UNIVERSITY OF MALTA
RESEARCH SEMINARS
Abstract form
Title: Salicylaldoximes and Anthranylaldoximes as Alternatives to Phenolbased Estrogen Receptor Ligands
Presenter: Prof Marco Macchia
Contact address: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via
Bonanno, 6, 56126, Pisa, Italy
Tel: +39-0502219553
Fax: +39-0502219605
Email: mmacchia@farm.unipi.it
Presentation date: 23 November 2005
Abstract
(approximately 200-250 words)
Estrogens regulate the development and the function of reproductive tissues. They also have
significant effects on a wide variety of other tissues, such as bone, cardiovascular and central nervous
systems, and liver. The actions of estrogens are mediated by specific receptors (ERs), which function
as ligand-inducible nuclear transcription factors. ERs are also involved in several diseases, such as
breast and uterine cancer, prostate hypertrophy and osteoporosis. Selective estrogen receptor
modulators (SERMs) are considered useful therapeutic agents, as they may stimulate the desired
estrogen action in bone and liver, and, at the same time, they may inhibit the undesirable estrogenic
effect on breast and uterus.
Two subtypes of the estrogen receptor, ERα and ERβ, have been described, although it is not
completely clear what specific roles ERα and ERβ play in the various physiological effects of
estrogens.
The typical estrogen ligand pharmacophoric model contains a generic and quite variable core
structure. It has an aromatic substituent, which can be differently substituted (R), and one or two
additional substituents, one of which may be another aromatic group. Finally, this pharmacophore
contains one phenolic ring (A), which represents the striking chemical feature common to nearly all
synthetic ligands possessing a good ER binding affinity, and seems to directly mimic the steroid Aring present in natural estrogens (e.g., estradiol and estrone).
In a search for new molecular entities that might bind to the ER and thereby increase the chemical
diversity of estrogen ligands, the possibility of replacing the phenolic ring (A) of estrogen ligands
with new chemical portions which might act as bioisosters has been considered.
Substituent
(aromatic)
R1
Core Structure
HO
HO
N
O
R1
A
R
H
R
R
Substituent
2
R
ER Pharmacophoric Model
H
A'
Salicylaldoximes
HO
N
N
A'
Anthranylaldoximes
To this purpose we investigated the structural basis for the phenol mimicry of salicylaldoximes and
anthranylaldoximes. These new classes of compounds showed interesting ER binding properties on
both receptors subtypes (ERα and ERβ), thus proving that the six-member ring formed by an
intramolecular hydrogen bond (A’), containing an exocyclic oxime OH, appears to be an effective
stereoelectronic replacement of the phenolic ring (A).