ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reactin... more ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.RésuméUne série de aryloxy-4 et arylthio-4 azétidinones-2 A et B ont été synthétisées, en faisant réagir l'acétoxy-4-azétidinone-2 avec des phénols ou des thiophénols, et ensuite par alkylation à l'azote avec des groupes alkylcarboxyméthyles. Plusieurs de ces composés ont montré une intéressante activité anti-fongique in vitro contre certaines espèces de Microsporum et Trichophyton; quelques-uns sont aussi actifs contre Candida. Une analyse à régression multiple de la dépendance de la concentration inhibitrice minimale sur T. mentagrophytes de logP et des paramètres de Verloop L, B1, B4 et B5, même si elle s'est avérée peu satisfaisante, a montré que les paramètres stériques jouent le rôle principal. La grande différence d'activité entre les énantiomères de la phénylthio-4-azétidinone-2 confirme l'hypothèse d'une corrélation entre la configuration 4S du β-lactame et l'activité anti-fongique, déjà proposée pour une série de clavames naturels.
European journal of medicinal chemistry, Mar 1, 1988
ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reactin... more ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.RésuméUne série de aryloxy-4 et arylthio-4 azétidinones-2 A et B ont été synthétisées, en faisant réagir l'acétoxy-4-azétidinone-2 avec des phénols ou des thiophénols, et ensuite par alkylation à l'azote avec des groupes alkylcarboxyméthyles. Plusieurs de ces composés ont montré une intéressante activité anti-fongique in vitro contre certaines espèces de Microsporum et Trichophyton; quelques-uns sont aussi actifs contre Candida. Une analyse à régression multiple de la dépendance de la concentration inhibitrice minimale sur T. mentagrophytes de logP et des paramètres de Verloop L, B1, B4 et B5, même si elle s'est avérée peu satisfaisante, a montré que les paramètres stériques jouent le rôle principal. La grande différence d'activité entre les énantiomères de la phénylthio-4-azétidinone-2 confirme l'hypothèse d'une corrélation entre la configuration 4S du β-lactame et l'activité anti-fongique, déjà proposée pour une série de clavames naturels.
14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor... more 14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to cisplatin. The drug induces an early G1/S cell cycle arrest associated with a modulation of genes involved in apoptosis and DNA damage. Although the ST1926 molecular targets are still not fully elucidated, some in vitro studies suggest that this drug induces activation of both intrinsic and extrinsic apoptotic pathways. Methods: ST1926 antiproliferative activity was evaluated in vivo by oral route using fractionated daily schedules in CD1 nude mice against different human tumor xenografts, including NSCLC, ovarian carcinoma, H&N, neuroblastoma and melanoma, as well as hematological malignancies. Pharmacokinetic and toxicological studies were conducted in rodents and dogs after single and repeated (5 days and 4 weeks) oral administration. Results: As monother...
The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl... more The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the retinoic acid receptor (RAR) trans-activating properties of the two RRMs and all-trans-retinoic acid (ATRA). ST1926 and CD437 are better RARgamma agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RARgamma in the activity of RRMs: F9-wild type (WT); F9gamma-/-, lacking the RARgamma gene; F9gamma51, aF9gamma-/-derivative, complemented for the RARgamma deficit. Similar to ATRA, ST1926 and CD437 activate cytodifferentiation only in F9-WT cells. Unlike ATRA, ST1926 and CD437 arrest cells in the G2/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RARgamma and the classic retinoid pathway are not relevant for the antiproliferative and apoptotic activities of RRMs in vitr...
... Ber., 1929, 62, 171 . 2, (a) RM Horowitz and B. Gentili, J. Agric. Food Chem., 1969, 17, 696 ... more ... Ber., 1929, 62, 171 . 2, (a) RM Horowitz and B. Gentili, J. Agric. Food Chem., 1969, 17, 696 ; (b) GE DuBois, GA Crosby and RA Stephenson, J. Med. ... Food Chem., 1986, 34, 339 Article CAS . 12, RM Horowitz and B. Gentili, Symposium: Sweeteners, ed. GE Inglett, Avi Publ. ...
Systematic modification of the structure of the sweet natural compound phyllodulcin, containing t... more Systematic modification of the structure of the sweet natural compound phyllodulcin, containing the isovanillyl glucophoric group, led to the synthesis of about 120 compounds. Features of the heterocyclic ring conferring high sweetness potency were identified. A strong increase in sweetness was obtained by the introduction of sulfur atoms in the ring and by separation of the enantiomers. Results of the quantitative structureactivity relationship (QSAR) studies on this series are reported. Application of the pseudoreceptor modeling approach afforded a three-dimensional binding site model for isovanillyl sweeteners. Extension of this methodology to a large group of structurally diverse compounds, including the commonly used sweeteners, gave a general pseudoreceptor for the sweet compounds, consisting of 16 amino acids. This pseudoreceptor, which has the peculiarity of giving a semiquantitative evaluation of the sweetness intensity, could be used as a valid tool to model the ligandre...
Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferativ... more Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (γ-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlyi...
The chemical structures of sweet compounds are very different, ranging from sugars to amino acids... more The chemical structures of sweet compounds are very different, ranging from sugars to amino acids and peptides or other compounds such as saccharin. The biological mechanism underlying the generation of sweet taste is still unknown, although in the past few years much research has provided evidence for the existence of a true chemoreception process, mediated by receptor proteins on the taste buds. In particular, the initial step of the process involves the reversible binding of the sweet compounds to their receptor(s). In this work, we have investigated this binding via a pseudoreceptor model, which has been developed using a training set of 24 compounds belonging to different families including sugars, peptides, and other intensive sweeteners. This model provided a correlation coefficient (r(2)) of 0.985 between the calculated and the experimental free energies of binding, which are related to the molar relative sweetness, for the training set and is able to predict semiquantitatively free energies of ligand binding for an independent set of five test ligand molecules within 0.3-2.1 kcal mol(-1) of the experimental values.
... SOC. 1982, 25 (2), 106, Sung, H. S.; Cho, S. H.; Park, M. H.; Yang, C. B. Effect of Extract-i... more ... SOC. 1982, 25 (2), 106, Sung, H. S.; Cho, S. H.; Park, M. H.; Yang, C. B. Effect of Extract-ing Conditions on the Mineral Content of Korean Red Gin-seng Extract. ... Lipophilicity-Antifungal Activity Relationships for Some Isoflavonoid Phytoalexins Anna Arnoldi' and Lucio Merlini ...
ABSTRACT The synthesis of the title coumarinolignoids by Ag2O oxidation of fraxetin and isoeugeno... more ABSTRACT The synthesis of the title coumarinolignoids by Ag2O oxidation of fraxetin and isoeugenol or coniferyl alcohol is reported. A simple diagnostic method based on 13C nmr spectra is proposed to distinguish regioisomers of natural benzodioxane lignoids
ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reactin... more ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.RésuméUne série de aryloxy-4 et arylthio-4 azétidinones-2 A et B ont été synthétisées, en faisant réagir l'acétoxy-4-azétidinone-2 avec des phénols ou des thiophénols, et ensuite par alkylation à l'azote avec des groupes alkylcarboxyméthyles. Plusieurs de ces composés ont montré une intéressante activité anti-fongique in vitro contre certaines espèces de Microsporum et Trichophyton; quelques-uns sont aussi actifs contre Candida. Une analyse à régression multiple de la dépendance de la concentration inhibitrice minimale sur T. mentagrophytes de logP et des paramètres de Verloop L, B1, B4 et B5, même si elle s'est avérée peu satisfaisante, a montré que les paramètres stériques jouent le rôle principal. La grande différence d'activité entre les énantiomères de la phénylthio-4-azétidinone-2 confirme l'hypothèse d'une corrélation entre la configuration 4S du β-lactame et l'activité anti-fongique, déjà proposée pour une série de clavames naturels.
European journal of medicinal chemistry, Mar 1, 1988
ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reactin... more ABSTRACT A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.RésuméUne série de aryloxy-4 et arylthio-4 azétidinones-2 A et B ont été synthétisées, en faisant réagir l'acétoxy-4-azétidinone-2 avec des phénols ou des thiophénols, et ensuite par alkylation à l'azote avec des groupes alkylcarboxyméthyles. Plusieurs de ces composés ont montré une intéressante activité anti-fongique in vitro contre certaines espèces de Microsporum et Trichophyton; quelques-uns sont aussi actifs contre Candida. Une analyse à régression multiple de la dépendance de la concentration inhibitrice minimale sur T. mentagrophytes de logP et des paramètres de Verloop L, B1, B4 et B5, même si elle s'est avérée peu satisfaisante, a montré que les paramètres stériques jouent le rôle principal. La grande différence d'activité entre les énantiomères de la phénylthio-4-azétidinone-2 confirme l'hypothèse d'une corrélation entre la configuration 4S du β-lactame et l'activité anti-fongique, déjà proposée pour une série de clavames naturels.
14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor... more 14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to cisplatin. The drug induces an early G1/S cell cycle arrest associated with a modulation of genes involved in apoptosis and DNA damage. Although the ST1926 molecular targets are still not fully elucidated, some in vitro studies suggest that this drug induces activation of both intrinsic and extrinsic apoptotic pathways. Methods: ST1926 antiproliferative activity was evaluated in vivo by oral route using fractionated daily schedules in CD1 nude mice against different human tumor xenografts, including NSCLC, ovarian carcinoma, H&N, neuroblastoma and melanoma, as well as hematological malignancies. Pharmacokinetic and toxicological studies were conducted in rodents and dogs after single and repeated (5 days and 4 weeks) oral administration. Results: As monother...
The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl... more The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the retinoic acid receptor (RAR) trans-activating properties of the two RRMs and all-trans-retinoic acid (ATRA). ST1926 and CD437 are better RARgamma agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RARgamma in the activity of RRMs: F9-wild type (WT); F9gamma-/-, lacking the RARgamma gene; F9gamma51, aF9gamma-/-derivative, complemented for the RARgamma deficit. Similar to ATRA, ST1926 and CD437 activate cytodifferentiation only in F9-WT cells. Unlike ATRA, ST1926 and CD437 arrest cells in the G2/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RARgamma and the classic retinoid pathway are not relevant for the antiproliferative and apoptotic activities of RRMs in vitr...
... Ber., 1929, 62, 171 . 2, (a) RM Horowitz and B. Gentili, J. Agric. Food Chem., 1969, 17, 696 ... more ... Ber., 1929, 62, 171 . 2, (a) RM Horowitz and B. Gentili, J. Agric. Food Chem., 1969, 17, 696 ; (b) GE DuBois, GA Crosby and RA Stephenson, J. Med. ... Food Chem., 1986, 34, 339 Article CAS . 12, RM Horowitz and B. Gentili, Symposium: Sweeteners, ed. GE Inglett, Avi Publ. ...
Systematic modification of the structure of the sweet natural compound phyllodulcin, containing t... more Systematic modification of the structure of the sweet natural compound phyllodulcin, containing the isovanillyl glucophoric group, led to the synthesis of about 120 compounds. Features of the heterocyclic ring conferring high sweetness potency were identified. A strong increase in sweetness was obtained by the introduction of sulfur atoms in the ring and by separation of the enantiomers. Results of the quantitative structureactivity relationship (QSAR) studies on this series are reported. Application of the pseudoreceptor modeling approach afforded a three-dimensional binding site model for isovanillyl sweeteners. Extension of this methodology to a large group of structurally diverse compounds, including the commonly used sweeteners, gave a general pseudoreceptor for the sweet compounds, consisting of 16 amino acids. This pseudoreceptor, which has the peculiarity of giving a semiquantitative evaluation of the sweetness intensity, could be used as a valid tool to model the ligandre...
Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferativ... more Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (γ-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlyi...
The chemical structures of sweet compounds are very different, ranging from sugars to amino acids... more The chemical structures of sweet compounds are very different, ranging from sugars to amino acids and peptides or other compounds such as saccharin. The biological mechanism underlying the generation of sweet taste is still unknown, although in the past few years much research has provided evidence for the existence of a true chemoreception process, mediated by receptor proteins on the taste buds. In particular, the initial step of the process involves the reversible binding of the sweet compounds to their receptor(s). In this work, we have investigated this binding via a pseudoreceptor model, which has been developed using a training set of 24 compounds belonging to different families including sugars, peptides, and other intensive sweeteners. This model provided a correlation coefficient (r(2)) of 0.985 between the calculated and the experimental free energies of binding, which are related to the molar relative sweetness, for the training set and is able to predict semiquantitatively free energies of ligand binding for an independent set of five test ligand molecules within 0.3-2.1 kcal mol(-1) of the experimental values.
... SOC. 1982, 25 (2), 106, Sung, H. S.; Cho, S. H.; Park, M. H.; Yang, C. B. Effect of Extract-i... more ... SOC. 1982, 25 (2), 106, Sung, H. S.; Cho, S. H.; Park, M. H.; Yang, C. B. Effect of Extract-ing Conditions on the Mineral Content of Korean Red Gin-seng Extract. ... Lipophilicity-Antifungal Activity Relationships for Some Isoflavonoid Phytoalexins Anna Arnoldi' and Lucio Merlini ...
ABSTRACT The synthesis of the title coumarinolignoids by Ag2O oxidation of fraxetin and isoeugeno... more ABSTRACT The synthesis of the title coumarinolignoids by Ag2O oxidation of fraxetin and isoeugenol or coniferyl alcohol is reported. A simple diagnostic method based on 13C nmr spectra is proposed to distinguish regioisomers of natural benzodioxane lignoids
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