Current Medicinal Chemistry - Anti-Cancer Agents - Volume 1, Issue 3, 2001

There is considerable interest in the development of sequence-selective DNA drugs. Chemical agents able to interfere with DNA topoisomerases - essential nuclear enzymes- are widespread in nature, and some of them have outstanding therapeutic efficacy in human cancer and infectious diseases. Several classes of antineoplastic drugs, such as amsacrine, daunorubicin, etoposide (acting on type II topoisomerases), camptothecin and indolocarbazole derivatives of the antibiotic rebeccamycin (acting on type IB topoisomerases, have been shown to stimulate DNA cleavage by topoisomerases leading to cell death. However, these molecules exhibit little sequence preference. A convenient strategy to confer sequence specificity consists in the attachment of these topoisomerase poisons to sequence-specific DNA binding elements. Among sequence-specific DNA ligands, oligonucleotides can bind with high specificity of recognition to the major groove of double-helical DNA, resulting in triple helix formation. In this context, derivatives of camptothecin, indolocarbazole, anthracycline and acridine poisons have been covalently tethered to triple helix-forming oligonucleotides. The use of triple-helical DNA structures offers an efficient system to target topoisomerase I and II-mediated DNA cleavage to specific sequences and to increase the drug efficacy at these sites. Chemical optimization of the conjugates is essential to the efficacy of drug targeting. Consequently, the rational design of this new class of anti-cancer agents, conceived from topoisomerase poisons and triplex-forming oligonucleotides, may be exploited to improve the efficacy and selectivity of the DNA damage induced by topoisomerases.

Naphthalimides are a class of compounds with high antitumor activity upon a variety of murine and human tumor cells. These compounds bind to DNA by intercalation of the chromophore and two of them, mitonafide and amonafide, were used in clinical trials. The therapeutic properties of these lead drugs were improved by designing bisintercalating agents. One of these, elinafide, showed intense in vitro and in vivo activity and is currently being used in clinical trials against solid tumors. In this paper, the history of elinafide is described.

Ecteinascidins are marine natural products consisting of two or three linked tetrahydroisoquinoline subunits and an active carbinolamine functional group. Their potent antiproliferative activity against a variety of tumor cells has made them attractive candidates for development as anticancer agents. The lead compound, ecteinascidin 743 (ET 743), is currently in phase II clinical trials but the low amounts present in its natural source, the tunicate Ecteinascidia turbinata, made it necessary to develop efficient synthetic procedures. Recent improvements on the original synthesis are reviewed as well as new strategies starting from readily available cyanosafracin B. ET 743 is known to bind to the minor groove of DNA giving rise to a covalent adduct with the exocyclic amino group at position 2 of a guanine in a fashion similar to saframycin antibiotics. Some of the resulting complexes have been studied by a variety of biochemical and spectroscopic methods and also by computer simulations. The rules for sequence specificity have been well established (preferred targets are RGC and YGG, where R and Y stand for purine and pyrimidine, respectively), and it has been shown that binding of ET 743 to DNA is accompanied by minor groove widening and DNA bending towards the major groove. Although the precise target for antitumor action remains to be unambiguously defined, a role in affecting the transcriptional regulation of some inducible genes is rapidly emerging.

The applications of surface plasmon resonance (SPR) and biosensor technology for biospecific interaction analysis (BIA) of molecular interactions between transcription modifiers and target biomolecules is here described for the identification of possible candidates for drug research and development in antitumor and antiviral therapy. SPR-based BIA offers many advantages with respect to most of the other available methodologies to study biomolecular interactions. It should be underlined that (a) most commercially available biosensors are fully automated instruments (b) no labelling is required (c) a large variety of activated sensor chips are commercially available allowing the immobilization of either proteins or target DNA or RNA (d) the amount of both ligand and analyte needed to obtain informative results is low (e) the assay is rapid and (f) the sensor chip could be re-used many times, leading to low running costs, with the only limitation of verifying the stability of the immobilized ligand. Approaches employing SPR-based BIA were described for the development of (a) triple-helix forming oligonucleotides (TFO) and peptide nucleic acids (PNAs), (b) DNA-binding drugs, (c) decoy molecules and (d) PNAs able to perform strand invasion. All these biomolecules are of great interest for the development of transcription modifiers. Since alteration of the expression of transcription factors is involved in tumor cell growth and metastasis, SPR-based BIA appears to be a methodology of great impact in the design and development of anti-cancer agents.

Many studies that have been conducted to establish the cytotoxic potency of styryl lactones for several tumor cell lines is described. Extensive examination of the activity of more than 50 cytotoxic styryl lactones isolated / synthesized belonging to the genus goniothalamus representing future generation of antitumor drugs is described for the first time at the molecular level. Goniopypyrone (39) is the most cytotoxic compound followed by altholactone (+)-1. Enantiomer (-)-1 and three stereocongeners 2-4 did not exhibit any significant increase in cytotoxicity. Cytotoxicity of semisynthetically derived products 5-11 is discussed recognising 11-nitro altho-lactone (+)-5 as a promising lead compound. Eight membered styryl lactones 12a - 12e are substrates with important cytotoxicity explained by the inhibition of the mammalian mitochondrial respiratory chain complex I. Among C7-C8 functionalised styryl lactones gonio diol (25) is the most active being selectively cytotoxic against A549 tumour cells. Goniofufurone (42) and several of its derivatives including one carbon homologues 43-50 were reported to be inactive.

Aminophosphonic acids were almost unknown in 1959 but today they are the subject of more than 6000 papers. Their negligible mammalian toxicity, and the fact that they very efficiently mimic aminocarboxylic acids makes them extremely important antimetabolites, which compete with their carboxylic counterparts for the active sites of enzymes and other cell receptors. Although biological importance of these compounds was recognized over 50 years ago they still represent promising and somewhat undiscovered class of potential drugs.

A variety of cancers are associated with bone. Primary tumors can arise in bone, common cancers, such as those of breast and prostate origin, metastasize to bone, and multiple myeloma neoplastic disease affects bone profoundly. The cellular and molecular mechanisms underlying these pathological processes are increasingly being understood. The interaction of tumor cells with bone cells, osteoblasts and osteoclasts, and with the bone local environment is a new promising direction in research, which should help to develop new therapies. In this article we will relate the newest developments in the molecular research to the pathology of the tumor bone disease. Potential new targets for drugs, aimed specifically at tumor bone diseases, will be highlighted. Furthermore, we will describe the existing compounds that are either used in treatment or have a potential as therapeutic agents, such as bisphosphonates, Src inhibitors, and selective estrogen receptor modulators.