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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 2, March 2006
Contents
Boron in Medicinal Chemistry
Guest Editor: M.G.H. Vicente
Editorial Pp. 73
Polyhedral Boron Compounds as Potential Diagnostic
and Therapeutic Antitumor Agents Pp. 75-109
V.I. Bregadze, I.B. Sivaev and S.A. Glazun
[Abstract]
The Synthesis and Use of Boronated Amino Acids for
Boron Neutron Capture Therapy Pp. 111-125
G.W. Kabalka and M.-L. Yao
[Abstract]
3-Carboranyl Thymidine Analogues (3CTAs) and Other
Boronated Nucleosides for Boron Neutron Capture Therapy
Pp. 127-144
Y. Byun, S. Narayanasamy, J. Johnsamuel, A.K. Bandyopadhyaya,
R. Tiwari, A.S. Al-Madhoun, R.F. Barth, S. Eriksson and W.
Tjarks
[Abstract]
Recent Progress in the Syntheses and Biological Evaluation
of Boronated Porphyrins for Boron Neutron Capture Therapy
Pp. 145-157
M.W. Renner, M. Miura, M.W. Easson and M.G.H. Vicente
[Abstract]
Boron-Containing Chlorins and Tetraazaporphyrins:
Synthesis and Cell Uptake of Boronated Pyropheophorbide A
Derivatives Pp. 159-166
M. Ratajski, J. Osterloh and D. Gabel
[Abstract]
Boron Containing Macromolecules and Nanovehicles as
Delivery Agents for Neutron Capture Therapy Pp. 167-184
G. Wu, R.F. Barth, W. Yang, R.J. Lee, W. Tjarks,
M.V. Backer and J.M. Backer
[Abstract]
Abstracts
[Back to top]
Editorial
Boron is a unique non-metallic element with the ability to
combine with itself and many other elements to form compounds
of extreme structural diversity and unusual properties. Boron
exists in nature as a mixture of two stable isotopes, 10B
(19.8%) and 11B (80.2%); the former possesses an
extremely high cross-section for neutron capture (3,840 barns),
producing high-energy alpha particles and recoiling lithium
nuclei, according to the 10B(n,α)7Li
nuclear reaction. The discovery of boron clusters of remarkably
high boron content in the 1950s and 1960s has widened their
application in various fields, mainly in medicinal chemistry
as radiolabeling and tumor treatment agents. The exceptional
stabilities of boron clusters, their unique hydrophobic and
potential amphiphilic properties, and the ability of the open-cage
clusters to form sandwich complexes with a variety of metals,
have led to the development of many interesting molecules
for application in tumor imaging and treatment using boron
neutron capture therapy (BNCT). Despite extraordinary advances
in the last decades on the synthesis and chemistry of boron
compounds and their enrichment in the 10B isotope
at ~95% levels, BNCT is still in the early stages of its practical
development. One of the main challenges to the BNCT modality
continues to be the discovery of uniquely tumor-selective
agents, capable of delivering therapeutic concentrations of
10B to target tumors, with low toxicity and high
specificity. In this Special Issue of Current Medicinal
Chemistry – Anti Cancer Agents, the main classes
of boron-containing molecules and the current state-of-the-art
in compound design and characterization are reviewed. The
scourge of cancer is still with us, but never before has there
been such an exciting time in the development of multi-faceted
boron molecules for application in medicinal chemistry, and
particularly for the treatment of cancer.
M.G.H. Vicente
Department of Chemistry
Louisiana State University
Baton Rouge, LA 70803
USA
E-mail: vicente@lsu.edu
[Back to top]
Polyhedral Boron Compounds as Potential Diagnostic
and Therapeutic Antitumor Agents
V.I. Bregadze, I.B. Sivaev and S.A. Glazun
The use of polyhedral boron hydrides for cancer treatment
is traditionally connected with boron neutron capture therapy.
More recently, polyhedral borate anions were proposed as carriers
of radionuclide label for targeted radionuclide therapy and
diagnostics of cancer. Some metal derivatives of carboranes
were found to demonstrate significant antitumor activity themselves.
This review is designed to highlight the recent work concerning
various fields of potential application of polyhedral boron
compounds in anticancer diagnostics and therapy.
[Back to top]
The Synthesis and Use of Boronated Amino Acids for
Boron Neutron Capture Therapy
G.W. Kabalka and M.-L. Yao
The treatment of cancer remains one of the most challenging
problems for humanity. Boron neutron capture therapy (BNCT)
is a binary approach for cancer treatment that is particularly
attractive in treating high-grade gliomas and metastatic brain
tumors. Among types of boron-containing molecules used as
BNCT agents, boronated amino acids have received significant
attention for their preferentially uptake by growing tumor
cells. This review emphasizes the synthesis of boronated amino
acids.
[Back to top]
3-Carboranyl Thymidine Analogues (3CTAs) and Other
Boronated Nucleosides for Boron Neutron Capture Therapy
Y. Byun, S. Narayanasamy, J. Johnsamuel, A.K. Bandyopadhyaya,
R. Tiwari, A.S. Al-Madhoun, R.F. Barth, S. Eriksson and W.
Tjarks
One category of boron neutron capture therapy (BNCT) agents
that has received extensive attention during recent years
is 3-carboranyl thymidine analogues (3CTAs). These molecules
are phosphorylated to the corresponding 5´-monophosphates
by human thymidine kinase 1 (TK1), an enzyme that is up-regulated
in dividing malignant cells. Thus, these phosphorylated molecules
are selectively entrapped in tumor cells due to the acquired
negative charge. This review will analyze design strategies
applied for the synthesis of boron-containing nucleosides
in general and in particular reference to 3CTAs. Results of
biological studies with these molecules will be discussed.
[Back to top]
Recent Progress in the Syntheses and Biological Evaluation
of Boronated Porphyrins for Boron Neutron Capture Therapy
M.W. Renner, M. Miura, M.W. Easson and M.G.H. Vicente
Boronated porphyrins are an important class of tumor-localizing
agents in two bimodal therapies for cancer currently under
study experimentally and clinically; boron neutron-capture
therapy (BNCT) and photodynamic therapy (PDT). The desirable
properties for the boronated porphyrins are that they are
easily synthesized, pure and well-characterized drugs, and
that in vivo, they are stable, tumor-specific, with
high tumor:blood and tumor:normal tissue boron concentration
ratios, and cause minimal toxicity. A large number of new
porphyrins and their syntheses are presented herein. The focus
is primarily on porphyrins published within the past 5 years,
but the implications and trends from porphyrins studied
in vivo over the past 15 years are also reviewed. Many
possess quite unusual, novel structures and others have appended
cell-targeting moieties for greater tumor specificity. Besides
the commonly used closo- and nido-o-carboranes
other boron cages and modes of attachment are presented. These
boron cages can selectively alter the lipophilic, hydrophilic
and amphiphilic properties of the porphyrins as well as their
boron content. New delivery modalities have also greatly improved
the targeting potential of compounds previously deemed unsuitable
for applications in BNCT.
[Back to top]
Boron-Containing Chlorins and Tetraazaporphyrins:
Synthesis and Cell Uptake of Boronated Pyropheophorbide A
Derivatives
M. Ratajski, J. Osterloh and D. Gabel
The literature on the synthesis and the biological properties
of boron-containing chlorins and phthalocyanines is reviewed.
A series of homologous derivatives of pyropheophorbide A is
described. The compounds contain the B12H11SH2-
cluster attached to the single carboxyl group and vary in
the length of the alkyl chain (methyl, propyl, pentyl, heptyl
and nonyl) attached via an ether linkage to the former
vinyl group. Cellular uptake was found for all derivatives
except the nonyl sidechain. The compounds were moderately
cell-toxic. Localization in lysosomes could be excluded; the
compounds localized probably in the mitochondria.
[Back to top]
Boron Containing Macromolecules and Nanovehicles as
Delivery Agents for Neutron Capture Therapy
G. Wu, R.F. Barth, W. Yang, R.J. Lee, W. Tjarks,
M.V. Backer and J.M. Backer
Boron neutron capture therapy (BNCT) is based on the nuclear
capture and fission reactions that occur when non-radioactive
boron-10 is irradiated with low energy thermal neutrons to
yield high linear energy transfer (LET) alpha particles (4He)
and recoiling lithium -7(7Li) nuclei. For BNCT
to be successful, a sufficient number of 10B atoms
(~ 109 atoms/cell) must be selectively delivered
to the tumor and enough thermal neutrons must be absorbed
by them to sustain a lethal 10B(n, α)
7Li capture reaction. BNCT primarily has been used
to treat patients with brain tumors, and more recently those
with head and neck cancer. Two low molecular weight (LMW)
boron delivery agents currently are being used clinically,
sodium borocaptate and boronophenylalanine. However, a variety
of high molecular weight (HMW) agents consisting of macromolecules
and nanovehicles have been developed. This review will focus
on the latter which include: monoclonal antibodies, dendrimers,
liposomes, dextrans, polylysine, avidin, folic acid, and epidermal
and vascular endothelial growth factors (EGF and VEGF). Procedures
for introducing boron atoms into these HMW agents and their
chemical properties will be discussed. In vivo studies
on their biodistribution will be described, and the efficacy
of a subset of them, which have been used for BNCT of tumors
in experimental animals, will be discussed. Since brain tumors
currently are the primary candidates for treatment by BNCT,
delivery of these HMW agents across the blood-brain barrier
presents a special challenge. Various routes of administration
will be discussed including receptor-facilitated transcytosis
following intravenous administration, direct intratumoral
injection and convection enhanced delivery by which a pump
is used to apply a pressure gradient to establish bulk flow
of the HMW agent during interstitial infusion. Finally, we
will conclude with a discussion relating to issues that must
be addressed if these HMW agents are to be used clinically.
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