Geiparvarin, a natural product that exhibits antiproliferative activity, inhibits the growth of v... more Geiparvarin, a natural product that exhibits antiproliferative activity, inhibits the growth of various tumour cell lines with a mechanism of action so far unknown. Our preliminary findings showed that geiparvarin and some derivatives obtained from its conjugation with diethylstilboestrol and meso-hexestrol significantly inhibit taxol-induced in vitro polymerization of both tubulin and microtubular protein. In this study we investigated the effect of geiparvarin and of the oestrogen-combined derivatives on the cellular microtubular network of fibroblasts. Geiparvarin altered the microtubular organization of fibroblasts and strengthened the derangement of the microtubular pattern in cells exposed simultaneously to taxol. However, the microtubular network remained quite well organized in fibroblasts exposed to geiparvarin and preincubated with taxol, which in this case prevented the deranging effect of the former. The antimicrotubular activity of the oestrogen-combined derivatives was more similar to that of geiparvarin than to that of the oestrogens, and often this activity was stronger than that of each reference drug alone; the cytotoxic activity examined in the same experimental conditions generally confirmed the microscopic analysis.
Geiparvarin is an antiproliferative compound whose mechanism of action has not yet been identifie... more Geiparvarin is an antiproliferative compound whose mechanism of action has not yet been identified. We have investigated the biochemical action on purified microtubular protein, as well as on tubulin, of geiparvarin and of some derivatives resulting from its conjugation with two synthetic oestrogens, diethylstilboestrol and meso-hexoestrol, in comparison with the antimicrotubular action of the reference oestrogens. Geiparvarin and derivatives did not inhibit colchicine binding to tubulin nor did they significantly influence GTP-induced polymerization. On the contrary, they effectively counteracted the stimulating effect of taxol on microtubule formation, both in the presence and in the absence of microtubule-associated proteins. A competitive inhibition mechanism at the taxol binding site of tubulin may thus be proposed to explain the antimicrotubular action of geiparvarin.
Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b ar... more Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b are more active in inhibiting the proliferation of F10 metastatic murine melanoma cells. In particular, 2a is 13 times more active at microM concentration after 48 h exposure.
Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce el... more Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Background: Malaria represents the major parasitic disease in tropical regions, and the developme... more Background: Malaria represents the major parasitic disease in tropical regions, and the development of new potent drugs is of pivotal importance. In this study, a series of hybrid molecules were designed by linking the 7-chloroquinoline core of chloroquine to different fluorinated flavonoid-related scaffolds. Materials & methods: Compounds were prepared by exploiting the click chemistry approach, allowing the introduction of a 1,2,3-triazole, a privileged structural motif in antiparasitic dug discovery. Results: Compounds 1b and 1c were the most interesting and were endowed with the highest in vitro activity, mainly against a resistant Plasmodium falciparum strain. They also inhibited hemozoin formation, and 1c was more effective than chloroquine against stage V gametocytes. Conclusion: The homoisoflavone core is a new, promising antimalarial scaffold that deserves further investigation.
Acetylcholinesterase inhibitors: We extended the AChE inhibitors SAR study to newly synthesized c... more Acetylcholinesterase inhibitors: We extended the AChE inhibitors SAR study to newly synthesized compounds based on the lead compound xantostigmine. Docking and molecular dynamics simulations were carried out to both define a new computational protocol, and to acquire a better understanding of the SAR data. These computations prompted us to evaluate two of the synthesized compounds as inhibitors of AChE‐induced Aβ aggregation.magnified imageStructure–activity relationship studies on acetylcholinesterase (AChE) inhibitors were extended to newly synthesized compounds derived from the lead compound xantostigmine (1). The xanthone ring of compound 1 was replaced with several different scaffolds based on the benzopyran skeleton, linked to the tertiary amino nitrogen through an heptyloxy chain. These modifications resulted in 19 new compounds, most of them showing activity in the nanomolar–subnanomolar range. Docking and molecular dynamics simulations were carried out to both define a new computational protocol for the simulation of pseudo‐irreversibile AChE covalent inhibitors, and to acquire a better understanding of the structure–activity relationships of the present series of compounds. The results of this computational work prompted us to to evaluate the ability of compounds 5 and 13 to inhibit acetylcholinesterase‐induced Aβ aggregation.
Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synt... more Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synthesized compounds was evaluated towards four tumoral cell lines, and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. Direct cytotoxic activity was very low for all derivatives. However, almost all compounds showed a remarkable increase of indirect cytotoxicity. In particular, compound 3i, which has an F atom in the 7 position of the flavone ring, was able to increase significantly the macrophage's lytic properties, and has been selected for further investigations.
With the aim to split the pharmacological properties of lefetamine (CAS 14148-99-3), some structu... more With the aim to split the pharmacological properties of lefetamine (CAS 14148-99-3), some structural modifications of this compound have been studied. The basic group of lefetamine has been shifted from the alkyl chain to the vicinal phenyl ring and the N-substitution has been changed. The dimethylaminomethyl derivatives and chiefly the o-morpholinometyhl exhibited a strong anti-visceral chemical antinociception activity stripped of thermal antinociception properties and physical dependence liability. Furthermore, through the introduction of a diethylaminomethyl group in the lefetamine structure some derivatives were selected exhibiting besided a significant increase in the anti-visceral chemical antinociception activity, remarkable local anesthetic properties.
Some coumarin-, flavonol- and flavanon-acetic acids are described. The cytotoxicity of the synthe... more Some coumarin-, flavonol- and flavanon-acetic acids are described. The cytotoxicity of the synthesized compounds was determined on a human colon carcinoma cell line (LoVo) through evaluation of neutral red uptake, performed by the Riddel method. All tested derivatives were able to induce a statistically significant reduction of lysosomal neutral red uptake at 5 x 10(-5) M concentration. Some compounds were more active than the reference compound flavon-8-acetic acid.
Current healthcare has significantly increased the average life expectancy, leading to a conseque... more Current healthcare has significantly increased the average life expectancy, leading to a consequently greater incidence of age-related diseases, such as Alzheimer's disease. Following a multitarget approach, in this paper a series of polycyclic maleimide-based derivatives were designed and synthesized aimed at simultaneously modulate neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3b), validated targets to combat Alzheimer' disease. Different structural modifications were performed on the polycyclic scaffold in order to investigate the structure-activity relationships and compound 10 emerged as a promising non-toxic lead compound, endowed with calcium modulating brain-addressed properties and significant GSK-3b inhibitory activity. Moreover, the easily affordable polycyclic core appears as a new appealing privileged structure in medicinal chemistry.
Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female popula... more Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC.
Geiparvarin, a natural product that exhibits antiproliferative activity, inhibits the growth of v... more Geiparvarin, a natural product that exhibits antiproliferative activity, inhibits the growth of various tumour cell lines with a mechanism of action so far unknown. Our preliminary findings showed that geiparvarin and some derivatives obtained from its conjugation with diethylstilboestrol and meso-hexestrol significantly inhibit taxol-induced in vitro polymerization of both tubulin and microtubular protein. In this study we investigated the effect of geiparvarin and of the oestrogen-combined derivatives on the cellular microtubular network of fibroblasts. Geiparvarin altered the microtubular organization of fibroblasts and strengthened the derangement of the microtubular pattern in cells exposed simultaneously to taxol. However, the microtubular network remained quite well organized in fibroblasts exposed to geiparvarin and preincubated with taxol, which in this case prevented the deranging effect of the former. The antimicrotubular activity of the oestrogen-combined derivatives was more similar to that of geiparvarin than to that of the oestrogens, and often this activity was stronger than that of each reference drug alone; the cytotoxic activity examined in the same experimental conditions generally confirmed the microscopic analysis.
Geiparvarin is an antiproliferative compound whose mechanism of action has not yet been identifie... more Geiparvarin is an antiproliferative compound whose mechanism of action has not yet been identified. We have investigated the biochemical action on purified microtubular protein, as well as on tubulin, of geiparvarin and of some derivatives resulting from its conjugation with two synthetic oestrogens, diethylstilboestrol and meso-hexoestrol, in comparison with the antimicrotubular action of the reference oestrogens. Geiparvarin and derivatives did not inhibit colchicine binding to tubulin nor did they significantly influence GTP-induced polymerization. On the contrary, they effectively counteracted the stimulating effect of taxol on microtubule formation, both in the presence and in the absence of microtubule-associated proteins. A competitive inhibition mechanism at the taxol binding site of tubulin may thus be proposed to explain the antimicrotubular action of geiparvarin.
Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b ar... more Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b are more active in inhibiting the proliferation of F10 metastatic murine melanoma cells. In particular, 2a is 13 times more active at microM concentration after 48 h exposure.
Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce el... more Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Background: Malaria represents the major parasitic disease in tropical regions, and the developme... more Background: Malaria represents the major parasitic disease in tropical regions, and the development of new potent drugs is of pivotal importance. In this study, a series of hybrid molecules were designed by linking the 7-chloroquinoline core of chloroquine to different fluorinated flavonoid-related scaffolds. Materials & methods: Compounds were prepared by exploiting the click chemistry approach, allowing the introduction of a 1,2,3-triazole, a privileged structural motif in antiparasitic dug discovery. Results: Compounds 1b and 1c were the most interesting and were endowed with the highest in vitro activity, mainly against a resistant Plasmodium falciparum strain. They also inhibited hemozoin formation, and 1c was more effective than chloroquine against stage V gametocytes. Conclusion: The homoisoflavone core is a new, promising antimalarial scaffold that deserves further investigation.
Acetylcholinesterase inhibitors: We extended the AChE inhibitors SAR study to newly synthesized c... more Acetylcholinesterase inhibitors: We extended the AChE inhibitors SAR study to newly synthesized compounds based on the lead compound xantostigmine. Docking and molecular dynamics simulations were carried out to both define a new computational protocol, and to acquire a better understanding of the SAR data. These computations prompted us to evaluate two of the synthesized compounds as inhibitors of AChE‐induced Aβ aggregation.magnified imageStructure–activity relationship studies on acetylcholinesterase (AChE) inhibitors were extended to newly synthesized compounds derived from the lead compound xantostigmine (1). The xanthone ring of compound 1 was replaced with several different scaffolds based on the benzopyran skeleton, linked to the tertiary amino nitrogen through an heptyloxy chain. These modifications resulted in 19 new compounds, most of them showing activity in the nanomolar–subnanomolar range. Docking and molecular dynamics simulations were carried out to both define a new computational protocol for the simulation of pseudo‐irreversibile AChE covalent inhibitors, and to acquire a better understanding of the structure–activity relationships of the present series of compounds. The results of this computational work prompted us to to evaluate the ability of compounds 5 and 13 to inhibit acetylcholinesterase‐induced Aβ aggregation.
Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synt... more Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synthesized compounds was evaluated towards four tumoral cell lines, and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. Direct cytotoxic activity was very low for all derivatives. However, almost all compounds showed a remarkable increase of indirect cytotoxicity. In particular, compound 3i, which has an F atom in the 7 position of the flavone ring, was able to increase significantly the macrophage's lytic properties, and has been selected for further investigations.
With the aim to split the pharmacological properties of lefetamine (CAS 14148-99-3), some structu... more With the aim to split the pharmacological properties of lefetamine (CAS 14148-99-3), some structural modifications of this compound have been studied. The basic group of lefetamine has been shifted from the alkyl chain to the vicinal phenyl ring and the N-substitution has been changed. The dimethylaminomethyl derivatives and chiefly the o-morpholinometyhl exhibited a strong anti-visceral chemical antinociception activity stripped of thermal antinociception properties and physical dependence liability. Furthermore, through the introduction of a diethylaminomethyl group in the lefetamine structure some derivatives were selected exhibiting besided a significant increase in the anti-visceral chemical antinociception activity, remarkable local anesthetic properties.
Some coumarin-, flavonol- and flavanon-acetic acids are described. The cytotoxicity of the synthe... more Some coumarin-, flavonol- and flavanon-acetic acids are described. The cytotoxicity of the synthesized compounds was determined on a human colon carcinoma cell line (LoVo) through evaluation of neutral red uptake, performed by the Riddel method. All tested derivatives were able to induce a statistically significant reduction of lysosomal neutral red uptake at 5 x 10(-5) M concentration. Some compounds were more active than the reference compound flavon-8-acetic acid.
Current healthcare has significantly increased the average life expectancy, leading to a conseque... more Current healthcare has significantly increased the average life expectancy, leading to a consequently greater incidence of age-related diseases, such as Alzheimer's disease. Following a multitarget approach, in this paper a series of polycyclic maleimide-based derivatives were designed and synthesized aimed at simultaneously modulate neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3b), validated targets to combat Alzheimer' disease. Different structural modifications were performed on the polycyclic scaffold in order to investigate the structure-activity relationships and compound 10 emerged as a promising non-toxic lead compound, endowed with calcium modulating brain-addressed properties and significant GSK-3b inhibitory activity. Moreover, the easily affordable polycyclic core appears as a new appealing privileged structure in medicinal chemistry.
Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female popula... more Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC.
Uploads
Papers by Angela Rampa