be briefly summarized into following equations:
DX2 +2H2O [D(H2O)2]2+ +2X-
[D(H2O)2]2+ + DNA [DNA-D]2+ +2H2O
DX2 is the pre-anticancer molecule,
[D(H2O)2]2+ is the active intermediate produced by hydrolysis,
DNA-D is DNA-drug complex.
DNA molecule is a two-pole molecule, its surface is a negatively-charged backbone of phosphatepentose chains. In the inside of double helix there exist hydrophobic bases stacking layer by layer. For exerting its potency, the drug molecules must build with the phosphate groups of DNA at first, and then, with the help of DNA’ conformational dynamic changes (partial unwinding of the double helix), the lipophilic groups of the drug molecule may be drawn by DNA’s hydrophobic sections, the nitrogen sites on DNA molecules may be exposed, the metal atom could invade into the internal part of DNA and coordinates with the bases. Oxygen site on the phosphate group has a higher negative charge relatively, it is a good donor with high electronegativity; so its action with the metal
atom was caused mainly by static electricity, forming electrovalency, belongs to chargecontrolling
reaction. Through the study on hydrolysis mechanism and relationship between structure and activity of metal anticancer agents, the following three points are key if the metal anticancer agents have activities:
(1) Appropriate hydrolysis rates of a complex. (2) Forming the active intermediate [cis-AnM(H2O)2]m+.
(3) Forming of the coordination both with the oxygen of phosphate groups and with nitrogen of bases.
The molecules with high anticancer activities should not only produce active intermediates by the proper hydrolysis rates, but also bind to both oxygen of phosphate groups and nitrogen of base in DNA, thus showing anticancer activity.
The two pole complementary principle (TPCP) has generalized the molecular
structure, action modes and steric selectivity for metal anticancer agents. TPCP includes
three aspects: (1) Two-pole complement in molecular structures: The drug molecules with anticancer activity always have two poles of hydrophilicity and hydrophobicity, positive and negative charges in their structures. Correspondingly, they will present easily-leaving groups and stable keeping groups in a solution. Such two-pole structures can lead the drug molecules not only to be dissolved in water and transported to the surface of the cell membranes, but also to cross the membranes by going through the lipid bilayers and arrive at the nearby of the target molecules.
(2) Two-pole complement in the receptor-substrate action mode: The interaction
between the drug molecule and its target molecule is always executed by forming.