Chemistry has had varying roles in the discovery and development of anticancer drugs since the beginning of cancer therapies.13 In its early history, chemical modification of sulfur mustard gas led to the serendipitous discovery of the still clinically useful nitrogen mustards. Since those years, synthetic chemistry has been extensively used to modify drug leads, especially those of natural origin, and to solve the problem of the often scarce supply of natural products by developing semisynthetic or synthetic strategies (see Section 3).
Since the 1950s, chemistry has also generated many antitumor drug leads through in vitro screening programs promoted by the National Cancer Institute (NCI) in the United States by using a range of cancer cell lines. In this early period, transplantable rodent tumors models characterized by a high growth rate were used for in vivo screening. Later on, human tumor xenografts, based on transplantation of human tumor tissue into immune-tolerant animals, became also important tools for selecting antitumor drugs because the xenograft models allowed to simulate a chemotherapeutic effect under conditions closer to man. In the late seventies and early eighties, the role of chemotherapy was extended to preoperative and postoperative adjuvants, radiosensitizers to enhance radiation effects, and supportive therapy to increase the tolerance of the organism toward toxicity.14
The rationale for the use of conventional cytotoxic antitumor drugs is based on the theory that rapidly proliferating and dividing cells are more sensitive to these compounds than the normal cells.15 The interactions of cytotoxic agents with DNA are now better defined, and new compounds that target particular base sequences may inhibit transcription factors in a more specific manner. DNA can be considered as a true molecular receptor that is capable of molecular recognition and of triggering response elements which transmit signals through protein interactions.16 The binding properties of DNA ligands can be rationalized on the basis of their structural and electronic complementarity with the functional groups present in the major and minor grooves of particular DNA sequences which are mainly recognized by specific hydrogen bonds.17
Although DNA continues to be an essential target for anticancer chemotherapy, much recent effort has been directed to discover antitumor drugs specifically suited to target molecular aberrations which are specific to tumor cells.18 This new generation of antitumor agents is based on research in areas such as cell signaling processes, angiogenesis and metastasis, and inhibition of enzymes that, like telo-merase, are reactivated in the majority of cancer cells.19 These goals may use small molecule drugs or other macromolecular structures, such as monoclonal antibodies that bind to antigens present preferentially or exclusively on tumor cells. The aim of other research programs is to develop compounds that interfere with gene expression to suppress the production of damaged proteins involved in carcinogenesis. In the antisense approach, the mRNA translation is interfered thereby inhibiting the translation of the information at the ribosome, while in the antigene therapy, a direct binding to the DNA double strand inhibits transcription.20
The knowledge of the three-dimensional structure of these new target macro-molecules, which are normally proteins, by using X-ray crystallography, permits the rational design of small molecules that mimic the stereochemical features of the macromolecule functional domains. The principal steps in structure-based drug design using X-ray techniques are summarized in Fig. 1.1. In the absence of a three-dimensional structure of a target protein, homology criteria may be applied using the experimental structure of similar proteins, which is especially useful in the case of individual subfamilies. The knowledge of the three-dimensional structure of a target also permits to design and generate virtual libraries of potential drug molecules to be used for in silico screening.
Progress in the development of potential drug molecules is often problematic because it is difficult to convert them into ''druggable'' compounds, that is, into molecules with adequate pharmaceutical properties. To this end, it is absolutely necessary to know the chemical properties of a lead compound, especially solubility and reactivity, because these properties are relevant for cellular uptake and metabolism in order to transform this lead compound into a real drug. The ''druggability'' of a drug candidate describes their adequate absorption, distribution, metabolism, and excretion (ADME) properties. In this task, the structural knowledge of important metabolic enzymes, such as cytochrome P450 3A4 (CYP3A4), will permit to improve the effectiveness and patient tolerance for antitumor compounds. A preliminary knowledge of ADME properties may be now gained by using in silico techniques, although an experienced chemist can provide
Define a target macromolecule
Isolate, purify and crystallize the target macromolecule
X-Ray three-dimensional structure determination of the target macromolecule
Find a ligand from a known lead compound or from screening
Propose a model of interaction
Corecrystallize the complex ligand-macromolecule and determine its structure
Propose and obtain ligands with improved interactions
Undertake cell-based and other biological assays
accurate insights into this picture only by simple inspection of a given structure. The chemical properties of a drug candidate also govern its proposed formulation.
In this list of contributions to the development of antitumor agents, it has to be mentioned that chemistry has also made possible important advances in prodrug development and in related targeted approaches, such as antibody-coupled drugs or photoactive agents.
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