Elisiário Tavares | University of Coimbra (original) (raw)

Papers by Elisiário Tavares

Journal of Medicinal Chemistry, 2005

Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cance... more Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New A,D-ring modified steroid analogues of formestane and testolactone were designed and synthesized and their biochemical activity was investigated in vitro in an attempt to find new aromatase inhibitors and to gain insight into their structure-activity relationships (SAR). All compounds tested were less active than formestane. However, the 3-deoxy steroidal olefin 3a and its epoxide derivative 4a proved to be strong competitive aromatase inhibitors (K i ) 50 and 38 nM and IC 50 ) 225 and 145 nM, respectively). According to our findings, the C-3 carbonyl group is not essential for anti-aromatase activity, but 5R-stereochemistry and some planarity in the steroidal framework is required. Furthermore, modification of the steroidal cyclopentanone D-ring, by construction of a δ-lactone six-membered ring, decreases the inhibitory potency. From the results obtained, it may be concluded that the binding pocket of the active site of aromatase requires planarity in the region of the steroid A,B-rings and the D-ring structure is critical for the binding.

Acta Crystallographica Section C-crystal Structure Communications, 2008

Bioorganic & Medicinal Chemistry, 2010

Lipophilic compounds structurally based on caffeic, hydrocaffeic, ferulic and hydroferulic acids ... more Lipophilic compounds structurally based on caffeic, hydrocaffeic, ferulic and hydroferulic acids were synthesized. Subsequently, their antioxidant activity was evaluated as well as their partition coefficients and redox potentials. The structure-property-activity relationship (SPAR) results revealed the existence of a clear correlation between the redox potentials and the antioxidant activity. In addition, some compounds showed a proper lipophilicity to cross the blood-brain barrier. Their predicted ADME properties are also in accordance with the general requirements for potential CNS drugs. Accordingly, one can propose these phenolic compounds as potential antioxidants for tackling the oxidative status linked to the neurodegenerative processes.

Steroids, 2002

A new convergent synthesis of the antitumor steroid formestane (4-OHA) 5 has been performed from ... more A new convergent synthesis of the antitumor steroid formestane (4-OHA) 5 has been performed from the easily available epimeric mixture of 5␣-and 5␤-androst-3-en-17-one 1a and 1b in order to attempt a yield improvement. A two-step oxidative route followed by base-catalyzed isomerization was applied to the 5␣-and 5␤-epimers 1a and 1b, either as a mixture or separately, leading to the title compound 5. From epimer 1a an efficient process was attained to prepare the desired aromatase inhibitor formestane. Epimer 1b led to the formation of the same compound 5. Additionally, 1b have also been converted in 5␤-hydroxyandrostane-3,17-dione 12 and androst-4-ene-3,17-dione 13, revealing an unexpected reactivity of the 3␤,4␤-epoxy-5␤-androstan-17-one intermediate 6 formed from 1b during the first oxidative step with performic acid. Cleavage of the epoxide 6 led to the trans-diaxial and the trans-diequatorial vic-diols 7 and 8 and to the 1,3-diol 9. The formation of the abnormal products 8 and 9 were investigated through X-ray and deuterium labeling studies. Diol 8 was formed through a trans-diequatorial epoxide ring opening and the 1,3-diol 9 was formed through an intramolecular rearrangement involving a 1,2-hydride shift. All the vic-diols 3, 7 and 8 formed, proved to be good precursors for the synthesis of the target compound 5.

Acta Crystallographica Section C-crystal Structure Communications, 1999

Acta Crystallographica Section E-structure Reports Online, 2001

ABSTRACT In the title 6–6–6–5 fused ring compound, C19H28O, all the ring junctions are trans. The... more ABSTRACT In the title 6–6–6–5 fused ring compound, C19H28O, all the ring junctions are trans. The unsaturated ring A shows a conformation intermediate between a 10β-sofa and a 1α,10β-half-chair.

Acta Crystallographica Section C-crystal Structure Communications, 1998

Journal of Fluorine Chemistry, 2009

In this work we describe and compare the synthesis of four new hexylamides of hydrocinnamic acids... more In this work we describe and compare the synthesis of four new hexylamides of hydrocinnamic acids, namely hexylamide of hydrocinnamic, 3,4-dimethoxyhydrocinnamic, 4-hydroxy-3-methoxyhydrocinnamic and 3,4-dihydroxyhydrocinnamic acids via pentafluorophenyl esters (PFPEs) versus pentafluorophenyl thioesters (PFPTs) intermediates. It was found that the PFPE are the best intermediates for this kind of synthesis giving reactions with less by products, easier work-up, higher overall yields and with the best reactivity towards hexylamine. The X-ray structures of two PFPE are also reported. ß

Acta Crystallographica Section C-crystal Structure Communications, 1998

Cheminform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Acta Crystallographica Section C-crystal Structure Communications, 1997

the opening sentence of the Comment should read 'As part of a study directed towards developing a... more the opening sentence of the Comment should read 'As part of a study directed towards developing an efficient strategy for the synthesis of formestane, an irreversible aromatase inhibitor which has been shown to be very effective in the treatment of oestrogen-dependent breast cancer, the title compound, (I), has been synthesized as an intermediate.'

Biological Chemistry, 2008

A recent approach for treatment and prevention of estrogen-dependent breast cancer focuses on the... more A recent approach for treatment and prevention of estrogen-dependent breast cancer focuses on the inhibition of aromatase, the enzyme that catalyzes the final step of estrogen biosynthesis. Some synthetic steroids, such as formestane and exemestane, resembling the natural enzyme substrate androstenedione, revealed to be potent and useful aromatase inhibitors (AIs) and were approved for the treatment of estrogen-dependent breast cancer in postmenopausal women. Recently, we found that five newly synthesized steroids with chemical features in the A- and D-rings considered important for drug-receptor interaction efficiently inhibit aromatase derived from human placental microsomes. In this work, these steroids showed a similar pattern of anti-aromatase activity in several aromatase-expressing cell lines. 5alpha-androst-3-en-17-one and 3alpha,4alpha-epoxy-5alpha-androstan-17-one were revealed to be the most potent inhibitors. These compounds induced a time-dependent inhibition of aromatase, showing to be irreversible AIs. The specific interactions of these compounds with aromatase active sites were further demonstrated by site-directed mutagenesis studies and evaluated by computer-aided molecular modeling. Both compounds were able to suppress hormone-dependent proliferation of MCF-7aro cells in a dose-dependent manner. These findings are important for the elucidation of a structure-activity relationship on aromatase, which may help in the development of new AIs.

BMC Cell Biology, 2008

Background: Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis,... more Background: Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.

Steroids, 2008

Breast cancer a b s t r a c t A series of 5␣-androst-3-enes and 3␣,4␣-epoxy-5␣-androstanes were s... more Breast cancer a b s t r a c t A series of 5␣-androst-3-enes and 3␣,4␣-epoxy-5␣-androstanes were synthesized and tested for their abilities to inhibit aromatase in human placental microsomes. In these series the original C-17 carbonyl group was replaced by hydroxyl, acetyl and hydroxyimine groups.

Acta Crystallographica Section C-crystal Structure Communications, 1999

PLOS One, 2012

Aromatase inhibitors (AIs), which block the conversion of androgens to estrogens, are used for ho... more Aromatase inhibitors (AIs), which block the conversion of androgens to estrogens, are used for hormone-dependent breast cancer treatment. Exemestane, a steroidal that belongs to the third-generation of AIs, is a mechanism-based inhibitor that binds covalently and irreversibly, inactivating and destabilizing aromatase. Since the biological effects of exemestane in breast cancer cells are not totally understood, its effects on cell viability, cell proliferation and mechanisms of cell death were studied in an ER-positive aromatase-overexpressing breast cancer cell line (MCF-7aro). The effects of 3-methyladenine (3-MA), an inhibitor of autophagy and of ZVAD-FMK, an apoptotic inhibitor, in exemestane treated cells were also investigated. Our results indicate that exemestane induces a strong inhibition in MCF-7aro cell proliferation in a dose-and time-dependent manner, promoting a significant cell cycle arrest in G 0 /G1 or in G 2 /M phases after 3 and 6 days of treatment, respectively. This was accompanied by a decrease in cell viability due to activation of cell death by apoptosis, via mitochondrial pathway and the occurrence of autophagy. Inhibition of autophagy by the autophagic inhibitor, 3-MA, resulted in a reduction of cell viability and activation of caspases. All together the results obtained suggest that exemestane induced mitochondrial-mediated apoptosis and autophagy, which act as a pro-survival process regulating breast cancer cell apoptosis.

Tetrahedron, 1999

An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ wit... more An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3cz-hydroxy-and 3(x,21-dihydroxy-Scvpregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swem type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6,17-trione, has been efficiently prepared using PCC on montmorillonite KI0, under ultrasonic irradiation.

Acta Crystallographica Section E-structure Reports Online, 2002

Single-crystal X-ray study T = 293 K Mean '(C±C) = 0.003 A Ê R factor = 0.035 wR factor = 0.108 D... more Single-crystal X-ray study T = 293 K Mean '(C±C) = 0.003 A Ê R factor = 0.035 wR factor = 0.108 Data-to-parameter ratio = 8.8

Cheminform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cheminform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Journal of Medicinal Chemistry, 2005

Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cance... more Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New A,D-ring modified steroid analogues of formestane and testolactone were designed and synthesized and their biochemical activity was investigated in vitro in an attempt to find new aromatase inhibitors and to gain insight into their structure-activity relationships (SAR). All compounds tested were less active than formestane. However, the 3-deoxy steroidal olefin 3a and its epoxide derivative 4a proved to be strong competitive aromatase inhibitors (K i ) 50 and 38 nM and IC 50 ) 225 and 145 nM, respectively). According to our findings, the C-3 carbonyl group is not essential for anti-aromatase activity, but 5R-stereochemistry and some planarity in the steroidal framework is required. Furthermore, modification of the steroidal cyclopentanone D-ring, by construction of a δ-lactone six-membered ring, decreases the inhibitory potency. From the results obtained, it may be concluded that the binding pocket of the active site of aromatase requires planarity in the region of the steroid A,B-rings and the D-ring structure is critical for the binding.

Acta Crystallographica Section C-crystal Structure Communications, 2008

Bioorganic & Medicinal Chemistry, 2010

Lipophilic compounds structurally based on caffeic, hydrocaffeic, ferulic and hydroferulic acids ... more Lipophilic compounds structurally based on caffeic, hydrocaffeic, ferulic and hydroferulic acids were synthesized. Subsequently, their antioxidant activity was evaluated as well as their partition coefficients and redox potentials. The structure-property-activity relationship (SPAR) results revealed the existence of a clear correlation between the redox potentials and the antioxidant activity. In addition, some compounds showed a proper lipophilicity to cross the blood-brain barrier. Their predicted ADME properties are also in accordance with the general requirements for potential CNS drugs. Accordingly, one can propose these phenolic compounds as potential antioxidants for tackling the oxidative status linked to the neurodegenerative processes.

Steroids, 2002

A new convergent synthesis of the antitumor steroid formestane (4-OHA) 5 has been performed from ... more A new convergent synthesis of the antitumor steroid formestane (4-OHA) 5 has been performed from the easily available epimeric mixture of 5␣-and 5␤-androst-3-en-17-one 1a and 1b in order to attempt a yield improvement. A two-step oxidative route followed by base-catalyzed isomerization was applied to the 5␣-and 5␤-epimers 1a and 1b, either as a mixture or separately, leading to the title compound 5. From epimer 1a an efficient process was attained to prepare the desired aromatase inhibitor formestane. Epimer 1b led to the formation of the same compound 5. Additionally, 1b have also been converted in 5␤-hydroxyandrostane-3,17-dione 12 and androst-4-ene-3,17-dione 13, revealing an unexpected reactivity of the 3␤,4␤-epoxy-5␤-androstan-17-one intermediate 6 formed from 1b during the first oxidative step with performic acid. Cleavage of the epoxide 6 led to the trans-diaxial and the trans-diequatorial vic-diols 7 and 8 and to the 1,3-diol 9. The formation of the abnormal products 8 and 9 were investigated through X-ray and deuterium labeling studies. Diol 8 was formed through a trans-diequatorial epoxide ring opening and the 1,3-diol 9 was formed through an intramolecular rearrangement involving a 1,2-hydride shift. All the vic-diols 3, 7 and 8 formed, proved to be good precursors for the synthesis of the target compound 5.

Acta Crystallographica Section C-crystal Structure Communications, 1999

Acta Crystallographica Section E-structure Reports Online, 2001

ABSTRACT In the title 6–6–6–5 fused ring compound, C19H28O, all the ring junctions are trans. The... more ABSTRACT In the title 6–6–6–5 fused ring compound, C19H28O, all the ring junctions are trans. The unsaturated ring A shows a conformation intermediate between a 10β-sofa and a 1α,10β-half-chair.

Acta Crystallographica Section C-crystal Structure Communications, 1998

Journal of Fluorine Chemistry, 2009

In this work we describe and compare the synthesis of four new hexylamides of hydrocinnamic acids... more In this work we describe and compare the synthesis of four new hexylamides of hydrocinnamic acids, namely hexylamide of hydrocinnamic, 3,4-dimethoxyhydrocinnamic, 4-hydroxy-3-methoxyhydrocinnamic and 3,4-dihydroxyhydrocinnamic acids via pentafluorophenyl esters (PFPEs) versus pentafluorophenyl thioesters (PFPTs) intermediates. It was found that the PFPE are the best intermediates for this kind of synthesis giving reactions with less by products, easier work-up, higher overall yields and with the best reactivity towards hexylamine. The X-ray structures of two PFPE are also reported. ß

Acta Crystallographica Section C-crystal Structure Communications, 1998

Cheminform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Acta Crystallographica Section C-crystal Structure Communications, 1997

the opening sentence of the Comment should read 'As part of a study directed towards developing a... more the opening sentence of the Comment should read 'As part of a study directed towards developing an efficient strategy for the synthesis of formestane, an irreversible aromatase inhibitor which has been shown to be very effective in the treatment of oestrogen-dependent breast cancer, the title compound, (I), has been synthesized as an intermediate.'

Biological Chemistry, 2008

A recent approach for treatment and prevention of estrogen-dependent breast cancer focuses on the... more A recent approach for treatment and prevention of estrogen-dependent breast cancer focuses on the inhibition of aromatase, the enzyme that catalyzes the final step of estrogen biosynthesis. Some synthetic steroids, such as formestane and exemestane, resembling the natural enzyme substrate androstenedione, revealed to be potent and useful aromatase inhibitors (AIs) and were approved for the treatment of estrogen-dependent breast cancer in postmenopausal women. Recently, we found that five newly synthesized steroids with chemical features in the A- and D-rings considered important for drug-receptor interaction efficiently inhibit aromatase derived from human placental microsomes. In this work, these steroids showed a similar pattern of anti-aromatase activity in several aromatase-expressing cell lines. 5alpha-androst-3-en-17-one and 3alpha,4alpha-epoxy-5alpha-androstan-17-one were revealed to be the most potent inhibitors. These compounds induced a time-dependent inhibition of aromatase, showing to be irreversible AIs. The specific interactions of these compounds with aromatase active sites were further demonstrated by site-directed mutagenesis studies and evaluated by computer-aided molecular modeling. Both compounds were able to suppress hormone-dependent proliferation of MCF-7aro cells in a dose-dependent manner. These findings are important for the elucidation of a structure-activity relationship on aromatase, which may help in the development of new AIs.

BMC Cell Biology, 2008

Background: Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis,... more Background: Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.

Steroids, 2008

Breast cancer a b s t r a c t A series of 5␣-androst-3-enes and 3␣,4␣-epoxy-5␣-androstanes were s... more Breast cancer a b s t r a c t A series of 5␣-androst-3-enes and 3␣,4␣-epoxy-5␣-androstanes were synthesized and tested for their abilities to inhibit aromatase in human placental microsomes. In these series the original C-17 carbonyl group was replaced by hydroxyl, acetyl and hydroxyimine groups.

Acta Crystallographica Section C-crystal Structure Communications, 1999

PLOS One, 2012

Aromatase inhibitors (AIs), which block the conversion of androgens to estrogens, are used for ho... more Aromatase inhibitors (AIs), which block the conversion of androgens to estrogens, are used for hormone-dependent breast cancer treatment. Exemestane, a steroidal that belongs to the third-generation of AIs, is a mechanism-based inhibitor that binds covalently and irreversibly, inactivating and destabilizing aromatase. Since the biological effects of exemestane in breast cancer cells are not totally understood, its effects on cell viability, cell proliferation and mechanisms of cell death were studied in an ER-positive aromatase-overexpressing breast cancer cell line (MCF-7aro). The effects of 3-methyladenine (3-MA), an inhibitor of autophagy and of ZVAD-FMK, an apoptotic inhibitor, in exemestane treated cells were also investigated. Our results indicate that exemestane induces a strong inhibition in MCF-7aro cell proliferation in a dose-and time-dependent manner, promoting a significant cell cycle arrest in G 0 /G1 or in G 2 /M phases after 3 and 6 days of treatment, respectively. This was accompanied by a decrease in cell viability due to activation of cell death by apoptosis, via mitochondrial pathway and the occurrence of autophagy. Inhibition of autophagy by the autophagic inhibitor, 3-MA, resulted in a reduction of cell viability and activation of caspases. All together the results obtained suggest that exemestane induced mitochondrial-mediated apoptosis and autophagy, which act as a pro-survival process regulating breast cancer cell apoptosis.

Tetrahedron, 1999

An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ wit... more An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3cz-hydroxy-and 3(x,21-dihydroxy-Scvpregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swem type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6,17-trione, has been efficiently prepared using PCC on montmorillonite KI0, under ultrasonic irradiation.

Acta Crystallographica Section E-structure Reports Online, 2002

Single-crystal X-ray study T = 293 K Mean '(C±C) = 0.003 A Ê R factor = 0.035 wR factor = 0.108 D... more Single-crystal X-ray study T = 293 K Mean '(C±C) = 0.003 A Ê R factor = 0.035 wR factor = 0.108 Data-to-parameter ratio = 8.8

Cheminform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cheminform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.