Mini-Reviews in Medicinal Chemistry, Volume 3, No. 3, 2003
Contents
Peptide Derivatives as Agonists or
Antagonists of Formylpeptide Receptors: Analysis of their Effects on
Neutrophils Pp.167-173
Alessandro
Dalpiaz and Angelo Scatturin
Biological Role of Formaldehyde, and Cycles
Related to Methylation, Demethylation, and Formaldehyde Production Pp.175-192
Huba
Kalasz
Vitamin D Receptor as a Drug Discovery Target Pp.193-204
Karen
V. Pinette , Ying K. Yee , Bernard Y. Amegadzie and Sunil Nagpal
New Aspects of Cyclosporin A Mode of Action:
from Gene Silencing to Gene Up-Regulation Pp.205-214
Laurent
Mascarell and Paolo Truffa-Bachi
The 1,4-Dihydropyridine Nucleus: A
Pharmacophoric Template Part 1. Actions at Ion Channels Pp.215-223
David
J. Triggle
Steroid 5a-Reductase Inhibitors Pp.225-237
Eugenio
Flores, Eugene Bratoeff , Marisa Cabeza , Elena Ramirez, Alexandra Quiroz and
Ivonne Heuze
Current Strategies for the Development of
Novel Antipsychotic Drugs
Pp.239-251
Jordi
Bolos
Biological Properties and Therapeutic
Potential of Bilirubin
Pp.253-256
Ross
P. McGeary , Alexander J. Szyczew and
Istvan Toth
The p53-Mdm2 Pathway: Targets for the
Development of New Anticancer Therapeutics Pp.257-270
Abstracts
[Back to top] Peptide Derivatives as Agonists or
Antagonists of Formylpeptide Receptors: Analysis of their Effects on
Neutrophils
Alessandro
Dalpiaz and Angelo Scatturin
The effects of
peptide derivatives as agonists or antagonists of formylpeptide receptors are
described, taking into account the related cellular responses by neutrophils.
These effects are related to the structure of peptide derivatives, some of
which are potent anti HIV-1 agents. Finally, formylpeptide receptor models are
depicted.
[Back to top] Biological Role of Formaldehyde, and Cycles
Related to Methylation, Demethylation, and Formaldehyde Production
Huba
Kalasz
An overview is
given on the analysis, formation, role and occurrence of formaldehyde in living
organisms.
Various methods
have been used for the determination of formaldehyde in tissues and body
fluids. Gas chromatography, thin-layer chromatography and HPLC were employed
for the analysis of formaldehyde, mainly after derivatization. The formaldehyde
level of human blood and urine was found at the low ppm level. The formaldehyde
level could be increased upto several ten mg/mL-1 following special dietary
supply.
Biochemical
pathway of both the formaldehyde production and demethylation/methylation
processes is generally connected to the methionine – homocysteine cycles.
Another important way of demethylation generated formaldehyde production is
given by microsomal cytochrome P-450 dependent oxidation of xenobiotics, such
as various drugs prescribed by doctors. Semicarbazide sensitive amine oxidase
also produces formaldehyde.
Increased level of
formaldehyde may be the indication of either patho-physiological processes, or
environmental contamination, or malnutrition.
The
formaldehyde-related methylation and demethylation procedures are also
detailed. DNA methylation may have an important role in the pathogenesis of
certain diseases.
[Back to top] Vitamin D Receptor as a Drug Discovery Target
Karen
V. Pinette , Ying K. Yee , Bernard Y. Amegadzie and Sunil Nagpal
1a, 25-dihydroxyvitamin D3 [1,25 (OH)2D3],
the active metabolite of vitamin D3, is known for the maintenance of normal
skeleton architecture and mineral homeostasis. Apart form these traditional
calcemic actions, 1,25 (OH)2D3 and its synthetic analogs
are increasingly recognized for their potent anti-proliferative,
prodifferentiative and immunomodulatory activities. The calcemic and
non-calcemic actions of 1,25 (OH)2D3 and its synthetic
analogs are mediated through vitamin D receptor (VDR), which belongs to the
superfamily of steroid/thyroid hormone nuclear receptors. Physiological and
pharmacological actions of 1,25 (OH)2D3 in various
systems, along with the detection of VDR in target cells, have indicated
potential applications of VDR ligands in inflammation, dermatological
indications, osteoporosis, cancers and autoimmune diseases. VDR ligands have
shown therapeutic potential in limited clinical trials as well as in animal
models of these diseases. As a result, a VDR ligand, calcipotriol is in clinic
for psoriasis and another, OCT, [2-oxa-1,25 (OH)2D3] is
being developed as a topical agent for the same indication. Further, 1a,-hydroxyvitamin D3 (alphacalcidol), a
prodrug of 1,25 (OH)2D3 is in clinic and a synthetic VDR
ligand, ED-71, is under consideration for approval in
[Back to top] New Aspects of Cyclosporin A Mode of Action:
from Gene Silencing to Gene Up-Regulation
Laurent Mascarell and Paolo Truffa-Bachi
Cyclosporin A
(CSA) has transformed clinical transplantation, both in term of success and of
quality-of-life of the patient. Studies aimed to unfold the site of CSA action
have shown that this molecule binds to cytosolic proteins of the cyclophilin
family. CSA:cyclophilin complexes have a high affinity for calcineurin, a key
enzyme in T-cell activation. By blocking the calcineurin activity, CSA prevents
the induction of genes encoding for cytokines and their receptors. Thus,
humoral and cellular immune responses are abolished, this resulting in the
successful graft acceptance. Disappointingly, CSA and the other molecules as
FK506, sharing the capacity to inhibit calcineurin, should be administered for
all patient life, as tolerance to alloantigens is not achieved by these
molecules. The long term utilization of this class of immunosuppressors
increases the incidence of different tumors. The finding that CSA does not
interfere with various biochemical pathways has prompted different groups to
analyze a possible effect of CSA on molecules that might be involved in
different functions of the immune response and/or in tumorogenesis. A new
picture of CSA mode of action is emerging in which the immunosuppressor
prevents the transcription of a group of genes, concomitantly inducing the
transcription of another set. Here, we review the data and discuss the
consequences of these new findings in term of T-cell activation mechanisms.
[Back to top] The 1,4-Dihydropyridine Nucleus: A
Pharmacophoric Template Part 1. Actions at Ion Channels
David
J. Triggle
The
1,4-dihydropyridine nifedipine is a prototypical example of the group of
calcium channel blockers that also includes a number of second and third
generation agents. These drugs enjoy substantial therapeutic prominence for
their cardiovascular actions, including hypertension and angina. These actions
are exerted at a specific member of the voltage-gated calcium channel family
–the L-type channel. However, it is increasingly clear that the
1,4-dihydropyridine structure is a pharmacophoric template or “privileged
structure” that, when appropriately substituted, can exert potent and selective
actions at a diverse set of membrane receptors, including ion channels, G
protein-coupled receptors and enzymes. This review will summarize the actions
of 1,4-dihydropyridines at these receptors and advance the case that the
4-phenyl-1,4- dihydropyridine structure is a particularly versatile drug
template. Part I of the review will summarize actions at ion channels and part
II will summarize actions at other receptor systems.
[Back to top] Steroid 5a-Reductase Inhibitors
Eugenio
Flores, Eugene Bratoeff , Marisa Cabeza , Elena Ramirez, Alexandra Quiroz and
Ivonne Heuze
The objective of
this study is to synthesize new steroidal compounds based on the progesterone
skeleton with a high inhibitory activity for the enzyme 5a-reductase. Presently similar compounds are
being used for the treatment of androgen dependent diseases such as: hirsutism,
androgenic alopecia, bening prostatic hyperplasia and prostate cancer.
Dihydrotestosterone 2 (Fig. (1)), a 5a-reduced
metabolite of testosterone 1 has been implicated as a causative factor in the
progression of these diseases, largely through the clinical evaluation of males
who are genetically deficient of steroid 5a-reductase
enzyme. As a result of this study, the inhibition of this enzyme has become a
pharmacological strategy for the design and synthesis of new antiandrogenic
drugs. The advent of finasteride 8 (Fig. (4)) a 5a-reductase
inhibitor has grately alleviated the symptoms associated with benign prostatic
hyperplasia.
In our laboratory
we recently synthesized several new 16b-methyl-pregnadiene-3,20-diones
derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16b-phenyl-pregnadiene-3,17a-dione
derivatives 32-33 (Fig. (7)), 16b-phenylpregnatriene-
3,17a-diones, 30, 31 (Fig. (7)) and 16b-methyl-pregnatriene-3,20-diones
43-46 (Fig. (11)). These compounds were evaluated as 5a-reductase inhibitors in the following
biological models: Penicillium crustosum broths, the flank organs of
gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate
into lipids, the effect of the new steroids on the reduction of the weight of
the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in
seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30,
31, and 43-46 in all biological models showed consistently a higher 5a-reductase inhibitory activity than the
corresponding dienones 27, 32, 33 and 38-42. We believe that with these
compounds the 5a-reductase enzyme is inactivated by an
irreversible Michael type addition of the nucleophilic portion of the enzyme to
the conjugated double bond of the steroid. The trienones having a more coplanar
structure react faster with the enzyme and thus show a higher inhibitory
activity.
[Back to top] Current Strategies for the Development of
Novel Antipsychotic Drugs
Jordi
Bolos
While classical
neuroleptics are characterized by dopamine D2 antagonism, this is
also considered to be the cause of their neurological side effects. In recent
years, novel antipsychotic drugs with improved efficacy, devoid of
extrapyramidal effects are being developed. The mechanisms of action of these
new atypical antipsychotics can be classified into three general groups: a)
binding to D2 together with non-dopaminergic receptors, b)
interaction with dopamine receptor subtypes other than D2 and c)
selective binding to nondopaminergic systems, such as glutamatergic, sigma,
neurotensin, and cannabinoid.
[Back to top] Biological Properties and Therapeutic
Potential of Bilirubin
Ross
P. McGeary , Alexander J. Szyczew and
Istvan Toth
Bilirubin was long
considered a useless metabolite of heme catabolism, responsible for the
clinical manifestation of jaundice, and potentially toxic in high doses,
particularly in neonates. In the past two decades the potent biological
properties of bilirubin, particularly as an antioxidant, have been recognised,
and this has prompted a number of investigations into this molecule concerning
its in vitro and in vivo properties. This review summarises that work, as well
as more recent investigations into the potential therapeutic uses of bilirubin.
[Back to top] The p53-Mdm2 Pathway: Targets for the
Development of New Anticancer Therapeutics
The tumour
suppressor p53 is at the centre of a network of regulatory pathways that guard
over the continued integrity of the living cell and its progeny after exposure
to different forms of stress, particularly those capable of inducing DNA
damage. Tumour cells very frequently circumvent this control by disabling the
function of p53, or other proteins in the p53 network, through mutation. Here
we review the different therapeutic strategies that have been adopted to
exploit common neoplastic aberrations in the p53 pathways. We emphasise in
particular those approaches where modulation with pharmaceutical agents has
already shown some promise, including pharmacological rescue of mutant p53,
modulation of the protein-protein interaction between p53 and one of its
negative regulators, Mdm2, as well as interference with downstream targets.