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Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 6, Number 1, January 2006
Contents
Emerging Hsp90 Inhibitors: From Discovery to Clinic
Pp. 1-8
G. Chiosis, A. Rodina and K. Moulick
[Abstract] [Purchase
Article]
Peptide Phage Display: Opportunities for Development
of Personalized Anti-Cancer Strategies Pp. 9-17
T.I. Samoylova, N.E. Morrison, L.P. Globa and N.R. Cox
[Abstract] [Purchase
Article]
Gold Coordination Complexes as Anticancer Agents Pp.
19-32
I. Kostova
[Abstract] [Purchase
Article]
Marine Peptides and Related Compounds in Clinical
Trial+ Pp. 33-40
D.S. Rawat, M.C. Joshi, P. Joshi and H. Atheaya
[Abstract] [Purchase
Article]
Understanding Apoptosis in Terms of QSAR Pp.
41-52
R.P. Verma
[Abstract] [Purchase
Article]
Vitamin D Analogs as Anti-Carcinogenic Agents
Pp. 53-71
E.S. Agoston, M.A. Hatcher, T.W. Kensler and G.H. Posner
[Abstract] [Purchase
Article]
Abstracts
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Emerging Hsp90 Inhibitors: From Discovery to Clinic
G. Chiosis, A. Rodina and K. Moulick
Hsp90 is a chaperone with important roles in maintaining
transformation and in elevating the survival and growth potential
of cancer cells. Activation of signaling pathways mediated
by Hsp90 protein clients is necessary for cell proliferation,
regulation of cell cycle progression and apoptosis. Additionally,
gain-of-function mutations responsible for transformation
often require Hsp90 for the maintenance of their folded, functionally
active conformations. These charac-teristics promise Hsp90
as an important target in cancer therapy and prompt for the
identification, development and clinical translation of small
molecule inhibitors of the chaperone. This review intends
to update the reader on the status of several existing and
emerging classes of direct inhibitors of Hsp90 ATPase activity.
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Peptide Phage Display: Opportunities for Development
of Personalized Anti-Cancer Strategies
T.I. Samoylova, N.E. Morrison, L.P. Globa and N.R. Cox
Personalized medicine is critical for cancer patients, because
(1) cancer is a highly heterogeneous disease with major molecular
differences in the expression and distribution of tumor cell
surface markers among patients with the same type and grade
of cancer, (2) cellular mutations tend to accumulate as cancer
progresses, further increasing tumor heterogeneity, and (3)
currently used cancer therapies often are toxic to normal
cells, causing severe side effects rarely seen in other diseases.
To prevent side effects and to improve effectiveness, cytotoxic
therapies should be targeted and each patient should be profiled
for the presence of cancer targets before the therapy is administered.
Phage display technology utilizes combinatorial libraries
of proteins expressed on phage particles that can be selected
for specific binding to cancer cells. Such cancer-specific
molecules can be used in a variety of applications, including
identification of cell-specific targeting molecules; identification
of cell surface biomarkers; profiling of specimens obtained
from individual cancer patients, and the design of peptide-based
anti-cancer therapeutics for personalized treatments. This
review is focused on peptide phage display strategies that
target cell surfaces because many biomarkers important in
cancer are differentially expressed molecules located on the
outside of the cell membranes.
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Gold Coordination Complexes as Anticancer Agents
I. Kostova
Metal ions are known to bind with nucleic acids and thereby
alter their conformation and biological function. The metal
ion-base interaction depends on the nature of both metal and
bases; a certain site of coordination is preferred. One of
the most notable successes for inorganic drugs has been the
effectiveness of platinum complexes against cancer. These
advances have spurred a surge of investigations to identify
new inorganic agents for use in chemotherapy with improved
specificity and decreased toxic side effects. Gold(I) and
gold(III) complexes, the last isostructural and isoelectronic
with platinum(II) complexes, are potentially attractive as
anticancer agents. The design of an effective anticancer agent
is a complicated game that must encompass not only the drug’s
inherent inhibitory properties but also its delivery, dosage,
and residence time in vivo. Gold(I) and gold(III)
complexes overcome some of these challenges by forming strong
covalent attachments to targets. Au(III) isoelectronic with
Pt(I1)-d8 system usually forms square planar complexes
in solution. Since the square planar geometry of Pt(II) is
important for its action as an anticancer drug, Au(III) compounds
also can be used for the same purpose with the added advantage
of decreased toxicity. This, together with the recent finding
that certain transitional metal complexes like Au and Pt complexes
have been found to be potentially useful in cancer chemotherapy,
created a renewed interest in the study of the interactions
of metal ions with respect to the site of binding and the
structure and stability of the complexes. This work was motivated
by the thought that information on the variety of Au(III)
complexes and their effects can be obtained by studying the
properties of Au complexes with various ligands. Various studies
in the past have shown that Au complexes are very attractive
in view of their application as anticancer agents.
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Marine Peptides and Related Compounds in Clinical
Trial+
D.S. Rawat, M.C. Joshi, P. Joshi and H. Atheaya
Advances in the sophisticated instruments for the isolation
and characterization of marine natural products, and development
in the biological assay systems, have resulted in the discovery
of various compounds of biomedical application. Marine natural
products have been a source of new leads for the treatment
of many deadly diseases such as cancer, acquired immuno-deficiency
syndrome (AIDS) etc. The compounds of marine origin are diverse
in structural class from simple linear peptides to complex
macrocyclic polyethers. Number of marine peptides have been
isolated in recent years which exhibit potent biological activities,
and many of the compounds showed promising anticancer activity.
Didemnin was the first marine peptide that entered in human
clinical trials in US for the treatment of cancer, and other
anticancer peptides such as kahalalide F, hemiasterlin, dolastatins,
cemadotin, soblidotin, didemnins and aplidine have entered
in the clinical trials. Clinical status of anticancer marine
derived peptides have been discussed and reviewed.
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Understanding Apoptosis in Terms of QSAR
R.P. Verma
Apoptosis is a cellular mechanism by which unwanted, defective,
or damaged cells are rapidly and selectively eliminated to
maintain healthy tissue homeostasis in multi-cellular organisms.
In this review, we have developed nine-teen quantitative structure-activity
relationships (QSAR) for different series of compounds with
respect to their apop-totic activities against five different
cancer cell lines that are T47D, ZR75-1, DLD-1, H1299, and
HL60 in order to un-derstand chemical-biological interactions.
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Vitamin D Analogs as Anti-Carcinogenic Agents
E.S. Agoston, M.A. Hatcher, T.W. Kensler and G.H. Posner
Deltanoids are the class of compounds comprising all
natural and synthetic vitamin D molecules. The anti-proliferative,
pro-differentiation, and pro-apoptotic properties of deltanoids
have garnered interest in the fields of cancer chemoprevention
and chemotherapy. The naturally occurring, biologically active
form of vitamin D, 1,25(OH)2D3, causes hypercalcemia at pharmacologically
relevant doses which forms a major obstacle in the clinical
development of this compound. Design of new deltanoids has
shown promise in separating the beneficial effects from the
toxic effects. The Vitamin D receptor (VDR) is a major target
for deltanoid design, and the structural features of deltanoid
binding have been described. Effective compounds must also
exhibit beneficial pharmacokinetic properties in vivo,
and the plasma vitamin D binding protein (DBP) is likely to
play an important role in the success of deltanoids in the
clinic. Further, dual strategies of avoiding vitamin D toxicity
through altering the dosing schedule and using less toxic
deltanoids are in development. The three main categories of
structural modification to the vitamin D backbone include
the C,D-ring, the A-ring, and the C,D-ring side chain, and
the ways each area has impacted efficacy and toxicity have
been described through structure-activity relationships (SARs).
Lastly, there is evidence that deltanoids can enhance the
activity of other chemopreventive agents. The use of a cocktail
approach will be discussed as a potential avenue for deltanoids
in chemoprevention and chemotherapy.
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