Introduction of metallo drugs into the body exposes them to reaction with many substances into the biological system. While the main targets for these agents are proteins and DNA. Metallo drugs are the pharmaceuticals that contain metals like silver, gold, platinum, especially such anticancer drugs.The complexes of these metals are useful in cancer and tumour treatment. Gold(I) phosphine complexes exhibit promising properties for anticancer drug development.Cisplatin is commonly used cancer drug.proties are easy targets for anticancer. DNA interstrand cross-linking compounds are used as clinical agents in the treatment of cancers and other medical disorders such as anemia and skin diseases.
Interactions of antitumor metallodrugs with serum proteins:-
Serum proteins play a crucial role in the transport, delivery and mechanism of action of anticancer metal-containing drugs, and efficient and convenient analytical methods for a better understanding of their functions help further in developing anti-tumour metallodrugs. Various aspects of protein -metallodrug binding studies are studied and the potential and utilization of conventional and advanced analytical techniques in this growing-in-importance area are examined.
Naphthalimide gold(I) phosphine complexes as anticancer metallodrugs:-
Gold(I) phosphine complexes exhibit promising properties for anticancer drug development. We know gold(I) phosphine complexes contain a naphthalimide ligand. Strong antiproliferative effects were observed in MCF-7 breast cancer cells as well as in HT-29 colon carcinoma cells. The cellular and nuclear gold levels were increased compared to analogues, in which the naphthalimide ligand was replaced by a chloro ligand. Compound 4a was selected for more detailed biochemical and biological studies, which revealed solvent dependent fluorescence emission, uptake of the compound into the organelles of tumor cells as well as antiangiogenic effects concerning angiogenesis and tumor-induced angiogenesis in vivo. Antiangiogenic properties of 4a were observed in two different zebrafish angiogenesis models, including a tumor-cell induced neovascularization assay.
Protein Targets for Anticancer Metallodrugs:-
A series of ruthenium(II)-arene (RAPTA) compds. were evaluated for their ability to inhibit thioredoxin reductase (either cytosolic or mitochondrial) and cathepsin B, two possible targets for anticancer metallodrugs. In general, inhibition of the thioredoxin reductases was lower than that of cathepsin B, although selected compds. were excellent inhibitors of both classes of enzymes in comparison to other metal-based drugs. Some initial structure-activity relationships could be established. On the basis of the obtained data, different mechanisms of binding/inhibition appear to be operative; remarkably the selectivity of the ruthenium compds. toward solid metastatic tumors also correlates to the obsd. trends. Notably, docking studies of the interactions of representative RAPTA compds. with cathepsin B were performed that provided realistic structures for the resulting protein-metallodrug adducts. Good agreement was generally found between the inhibiting potency of the RAPTA compds. and the computed stability of the corresponding cat B/RAPTA adducts.
MECHANISM OF DRUG BINDING TO DNA:-
There are several mechanisms by which drugs can bind DNA [1], the most well understood being alkylation of nucleophilic sites within the double helix. Most clinically effective alkylating agents have two moieties capable of developing transient carbocations that bind covalently to the electron-rich sites on DNA such as the N7 position of guanine (electrophilic agents).
A second mechanism of drug binding to nucleic acids is intercalation, that is, the insertion of a planar (generally aromatic) ring molecule between two adjacent nucleotides of DNA. This mechanism is characteristic of many antitumor antibiotics, such as daunorubicin and doxorubicin. The antibiotic molecule is noncovalently, although firmly, bound to DNA and distorts the shape of the double helix resulting in inhibition of DNA replication and RNA transcription.
Third mechanism of DNA damage is illustrated by bleomycins. These glycopeptides intercalate between guanine-cytosine base pairs of DNA. The end of the peptide binds Fe(II), able to catalyze the reduction of molecular oxygen to superoxide or hydroxyl radicals, that produce DNA strand scission by oxidative stress.
DEVELOPMENT OF ANTI TUMOR METALLO DRUGS:-
The development of antitumor metallodrugs has been stimulated by the clinical success of
cis-diamminedichloroplatinum(II) (cisplatin) and its analogues and by the clinical trials of
other platinum complexes with activity against resistant tumors and reduced toxicity.
Broadening the spectrum of antitumor drugs depends on understanding existing agents with a
view toward developing new modes of attack. It is therefore of great interest to understand
details of molecular and biochemical mechanisms underlying the biological efficacy of the
platinum and other transition metal compounds. There is a large body of experimental
evidence that the success of platinum complexes in killing tumor cells results from their
ability to form on DNA various types of covalent adducts so that the research of DNA
modifications by platinum complexes exhibiting different antitumor efficacy has
predominated. The present review summarizes recent advances in this research area also
including recognition of platinated DNA by specific proteins and its repair. It also provides a
strong support for the view that (i) there is a correlation between antitumor activity of
platinum compounds and their capability to induce in DNA a certain sort of conformational
and other alterations; (ii) this correlation may be exploited for simple screening of new
platinum complexes for antitumor activity in the search for new antitumor platinum drugs. It
is also demonstrated in the present article that this concept has already led to the synthesis of
several new platinum antitumor compounds that violate the original structure-activity
relationships.
