Current Medicinal Chemistry - Anti-Cancer Agents, Vol. 5, No. 5, 2005
Contents
Recent Advances in
Understanding and Exploiting the Activation of Anthracyclines by Formaldehyde
Pp.431-447
S.M. Cutts, L.P.
Swift, A. Rephaeli, A. Nudelman and D.R. Phillips
Blocking the PI3K/PKB
Pathway in Tumor Cells Pp.449-462
Frederic Stauffer,
Philipp Holzer and Carlos Garcia-Echeverria
Quadruplex-Forming
Oligonucleotides as Tools in Anticancer Therapy and Aptamers Design: Energetic
Aspects Pp.463-475
L. Petraccone, G.
Barone and C. Giancola
Sesquiterpenes:
Natural Products That Decrease Cancer Growth Pp.477-499
Aneta Modzelewska,
Surojit Sur, Srinivas K. Kumar and Saeed R. Khan
Fundamental, Electron
Transfer Mechanism by Pyrylium-Type Ions for the Anticancer Drugs
5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA) and Flavone-8-Acetic Acid (FAA)
Pp.501-506
Peter Kovacic
Steroid Sulfatase
Inhibitors: Their Potential in the Therapy of Breast Cancer Pp.507-528
Peter Nussbaumer and
Andreas Billich
Histone Deacetylase Inhibitors:
Latest Developments, Trends and Prospects Pp.529-560
Oscar Moradei,
Christiane R. Maroun, Isabelle Paquin and Arkadii Vaisburg
An Analysis of the Binding
Modes of ATP-Competitive CDK2 Inhibitors as Revealed by X-Ray Structures of
Protein-Inhibitor Complexes Pp.561-573
Anna Vulpetti and
Paolo Pevarello
Abstracts
[Back
to top] Recent Advances in Understanding and
Exploiting the Activation of Anthracyclines by Formaldehyde
S.M. Cutts, L.P.
Swift, A. Rephaeli, A. Nudelman and D.R. Phillips
The anthracycline group of compounds are amongst the most effective chemotherapy agents currently in use for cancer treatment. They are generally classified as topoisomerase II inhibitors but also have a variety of other targets in cells. It has been known for some years that the anthracyclines are capable of forming DNA adducts, but the relevance and extent of these DNA adducts in cells and their role in causing cell death has remained obscure. When the adduct structure was solved, it became clear that formaldehyde was an absolute requirement for adduct formation. This led to a renewed interest in the capacity of anthracyclines to form DNA adducts, and there are now several ways in which adduct formation can be facilitated in cells. These involve strategies to provide the requisite formaldehyde in the form of anthracyclineformaldehyde conjugates, and the use of formaldehyde-releasing drugs in combination with anthracyclines. Of particular interest is the new therapeutic compound AN-9 that releases both butyric acid and formaldehyde, leading to efficient anthracycline- DNA adduct formation, and synergy between the two compounds. Targeted formation of adducts using anthracycline- formaldehyde conjugates tethered to cell surface targeted molecules is now also possible. Some of the cellular consequences of these adducts have now been studied, and it appears that their formation can overcome anthracyclineresistance mechanisms, and that they are more efficient at inducing apoptosis than when functioning primarily through impairment of topoisomerase II. The clinical application of the use of anthracyclines as DNA adduct forming agents is now being explored.
[Back
to top] Blocking the PI3K/PKB Pathway in Tumor Cells
Frederic Stauffer,
Philipp Holzer and Carlos Garcia-Echeverria
A substantial number of experimental and epidemiological studies support an important role for the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway in the biology of human cancers. Components of this signaling cascade have been found to be deregulated in a wide range of solid tumors and hematologic malignancies, and extensive anti-cancer therapeutic programs are now devoted to the identification of agents that specifically block this molecular pathway.
This article focuses on the current knowledge of the alterations of the PI3K/PKB pathway in cancer cells and ongoing drug discovery efforts to therapeutically target it. Particular emphasis is placed on medicinal chemistry activities to identify and develop compounds able to modulate the kinase activity of its main molecular components.
[Back
to top] Quadruplex-Forming Oligonucleotides as Tools
in Anticancer Therapy and Aptamers Design: Energetic Aspects
L. Petraccone, G.
Barone and C. Giancola
Recent investigations on the G-quadruplex motif propose a new strategy for the making of antitumour drugs. Quadruplex-drug complexes have been suggested to inhibit telomerase activity; further, aptamers based on the quadruplex motif have been proved useful as tools aimed at binding and inhibiting particular proteins, thus serving as pharmaceutically active agents. However, the design of new aptamers is difficult because many factors affecting their activity and stability have not still been clarified. The knowledge of the energetics of quadruplex formation is a crucial point in view of their potential therapeutic utilization both as targets as well as therapeutic agents. In this review the energetic aspects of both quadruplex assembly and quadruplex-ligand interactions are discussed together with a summary of recent studies on physico-chemical properties in solution of quadruplex structures obtained from synthetic aptamers, including PNA-DNA chimeras.
[Back
to top] Sesquiterpenes: Natural Products That Decrease
Cancer Growth
Aneta Modzelewska,
Surojit Sur, Srinivas K. Kumar and Saeed R. Khan
Despite recent advances in our understanding of the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. One of the oldest and most effective strategies for developing new chemotherapeutics is the isolation and evaluation of chemicals of natural origin. The importance of natural products for drug discovery has been impressive: One has to only look at the number of clinically active drugs that are used in cancer therapy to see how many are either natural products or are based on natural products. It is also apparent that materials from natural sources are excellent probes (indicators) for cellular targets that, when modulated, may have a deleterious effect upon the survival or proliferation of tumor cells. And the search goes on.
Sesquiterpenes are a class of naturally occurring molecules that have demonstrated therapeutic potential in decreasing the progression of cancer. These molecules are 15-carbon isoprenoid compounds that are typically found in plants and marine life. Although this class of compounds has frequently provided encouraging leads for chemotherapeutics, they have not been evaluated as potential anticancer agents. In this review, we provide a current overview of sesquiterpenoids that have potential as anticancer agents.
[Back
to top] Fundamental, Electron Transfer Mechanism by
Pyrylium-Type Ions for the Anticancer Drugs 5,6-Dimethylxanthenone-4-Acetic
Acid (DMXAA) and Flavone-8-Acetic Acid (FAA)
Peter Kovacic
Pyrylium-type salts derived from DMXAA and FAA are proposed to play an important mechanistic role in anticancer action. Electron transfer (ET) processes apparently initiate cell signaling cascades that lead to the observed effects, such as, antivascular influences, cytokine induction, and apoptosis. Possible participation of nitric oxide and serotonin is discussed. Structure-activity relationships involving DMXAA, FAA, acridines, and quinolines support the hypothetical framework, as well as electrochemistry and photochemistry. Similarity is pointed out to the action of plant hormones, e.g. ethylene. Involvement of ET pathways places the cationic salts within the general mechanistic framework for other anticancer agents. Other drug activities of xanthenones are in accord with the ET approach. Insight into fundamental mechanistic aspects should aid in development of improved drugs in this class through rational design.
[Back
to top] Steroid Sulfatase Inhibitors: Their Potential
in the Therapy of Breast Cancer
Peter Nussbaumer and
Andreas Billich
Steroid sulfatase (STS) is the only well characterized enzyme in human cells that is capable to desulfate estrone 3-sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) as a first step in the conversion of these precursors to active hormones. STS has been found to be highly expressed in estrogen-dependent breast tumors in post-menopausal women and is regarded as a crucial component of the local estrogen production that is required for tumor growth and survival. Inhibitors of STS are expected to block the intra-tumoral estrogen synthesis and, therefore, are considered as potential new therapeutic agents for the treatment of estrogen-dependent cancers of the breast and the endometrium.
In this review, we give an overview on the current status in the field of medicinal chemistry of STS inhibitors. Newer developments comprise potent aryl sulfamate-based irreversible inhibitors, and several types of reversible inhibitors. Other directions include compounds with dual mode of action, such as compounds that block both STS and aromatase, or act as STS inhibitors and antiproliferative or antiangiogenic agents at the same time. In particular, these agents featuring an extended mode of action hold promise to be included in the armamentarium to fight endocrine-dependent cancer.
[Back
to top] Histone Deacetylase Inhibitors: Latest
Developments, Trends and Prospects
Oscar Moradei,
Christiane R. Maroun, Isabelle Paquin and Arkadii Vaisburg
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that catalyze the deacetylation and acetylation of lysine residues located in the NH2 terminal tails of histones and non-histone proteins. Perturbation of this balance is often observed in human cancers and inhibition of HDACs has emerged as a novel therapeutic strategy against cancer. To date, more that 30 groups, academic and industrial, are involved in research related to these target enzymes. Over the past year, dozens of research papers and patent applications describing new HDAC inhibitors belonging to different structural classes have been disclosed. The present review highlights the latest developments in design and synthesis of HDAC inhibitors - potential anti-cancer drugs.
[Back
to top] An Analysis of the Binding Modes of
ATP-Competitive CDK2 Inhibitors as Revealed by X-Ray Structures of
Protein-Inhibitor Complexes
Anna Vulpetti and
Paolo Pevarello
CDK2 is an attractive target for the design of new therapeutic antitumor agent. Numerous CDK2 inhibitors have been discovered and their crystallographic structures either in complex with CDK2 or CDK2/Cyclin A have been published. This review aims to summarize the publicly available structural characterization of CDK2/(Cyclin A) – ligand complexes and to highlight the similarities among the binding modes of structurally diverse inhibitors.