Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 3, 2009

In the present review, the discovery and development of quinazoline as tyrosine kinase inhibitors has been described. The synthesis of most potent quinazoline inhibitors of EGFR, VEGFR and PDGRF has been discussed. Structure activity relationship for quinazoline as tyrosine kinase inhibitors has been established. It was found that C-4, C-6 and C-7 positions in quinazoline are appropriate sites for designing new tyrosine kinase inhibitors. This review should help the medicinal chemist in designing more effective tyrosine kinase inhibitors.

Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.

Quantum dots (QDs) are fluorescent inorganic nanocrystals with advantageous optical properties, which have been applied for biomedical purposes including imaging, diagnostic, drug delivery or therapy. Potential toxicity of QDs remains the major barrier to clinical translation, and as such the precise analysis of in vivo QDs distribution and pharmacokinetics is of major importance. Biodistribution studies in animal models are, however, sparse. The present review provides in a first lieu a summary of different techniques, which are currently used for relative quantification of QDs in vivo or their absolute quantification ex vivo. Fluorescence and radioactivity based techniques along with mass-spectrometry detection at the elementary level are addressed in this review. We further introduce biodistribution studies in animal models and discuss the possibilities to modify quantum dots biodistribution in function of different injection ways.

In recent years, a series of new and highly cytotoxic analogues of CC-1065 and the duocarmycins have been developed that can be transformed into much less toxic prodrugs for the use in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) and prodrug monotherapy (PMT) of cancer. In all these approaches, a relatively non-toxic prodrug is applied and subsequently converted selectively in the tumour tissue into a highly cytotoxic drug, thus reducing undesired side effects accompanying conventional chemotherapy. Here, the design and biological evaluation of prodrugs based on analogues of CC-1065 and the duocarmycins for the use in tumour selective cancer therapies is reviewed. The advantage of this approach is the excellent therapeutic index of some of the new prodrugs of over 5000 and the high cytotoxicity of the corresponding drugs with IC50 values of as low as 16 pM (IC50: concentration required for 50 % growth inhibition of target cells). In addition, a novel method for the correlation of the alkylation efficiency and the cytotoxicity based on mass spectrometry is described.

Bone metastases are common in the event of malignancy and are inevitably associated with serious complications that may deteriorate the quality of life (QOL) of patients and threaten life. Both radiotherapy (RT) and bisphosphonates (BPs) have an established role in the management of metastatic bone disease. Many clinical trials have demonstrated their effectiveness when used as sole treatment modalities, but only a few have evaluated their therapeutic value when applied concomitantly. We herein discuss the pathophysiology of bone metastases and the potential interactions between RT and BPs. Moreover, the results of both animal models and clinical studies are presented in detail. Apart from aspects of normal tissue tolerance, other interactions include spatial cooperation and additive or super-additive effects. The latter brings about a synergistic activity that results in an enhanced reossification, improved bone stability and microarchitecture, and increased mechanical strength, as documented through animal model studies. The results of published clinical studies investigating the effectiveness of concomitant application of RT and BPs are promising, reporting a significant clinical and radiologic response. More specifically, a significant reduction of pain scores and a worth noticing improvement in QOL and performance status (PS) were noted, accompanied by a considerable increase in bone density. Pain relief was accompanied by a marked reduction in analgesic opioid need. The enhanced reossification may be responsible for the improved therapeutic response, since it was shown that the correlation between pain and bone density is negative and strong. Although promising and encouraging, the results of such studies should be corroborated by larger, randomized trials.

The development of chalcones as antimitotic agents has led to the design of other analogues able to interact with tubulin and inhibit its assembly into microtubules. This activity has also been associated with their anti-vascular activity. This review focuses on the development of chalcones and related analogues as antimitotic agents.

Amplification of the HER2/neu gene occurs in approximately 20-25% of invasive breast cancers and is associated with poor patient outcome. The development of trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of HER2, has led to a significant improvement in outcomes of patients with HER2-positive breast cancer. However, many patients with HER2- positive metastatic breast cancer do not respond to trastuzumab, or eventually become resistant to it. In addition, approximately 15% of patients treated with trastuzumab-based therapy in the adjuvant setting relapse. In this review, we discuss the mechanisms of antitumor activity of trastuzumab, potential mechanisms contributing to its resistance, and novel therapeutic agents that may provide a means to overcome trastuzumab resistance.

Research has proven that the most effective and widely used metal-containing chemotherapy anticancer drugs are cisplatin ([cis-PtCl2(NH3)2]) and many platinum complexes, however, these compounds have significant disadvantages including poor water solubility and serious side effects. Thus researches in order to overcome these shortcomings have never interrupted. Many non-platinum complexes have been synthesized and tested, in which some palladium complexes show significant antitumor activity in normal tumor cells and lower resistance of tumor cells to clinical treatments as well as lower side effects. Mononuclear palladium complexes with aromatic N-containing ligands, amino acid ligands, S-donor ligands, and P-containing ligands have respective qualities and properties due to the different structures and properties of the ligands; some dinuclear palladium complexes possess interesting steric structures and good antitumor activity; a try to modify natural medicines with Pd2+ leads the research to a new route. In this review, medicinal chemistry, the development status and interactions of palladium complexes with DNA are discussed in order to provide guidance and determine structure and antitumor activity relationships for continuing studies of these systems.