Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 8, Number 6, 2008
Contents
Enediynes and Related Structures in Medicinal
and Biorganic Chemistry
Guest Editor: Ajoy Basak
Editorial Pp. 435
Congeners of the Enediyne Neocarzinostatin
Chromophore: Designed Agents for bulged Nucleic Acid Targets
Pp. 436-447
Graham B. Jones, Yiqing Lin, Dong Ma, Ziwei Xiao, Geum-Sook
Hwang, Lizzy Kappen and Irving H. Goldberg
[Abstract]
Biosynthesis of Enediyne Antitumor Antibiotics
Pp. 448-459
Steven G. Van Lanen and Ben Shen
[Abstract]
Towards Photoswitchable Enediyne Antibiotics:
Single and Two-Photon Triggering of Bergman Cyclization
Pp. 460-469
Andrei Polukhtine, Grigori Karpov and Vladimir V. Popik
[Abstract]
The Critical Distance for the Cycloaromatization
Reactions of Enediynes Pp. 470-486
Joseph F. Capitani, Shannon M. Gaffney, Lyana Castaldo
and Abhijit Mitra
[Abstract]
Synthesis of Highly Strained Enediynes and Dienediynes
Pp. 487-504
Amit Basak, Sandip Kumar Roy, Basab Roy and Ajoy Basak
[Abstract]
Editorial:
HPA Axis Pp. 505
Guest Editor: Brian Dyck
Small Molecule Antagonists of the Corticotropin
Releasing Factor (CRF) Receptor: Recent Medicinal Chemistry
Developments Pp. 506-520
John E. Tellew and Zhiyong Luo
[Abstract]
Recent Progress in the Discovery of Novel Glucocorticoid
Receptor Modulators Pp. 521-530
Hidenori Takahashi, Hossein Razavi and David Thomson
[Abstract]
Molecule
of Month Pp. 531
Abstracts
[Back to top]
Editorial
Mother nature often provides scientists with new and innovative
ideas. One perfect example is enediynes which have now become
the core of research in cancer therapeutics. Enediynes are
a group of cyclic natural molecules that consist of at least
two triple bonds separated by a double bond in conjugation.
These products of bacterial origin were first isolated in
1960s and have drawn special attention since mid-eighties
following the discovery that they possess powerful antitumor
antibiotic activity. The enediyne group is often called a
“warhead” because it can easily cyclize
to form aromatic ring system via a highly reactive 1,4 benzeniod
diradical intermediate. This cyclization process is called
the “Bergman cyclo-aromatization reaction”
after the name of the discoverer (Bergman, R.G. Accts.
Chem. Res., 1973). The diradical intermediate can cause
oxidative cleavage to double stranded DNA, giving rise to
enediyne’s powerful antitumor activity. Depending on
the nature of substitution and ring size, the above cyclization
can be triggered by temperature, light, pH changes, catalyst,
suitable donors, oxidative state, metal coordination/induction
as well as transformation from one tautomeric form to the
other. Other triggering methods such as release of ring strain,
acid base induction and enzyme mediated cleavage of protecting
group have also been demonstrated. Recently conditions have
been developed for transformation of enediynes to fulvene
and indene derivatives.
Bergman cyclo-aromatization reaction proceeds more efficiently
and under milder condition when enediyne system is present
within a constrained cyclic (mostly 9 and 10 membered) system
compared to the acyclic one. The size of the ring structure
also plays a significant role on the ease of cyclo-aromatisation.
Enediynes find very useful applications in the study of biological
systems. Thus it is applied to the development of “catalytic
antibody or Abzyme” and “novel anticancer
agents”. So far four principle effects of the enediynes
on mammalian cells have been identified. These are (a) Mutagenicity,
(b) Antimitotic activity associated with cell-cycle arrest,
(c) Apoptosis induction and (d) Differential induction. Overall
enediynes act as antimitotic agents by inducing a temporary
delay in the cell lines during division of nucleus and form
an important class of antibiotics. So far there are reports
of three types of natural enediynes: (i) Type I with 10-membered
ring and a 3-ene-1, 5-diyne function eg. calicheamicin/dynemicin),
(ii) Type II with 9-membered ring and a 3-ene-1, 5-diyne moiety
e.g. kedarcidin and, (iii) Type III with 9-memdered ring containing
a dienediyne function eg. neocarzinostatin.
Calicheamicin/Dynemicin represent the most potent antitumor
agents known. However they are limited by their high toxicity
and selectivity. Several pharamaceutical companies including
the Bristol-Myers Squibbs made significant contributions in
this area. They developed dynemicin class of antibiotics that
contain a hydroxyanthraquinone chromophore instead of sugar
moiety as found in calicheamicin/esperamicin. Chromoproteins
eg. C1027 (discovered in 1988/89) have proteins that wrap
around the enediyne, which stabilizes it, and takes it out
of the cell. The study of C1027 suggests that all enediynes
share a common polyketide biosynthetic pathway. This opens
the door to genetic manipulation of these biosynthetic pathways
to develop new drug candidates with less toxicity.
Of all the enediynes, only neocarzinostatin, which is a chromoprotein,
is approved as a drug to treat liver cancer in Japan only.
The United States has not approved such a drug. However calicheamicin
is now heading most directly to clinical studies, compared
to the rest of the enediynes. Efforts to attach calicheamicin
to various drug antibody conjugates, peptides or steroids
that seem suitable for clinical trials, make calicheamicin
an enediyne of interest. Its derivative “Mylotarg”
(an antibody conjugate) has now been approved for treatment
of Acute Myeloid Leukemia (AML). This drug acts as targeted
therapy by delivering the enediyne derivative directly to
the cancer cells, thereby not affecting normal cells. Because
of these developments enediynes have stimulated considerable
synthetic interest, although their clinical use has been limited
because of their modest selectivity for cancer cells. The
biological mode of action occurs along one of two general
pathways, depending on the type of enediyne structure. The
majority of enediyne natural products, including calicheamicin
undergo Bergman cyclization whereas others such as neocarsinostatin
operates via a Myers-Saito pathway. In both cases the end
result is cleavage of double stranded DNA leading to apoptosis.
Enediynes remain as the major focus of chemists and biologists
for future development of more useful and selective antitumor
antibiotic drugs which may be useful to degrade harmful DNAs,
Proteins, Enzymes and possibly other macromolecules. It is
hoped that enediyne based antibiotics may one day be able
to kill all types of cancer and bacteria including those of
resistant type.
Ajoy Basak
Scientist, Ottawa Health Research Institute
University of Ottawa
Canada
[Back to top]
Congeners of the Enediyne Neocarzinostatin Chromophore: Designed
Agents for bulged Nucleic Acid Targets
Graham B. Jones, Yiqing Lin, Dong Ma, Ziwei Xiao, Geum-Sook
Hwang, Lizzy Kappen and Irving H. Goldberg
Of the commonly recognized structural elements within
nucleic acids, bulges are among the least developed as targets
for small molecules. Bulges in DNA and RNA have been linked
to biomolecular processes involved in numerous diseases, thus
probes with affinity for these targets would be of considerable
utility to chemical biologists and medicinal chemists. Despite
such opportunity, there is a dearth of small molecules available
with affinity for bulges, which has hampered exploitation
of these key targets. We have used guided chemical synthesis
to prepare small molecules capable of binding to DNA and RNA
bulges. Our design is based on a template which mimics a metabolite
of the enediyne neocarzinostatin. The key spirocylic building
block was formed through an intramolecular aldol process and
the parent template shows pronounced affinity for 2 base bulges.
Functionalization with specific aminosugar moieties confers
nanomolar binding affinity for selected bulged DNA targets,
and installation of reactive functional groups allows covalent
modification of bulges. These rationally designed agents can
now be used to study the stereochemistry and architecture
of bulge-drug complexes and investigate the molecular biology
of bulge induced processes. Members of this class have been
shown to induce slipped synthesis of DNA, suggesting the agents,
in addition to recognizing and binding to pre-formed bulges,
can also induce bulge formation on demand.
[Back to top]
Biosynthesis of Enediyne Antitumor Antibiotics
Steven G. Van Lanen and Ben Shen
The enediyne polyketides are secondary metabolites isolated
from a variety of Actinomycetes. All members share very potent
anticancer and antibiotic activity, and prospects for the
clinical application of the enediynes has been validated with
the recent marketing of two enediyne derivatives as anticancer
agents. The biosynthesis of these compounds is of interest
because of the numerous structural features that are unique
to the enediyne family. The gene cluster for five enediynes
has now been cloned and sequenced, providing the foundation
to understand natures’ means to biosynthesize such complex,
exotic molecules. Presented here is a review of the current
progress in delineating the biosynthesis of the enediynes
with an emphasis on the model enediyne, C-1027.
[Back to top]
Towards Photoswitchable Enediyne Antibiotics: Single and Two-Photon
Triggering of Bergman Cyclization
Andrei Polukhtine, Grigori Karpov and Vladimir V. Popik
The concept of photoswitchable enediynes, which are stable
in the dark but undergo efficient cycloaromatization reaction
to produce p-benzyne diradical after irradiation with light
of an appropriate wavelength, is discussed. Two novel methods
for the generation of reactive enediyne compounds from thermally
stable precursors have been developed. In the first approach,
one of the triple bonds of cyclodeca-3-ene-1,5-diynes is replaced
with cyclopropenone group. Cyclopropenone-containing enediyne
precursors are unable to undergo cycloaromatization because
the enediyne fragment is incomplete. Photolysis of cyclopropenones
results in the efficient decarbonylation and the regeneration
of a triple bond thus completing the enediyne π-system.
The second method employs photo-Wolff reaction to achieve
ring contraction of stable eleven-membered ring precursor
enediynes. Benzannulated cyclic enediynes produced by the
photodecomposition of enediyne precursor containing 2-diazo-1,3-diketones
possess enolized β-ketoester
fragment and undergo remarkably facile τ360
= 5 min - 3 h) Bergman cyclization. The generation of reactive
enediyne was also achieved with NIR light by non resonant
two-photon excitation.
[Back to top]
The Critical Distance for the Cycloaromatization Reactions
of Enediynes
Joseph F. Capitani, Shannon M. Gaffney, Lyana Castaldo
and Abhijit Mitra
It has been shown that the enediyne anticancer antibiotics
e.g., calicheamicin, neocarzinostatin and others cleave DNA
via the putative intermediate 1,4-diradical formed
in the Bergmann cyclization and are thus useful for cancer
chemotherapy. The pharmacological activity of these drugs
is based, in general, on the activation of the pharmacophore
and the subsequent cyclization leading to the formation of
a radical, the rate of which is, in part, based on the terminal
distance of the 1,5-diyne functionality, also known as the
critical distance. But the critical distance alone cannot
govern the rate of cyclization of the enediynes. A theoretical
model has been developed to predict the rate of cyclization,
and the thus the pharmacological activity, of these antibiotics
based on the critical distance and the energy of activation.
[Back to top]
Synthesis of Highly Strained Enediynes and Dienediynes
Amit Basak, Sandip Kumar Roy, Basab Roy and Ajoy Basak
Enediynes continue to fascinate scientists working in
various domains because of their structural complexity and
fascinating biological mode of action. They represent a masterpiece
of nature’s ingenuity. Besides the warhead which is
the enediyne moiety, these molecules are equipped with a locking
device, a delivery system and a chemical trigger for activation.
Upon triggering, the molecules become active and undergo a
thermal rearrangement that was disclosed in the early ’70
by Masamune and Bergman and commonly known as Bergman cyclization.
The reaction is believed to precede through a diradical benzenoid
species (a p-benzyne). This review describes the
various strategies employed for the synthesis of highly strained
enediynes and dienediynes, both naturally occurring and the
designed ones.
[Back to top]
Editorial:
The pituitary is the preeminent gland of the body, synthesizing
and releasing key hormones including growth hormone, thyroid-stimulating
hormone, prolactin, luteinizing hormone, follicle-stimulating
hormone and adrenocorticotropic hormone. The secretion of
these hormones is regulated by the hypothalamus via the hypothalamus-hypophyseal
portal veins. The target organ of adrenocorticotropic hormone
is the adrenal gland, which regulates serum levels of cortisol.
The trio of the hypothalamus, pituitary, and adrenal glands,
termed the HPA axis, is responsible for coordinating an organism’s
response to exogenous stressors. A number of hormone-receptor
systems within the HPA axis provide likely targets for pharmacological
manipulation, three of which are reviewed in this issue.
For some time, the importance of the hormone corticotropin
releasing factor (CRF) as a regulator of stress states in
mammals has been recognized. It is a key controller of the
neuroendocrine system and is the dominant hormone responsible
for governing stress response. However, despite the fact that
peptide CRF receptor antagonists have been known for twenty
years and small molecule antagonists have been known for more
than a decade, no phase two, placebo-controlled proof of concept
study showing efficacy has been disclosed. In their review,
Tellew and Luo discuss recent advances in the field of CRF
receptor antagonists and speculate on the characteristics
of the ideal molecule.
In contrast to CRF receptor antagonists, which have not been
used medicinally, modulators of the glucocorticoid (GC) receptor
have been used to treat inflammatory and immune conditions
for more than half of a century. These drugs, however, come
with significant side effects, which limit their use as first
line therapies. One innovative solution to the unfavorable
side effect profile of current glucocorticoids is to find
organ (tissue) selective agonists. Takahashi, Razavi and Thomson
discuss progress towards this goal and also speculate on the
issues that may arise from the discovery and development of
GC receptor antagonists for the treatment of diseases resulting
from excess circulating cortisol.
Calcitonin gene-related peptide (CGRP) and its receptor are
best known for their role in vasodilation and their potential
application to migraine. However, CGRP has wide expression
throughout the central nervous system and has been shown to
interact with the HPA. Rudolf, Arndt, Muller and Doods review
recent reports in the field of CGRP receptor antagonists and
speculate on the potential of a CNS-penetrating GCRP receptor
antagonist.
These reviews present an update on several drug targets related
to the HPA axis. It is hoped they will not only provide the
background and state-of-the-art for these molecular targets,
but will also help to spur further research in this area.
Brian Dyck
Neurocrine Biosciences
Department of Medicinal Chemistry
12790 El Camino Real
San Diego, CA
92130
[Back to top]
Small Molecule Antagonists of the Corticotropin Releasing
Factor (CRF) Receptor: Recent Medicinal Chemistry Developments
John E. Tellew and Zhiyong Luo
Antagonists of the corticotropin releasing factor (CRF
or CRH) receptor have shown promise for the treatment of anxiety,
depression, and irritable bowel syndrome. In the present article,
medicinal chemistry developments surrounding small molecule
CRF receptor antagonists are reviewed, focusing on publications
and patents from mid-2004 through the first quarter of 2006.
While the CRF type 2 receptor remains an intractable target,
incremental progress has been made in the search for drug-like
antagonists of the CRF type 1 receptor. Most recent work has
not ventured far from previously-established pharmacophoric
topologies. A common theme in recent patent disclosures is
the addition of novel polar substituents to known heterocyclic
core structures to reduce overall lipophilicity. New disclosures
of pharmacokinetic (PK) data for several series of antagonists
reveal that achieving appropriate PK remains a challenge for
the field. The recent publication of selection patents and
patents relating to salt and crystal forms of particular compounds
suggests that several second generation compounds are nearing
or have entered clinical development.
[Back to top]
Recent Progress in the Discovery of Novel Glucocorticoid Receptor
Modulators
Hidenori Takahashi, Hossein Razavi and David Thomson
Glucocorticoids have been used in modern clinical practice
for over fifty years. Although they have demonstrated potent
anti-inflammatory and immunosuppressive activities, their
association with debilitating and life-threatening side effects
has been a major drawback. Recent insights into glucocorticoid
biology have lent support to the hypothesis that the glucocorticoid
anti-inflammatory activities could be dissociated from their
adverse side effects. Inspired by these biological findings,
the search for dissociated glucocorticoid receptor agonists
has intensified. Antagonists of the glucocorticoid receptor
that offer therapeutic benefits for the treatment of diseases
such as diabetes have also been pursued. These efforts have
been partly focused on the development of tissue, especially
liver, selective glucocorticoid receptor antagonists, which
are thought to have improved safety profiles. This review
offers a summary of the research and development activities
in this field and covers journal and patent publications from
2003 to March 2006.
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