0000000000248087
AUTHOR
Francesco Paolo Invidiata
showing 30 related works from this author
1,5,7-Triazabicyclo[4.4.0]dec-1- ene (TBD), 7-Methyl-TBD (MTBD) and the polymer-supported TBD (P-TBD):Three efficient catalysts for the nitroaldol (H…
2000
Abstract The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its 7-methyl derivative (MTBD) have been proven to be of great synthetic utility as catalysts in the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to a variety of carbonyl compounds. The catalysts were in many cases superior to the parent tetramethylguanidine (TMG). In general the reaction proceeds in a few minutes at 0°C. The polymer-supported-TBD (P-TBD) was also proven to be an efficient promoter of the above cited nucleophilic additions.
ChemInform Abstract: Two-Carbon Bridge Substituted Cocaines: Enantioselective Synthesis, Attribution of the Absolute Configuration, and Biological Ac…
2010
In an effort to learn more about the general structure-activity relationships of cocaine with the aim to elucidate those structural features that might confer antagonistic properties to such analogues, we describe herein our synthetic efforts to prepare two-carbon bridge functionalized (methoxylated and hydroxylated) analogues. Our approach makes use of a modification of the classical Willstatter synthesis of cocaine: Mannich type cyclization of acetonedicarboxylic acid monomethyl ester with methylamine hydrochloride and 2-methoxysuccindialdehyde in a citrate buffer solution afforded the 6- and 7-substituted 2-carbomethoxy-3-tropinones 3a,b and 4a,b in approximate yields of 64%. Reduction o…
Tetramethylguanidine (TMG)-catalyzed addition of dialkyl phosphites to α,β-unsaturated carbonyl compounds, alkenenitriles, aldehydes, ketones and imi…
1998
Abstract Tetramethylguanidine-catalyzed addition of dialkyl phosphites to α,β-unsaturated carbonyl compounds, alkenenitriles, aldehydes and ketones constitutes a practical route to a variety of phosphonate synthons. The very mild conditions employed, together with the short reaction times, make the procedure highly versatile and tolerant to a range of functionalities. The proposed methodology is also convenient for the preparation of α-aminophosphonates.
ChemInform Abstract: Tetramethylguanidine (TMG)-Catalyzed Addition of Dialkyl Phosphites to α,β-Unsaturated Carbonyl Compounds, Alkenenitriles, Aldeh…
2010
Abstract Tetramethylguanidine-catalyzed addition of dialkyl phosphites to α,β-unsaturated carbonyl compounds, alkenenitriles, aldehydes and ketones constitutes a practical route to a variety of phosphonate synthons. The very mild conditions employed, together with the short reaction times, make the procedure highly versatile and tolerant to a range of functionalities. The proposed methodology is also convenient for the preparation of α-aminophosphonates.
Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocyte…
2008
A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human gammadelta T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate gammadelta T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of gammadelta T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new…
Two-carbon bridge substituted cocaines: enantioselective synthesis, attribution of the absolute configuration and biological activity of novel 6- and…
1999
In an effort to learn more about the general structure-activity relationships of cocaine with the aim to elucidate those structural features that might confer antagonistic properties to such analogues, we describe herein our synthetic efforts to prepare two-carbon bridge functionalized (methoxylated and hydroxylated) analogues. Our approach makes use of a modification of the classical Willstatter synthesis of cocaine: Mannich type cyclization of acetonedicarboxylic acid monomethyl ester with methylamine hydrochloride and 2-methoxysuccindialdehyde in a citrate buffer solution afforded the 6- and 7-substituted 2-carbomethoxy-3-tropinones 3a,b and 4a,b in approximate yields of 64%. Reduction o…
ChemInform Abstract: 1,5,7-Triazabicyclo[4.4.0]dec-1-ene (TBD), 7-Methyl-TBD (MTBD) and the Polymer-Supported TBD (P-TBD): Three Efficient Catalysts …
2010
Abstract The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its 7-methyl derivative (MTBD) have been proven to be of great synthetic utility as catalysts in the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to a variety of carbonyl compounds. The catalysts were in many cases superior to the parent tetramethylguanidine (TMG). In general the reaction proceeds in a few minutes at 0°C. The polymer-supported-TBD (P-TBD) was also proven to be an efficient promoter of the above cited nucleophilic additions.
Studies on the apoptotic activity of natural and synthetic retinoids: discovery of a new class of synthetic terphenyls that potently support cell gro…
2005
New terphenyl derivatives have been synthesized and tested for their effect on cell survival in serum-free cultures. These compounds protected HL60 cells from death and supported their growth with an activity higher than that of the natural 14-hydroxy-retro-retinol. Terphenyls 26 and 28 also possess antiapoptotic activity on neuronal cells, proving them as possible candidates for the treatment of neurodegenerative and ischemic diseases.
Galangin increases the cytotoxic activity of imatinib mesylate in imatinib-sensitive and imatinib-resistant Bcr-Abl expressing leukemia cells
2008
Resistance to imatinib mesylate is an emergent problem in the treatment of Bcr-Abl expressing myelogenous leukemias and additional therapeutic strategies are required. We observed that galangin, a non-toxic, naturally occurring flavonoid was effective as anti-proliferative, and apoptotic agent in Bcr-Abl expressing K562 and KCL22 cells and in imatinib mesylate resistant K562-R and KCL22-R cells. Galangin induced an arrest of cells in G0–G1phase of cell cycle and a decrease in pRb, cdk4, cdk1, cycline B levels; moreover, it was able to induce a monocytic differentiation of leukemic Bcr-Abl+ cells. Of note, galangin caused a decrease in Bcl-2 levels and markedly increased the apoptotic activi…
Effects of two-carbon bridge region methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter
2001
6-Methoxylated and 8-oxygenated benztropines were prepared and evaluated for their DAT and SERT activity (binding and uptake inhibition). Methoxylation at the two-carbon bridge of benztropine produced a novel class of potent and selective DAT ligands. An interesting enantioselectivity was also observed for this new class of chiral benztropines. The inactivity of the 8-oxygenated analogues seems to point out that, unlike cocaine and its analogues, interactions of benztropine ligands with DAT may be strongly governed by the nitrogen atom.
ChemInform Abstract: Facile Synthesis of 2-Nitroalkanols by Tetramethylguanidine (TMG)- Catalyzed Addition of Primary Nitroalkanes to Aldehydes and A…
2010
Abstract Tetramethylguanidine-catalyzed addition of primary nitroalkanes to aldehydes and alicyclic ketones constitutes a practical means to perform the nitro-aldol reaction (Henry reaction). The very mild conditions employed, together with the short reaction times, make the procedure tolerant of a range of functionalities and highly versatile for the synthesis of a variety of 2-nitroalkanols.
Programmed cell death (PCD) associated with the stilbene motif of arotinoids: discovery of novel apoptosis inducer agents possessing activity on mult…
2000
Considering that the stereochemistry of the C9-C10 alkenyl portion of natural 9-cis-RA, as the one of the olefinic moiety of the previously described isoxazole retinoid 4, seems of particular importance for their apoptotic activity, we prepared a novel class of TTNPB analogues bearing both the cis or trans configuration of the alkenyl portion. The compounds were evaluated in vitro for their cytotoxic and apoptotic activities. We discovered that the cis-TTNPB 9c possesses apoptotic activity comparable with that of the retinoid 4. Moreover, the amino arotinoid 16c showed potent apoptotic activity in HL60 promyelocytic leukemia cells. Interestingly, 16c proved to be a particularly potent apopt…
Synthesis of new 2,2′-disubstituted 5,5′-dimethyl-4,4′-bitriazoles and 2-(4-Triazolyl)quinoxalines
2000
Thermal rearrangement of 3-acylisoxazole arylhydrazones allowed facile preparation of 2H-1,2,3-triazoles which were firstly reacted with isoamyl nitrite and then with an opportune arylhydrazine to produce the corresponding α-hydroxyiminohydrazones 8a-h. The reaction of compounds 8a-h with phosphorus pentachloride afforded the desired 4,4′-bitriazoles 1a-h. The α-hydroxyiminoketone derivative 7 or the α-diketone 14 reacted easily with 1,2-phenylenediamine to afford 1,2,3-triazoles 2a-c bearing the quinoxaline moiety at position 4. Improved yields of the quinoxalines 2a-c were obtained when 1,2-phenylenediamine was reacted with the dioxime 15.
Facile synthesis of pyrazoles and pyrroles via thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines and tetrazolo[1,5-a]pyridines
2000
Abstract A simple and high yielding preparation of pyrazoles and pyrroles is described. Thermolysis of tetrazolo[1,5- b ]pyridazines, tetrazolo[1,5- a ]pyrimidines and tetrazolo[1,5- a ]pyridines allowed easy ring contraction thus providing a facile preparation of cyanopyrazole and cyanopyrrole heterocycles. Since the cyano group is a versatile precursor of other functionalities, the reaction appears of particular interest for the construction of a variety of pyrazoles and pyrroles. The simple preparation of the starting tetrazole derivatives, the relatively mild conditions employed, and the very short reaction times make this versatile procedure of great synthetic utility and applicable bo…
Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopami…
2005
A series of 6alpha- and 6beta-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6beta-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6alpha-methoxy-3-(4',4' '-difluorodiphenylmethoxy)tropane (5 g) was the most potent compound. It has been found that modifications at the 6-position of benztropine might reduce the DAT binding affinity, maintaining otherwise a significant dopamine uptake inhibitory activity. A reinvestigation of the absolute configuration of 6beta-methoxytropinone proved the 6R configuration for the (+)-enantiomer.
Design, synthesis and biological evaluation of novel stilbene-based antitumor agents
2008
A series of novel stilbene derivatives has been synthesized and studied with the main goal to investigate SAR of the amino compound 1a, as well as to improve its water solubility, a potentially negative aspect of the molecule that could be a serious obstacle for a pre-clinical development. We have obtained derivatives with good cytotoxic activity, in particular, the derivatives 5c and 6b could represent two novel leads for further investigation. Compound 8b, a morpholino-carbamate derivative, prodrug of 1a, has a very good solubility in water, and is active in suppressing growth of tumor cells at a concentration of 5000 nM, which is a concentration 100 times higher than the parent stilbene …
The synergistic apoptotic effects of thiophenfurin, an inosine monophosphate dehydrogenase inhibitor, in combination with retinoids in HL60 cells
2006
New effective cytotoxic agents and combinations are urgently needed in cancer treatment. The enzyme inosine monophosphate dehydrogenase is a potentially useful target for drug development, since its activity has been shown to be amplified in malignant cells. Thiophenfurin, an inhibitor of the enzyme synthesized by us, is endowed with a significant apoptotic activity in promyelocytic leukaemia HL60 cells. Since retinoids were successfully employed in the treatment of patients with leukaemia, demonstrating significant differentiation-inducing and apoptotic effects, we carried out this study to evaluate the effects of the combination of thiophenfurin and several retinoid molecules, acting in d…
Retinoid acid and analogs as potent inducers of differentiation and apoptosis. New promising chemopreventive and chemotherapeutic agents in oncology
2001
Abstract In this report we will describe the preparation and the biological activity of a novel class of heterocyclic arotinoids endowed with potent cytotoxic and apoptotic acitivity. Structureactivity relationship studies revealed that the different stereochemistry at the C9 double bond of retinoids seems associated with a different biological activity: potent apoptotic activity for the cis-isomers, whereas differentiating activity for the trans structures. An interesting modified Wittig procedure that allows easily to arotinoids will also be described. The substitution of the alkenyl portion with a more flexible oxymethyl or aminomethyl moiety gave compounds with poor activity, whereas i…
Antitumor effects of curcumin and structurally β-diketone modified analogs on multidrug resistant cancer cells
2007
Abstract Using concepts of bioisostery a series of curcumin analogs were synthesized: the diketonic system of the compound was elaborated into enaminones, oximes, and the isoxazole heterocycle. The cell growth inhibitory and apoptosis inducing effects of the new analogs were evaluated by in vitro assays in the hepatocellular carcinoma HA22T/VGH cells, as well as in the MCF-7 breast cancer cell line and in its multidrug resistant (MDR) variant MCF-7R. Increased antitumor activity on all cell lines was found with the isoxazole analog and especially with the benzyl oxime derivative; in the HA22T/VGH cell model, the latter compound inhibited constitutive NF-κB activation.
Stilbene-based anticancer agents: Resveratrol analogues active toward HL60 leukemic cells wit a non-specific phase mechanism
2006
Several stilbenes, related to known resveratrol, have been synthesized and tested for their anticancer effect on HL60 leukemia cell line, taking particular care of the cell cycle analysis. The most potent compound was the known (Z)-3,4',5-trimethoxystilbene (6b) which was active as apoptotic agent at 0.24 microM. Differently from other stilbenes (including resveratrol) that induced a prevalent recruitment of cells in S phase of cell cycle, we found a peculiar behavior of 6b that caused a decrease of cells in all phases of cell cycle (G0-G1, S, and G2-M) and a proportional increase of apoptotic cells. The potent pro-apoptotic activity shown by compound 6b and its effects on cell cycle make t…
ChemInform Abstract: Facile Synthesis of Pyrazoles and Pyrroles via Thermolysis of Tetrazolo[1,5-b]pyridazines, Tetrazolo[1,5-a]pyrimidines and Tetra…
2010
Abstract A simple and high yielding preparation of pyrazoles and pyrroles is described. Thermolysis of tetrazolo[1,5- b ]pyridazines, tetrazolo[1,5- a ]pyrimidines and tetrazolo[1,5- a ]pyridines allowed easy ring contraction thus providing a facile preparation of cyanopyrazole and cyanopyrrole heterocycles. Since the cyano group is a versatile precursor of other functionalities, the reaction appears of particular interest for the construction of a variety of pyrazoles and pyrroles. The simple preparation of the starting tetrazole derivatives, the relatively mild conditions employed, and the very short reaction times make this versatile procedure of great synthetic utility and applicable bo…
Heterocycle-containing retinoids. Discovery of a novel isoxazole arotinoid possessing potent apoptotic activity in multidrug and drug-induced apoptos…
2001
In a search for retinoic acid (RA) receptor ligands endowed with potent apoptotic activity, a series of novel arotinoids were prepared. Because the stereochemistry of the C9-alkenyl portion of natural 9-cis-RA and the olefinic moiety of the previously synthesized isoxazole retinoid 4 seems to have particular importance for their apoptotic activity, novel retinoid analogues with a restricted or, vice versa, a larger flexibility in this region were designed and prepared. The new compounds were evaluated in vitro for their ability to activate natural retinoid receptors and for their differentiation-inducing activity. Cytotoxic and apoptotic activities were, in addition, evaluated. In general, …
1,2,4-Triazoles. Improved synthesis of 5-substituted 4-amino-3-mer-cato-(4H)-1,2,4-triazoles and a facile route to 3,6-disubstituted 1,2,4-triazolo[3…
1997
The reaction of thiocarbohydrazide with carboxylic acids at the melting temperature allows an improved preparation of the S-substituted 4-amino-3-mercapto-1,2,4-triazole heterocycles. The crude 4-amino-5-mercapto-1,2,4-triazoles react easily with carboxylic acids or carboxylic acid chlorides to afford the 1,2,4-triazolo[3,4-fc][1,3,4]thiadiazole ring system.
Structure-activity relationship studies of novel heteroretinoids: induction of apoptosis in the HL-60 cell line by a novel isoxazole-containing heter…
1999
In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional activation and competition binding assays for RARs and RXRs. In addition, these compounds were evaluated for their differentiating, cytotoxic, and apoptotic activities. In general, these derivatives showed scarcely any binding affinity and were not active in the transcriptional assay. However, among these isoxazole derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis, and its activity was found to be 6.5 and 4 times superior than that of 13-cis- and 9-cis-retinoic acids, respectively. On the other hand, c…
Pig liver esterase (PLE)-mediated resolution of N-substituted 4-benzoyloxy-3-carbomethoxypiperidines: A convenient preparation of 4-hydroxy- and 4-be…
2000
Abstract Pig liver esterase (PLE) afforded smooth chemical resolution of racemic N -substituted 4-(benzoyloxy)-3-carbomethoxypiperidines. The enzyme showed good chemo- and enantioselective properties, thus allowing discrimination between the carbomethoxy and benzoate ester groups, the latter being more easily hydrolyzed. The proposed methodology also represents a practical means for the procurement of N -substituted 4-hydroxy-3-carbomethoxypiperidines in enantiomerically pure form.
Pterostilbene and 3′-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells
2005
Pterostilbene and 3,5-hydroxypterostilbene are the natural 3,5-dimethoxy analogs of trans-resveratrol and piceatannol, two compounds which can induce apoptosis in tumor cells. In previous studies we demonstrated the importance of a 3,5-dimethoxy motif in conferring pro-apoptotic activity to stilbene based compounds so we now wanted to evaluate the ability of pterostilbene and 3,5-hydroxypterostilbene in inducing apoptosis in sensitive and resistant leukemia cells. When tested in sensitive cell lines, HL60 and HUT78, 3'-hydroxypterostilbene was 50-97 times more potent than trans-resveratrol in inducing apoptosis, while pterostilbene appeared barely active. However, both compounds, but not tr…
Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-inducing activity in HL60 and in MDR Cell lines
2005
Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC501 microM) and apoptosis-inducing activity but poor antitubulin activity. The isoxazoline derivatives 18b, 20a, and 21a, demonstrated potent apoptotic activity different from that of natural CA-4. Their ability to block most cells in the G2 phase suggests…
Facile synthesis of 2-nitroalkanols by tetramethylguanidine (TMG)-catalyzed addition of primary nitroalkanes to aldehydes and alicyclic ketones
1997
Abstract Tetramethylguanidine-catalyzed addition of primary nitroalkanes to aldehydes and alicyclic ketones constitutes a practical means to perform the nitro-aldol reaction (Henry reaction). The very mild conditions employed, together with the short reaction times, make the procedure tolerant of a range of functionalities and highly versatile for the synthesis of a variety of 2-nitroalkanols.
Novel Terphenyls and 3,5-Diaryl Isoxazole Derivatives Endowed with Growth Supporting and Antiapoptotic Properties
2008
A new study on terphenyl and diaryl-isoxazole and -isoxazoline derivatives, maintaining a common 3-adamantyl-4-hydroxyphenyl moiety, has been conducted to find compounds with growth supporting and antiapoptotic properties. Unexpectedly, diphenyisoxazole derivatives bearing a nitro group replacing the carboxylic function have been found with the highest cell protective activity within the series, in complete and in serum-free conditions. Inhibition of apoptosis induced by daunorubicin has also been observed for the most active compound.
A convenient synthesis of unsymmetrically substituted terphenyls of biologically active stilbenes via a double Suzuki cross-coupling protocol
2003
A double Suzuki cross-coupling protocol has been devised as a practical route to a variety of terphenyls. Good chemoselectivity was observed. Unsymmetrically substituted triphenylenes were also easily prepared.