Pharmachemie BV

Haarlem, Netherlands

Pharmachemie BV

Haarlem, Netherlands
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Baul T.S.B.,North - Eastern Hill University | Dutta D.,North - Eastern Hill University | De Vos D.,Pharmachemie BV | Hopfl H.,Autonomous University of the State of Morelos | And 2 more authors.
Current Topics in Medicinal Chemistry | Year: 2012

Three new triphenyltin(IV) complexes, viz., triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(methoxy-carbonyl)phenyl)imino)methyl)phenyl)-diazenyl)benzoate (Ph3SnL2H: 2), methyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate (Ph3SnL2H: 3), and triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate ((Ph3Sn)2 L4H: 4) were synthesized and characterized by spectroscopic (1H, 119Sn NMR and IR) techniques in combination with elemental analysis. The 119Sn NMR spectral data were recorded in a non-coordinating solvent and indicate tetrahedral co-ordination geometry in solution. In the solid state, a single-crystal X-ray diffraction analysis of the dinuclear complex (Ph3Sn)2L4H (4) revealed a monocapped tetrahedral coordination geometry with anisobidentate coordination modes of the carboxylate groups with average bond angles around the Sn atoms of 113.5 and 112.2°, respectively. In vitro cytotoxicity studies were performed with all three complexes 2-4, along with a previously reported parent aquatriphenylstannyl complex, 2-((3-formyl-4-hydroxyphenyl)diazenyl)benzoate (Ph3SnL1H.OH2 (1)) across a panel of human tumor cell lines, viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with those from related triphenyltin(IV) carboxylates containing (i) imino (11-16) and (ii) diazenyl frameworks (1, 5-10). In general, complexes 2-4 exhibited good cytotoxic activity and among them, compound 4 was found to be the best performer, particularly for EVSA-T and MCF-7 cell lines. Additionally, 4 scored better activity than cisplatin (2-15 folds), 5-fluorouracil and etoposide across a panel of cell lines. Docking studies indicated that the diazenyl and imino nitrogen atoms, and the oxygen atoms of triphenyltin ester, methyl ester and phenolic group play an important role for the complexation of the organotin compounds in the active sites of enzymes such as ribonucleotide reductase (pdb ID: 4R1R), thymidylate synthase (pdb ID: 2G8D), thymidylate phosphorylase (pdb ID: 1BRW) and topoisomerase II (pdb ID: 1QZR). © 2012 Bentham Science Publishers.


Basu Baul T.S.,North - Eastern Hill University | Paul A.,North - Eastern Hill University | Pellerito L.,University of Palermo | Scopelliti M.,University of Palermo | And 5 more authors.
Journal of Inorganic Biochemistry | Year: 2012

Four new triphenyltin(IV) complexes of composition Ph 3SnLH (where LH = 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoate) (1-4) were synthesized and characterized by spectroscopic ( 1H, 13C and 119Sn NMR, IR, 119Sn Mössbauer) techniques in combination with elemental analysis. The 119Sn NMR spectroscopic data indicate a tetrahedral coordination geometry in non-coordinating solvents. The crystal structures of three complexes, Ph 3SnL 1H (1), Ph 3SnL 3H (3), Ph 3SnL 4H (4), were determined. All display an essentially tetrahedral geometry with angles ranging from 93.50(8) to 124.5(2)°; 119Sn Mössbauer spectral data support this assignment. The cytotoxicity studies were performed with complexes 1-4, along with a previously reported complex (5) in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with the results from other related triphenyltin(IV) complexes (6-7) and tributyltin(IV) complexes (8-11) having 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates framework. In general, the complexes exhibit stronger cytotoxic activity. The results obtained for 1-3 are also comparable to those of its o-analogs i.e. 4-7, except 5, but the advantage is the former set of complexes demonstrated two folds more cytotoxic activity for the cell line MCF-7 with ID 50 values in the range 41-53 ng/ml. Undoubtedly, the cytotoxic results of complexes 1-3 are far superior to CDDP, 5-FU and ETO, and related tributyltin(IV) complexes 8-11. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of triphenyltin(IV) complexes 1-7 and tributyltin(IV) complexes 8-11 is also discussed against a panel of human tumor cell lines. © 2011 Elsevier Inc. All rights reserved.


Basu Baul T.S.,North - Eastern Hill University | Paul A.,North - Eastern Hill University | Pellerito L.,University of Palermo | Scopelliti M.,University of Palermo | And 3 more authors.
Investigational New Drugs | Year: 2010

Summary: Triphenyltin(IV) complexes of composition [Ph3SnL 1H]n (1) and [Ph3SnL2H]n (2) (where L1H=2-[(E)-2-(3-formyl-4-hydroxyphenyl)-1-diazenyl] benzoate and L2H = 2-[(E)-2-(4-Hydroxy-5-methylphenyl)-1-diazenyl] benzoate) were synthesized and characterized by spectroscopic (1H, 13C and 119Sn NMR, IR, 119Sn Mössbauer) techniques in combination with elemental analysis. The molecular structures and geometries of the complexes (1 and 2) were fully optimized using the quantum mechanical method (PM3). Complexes (1 and 2) were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumour cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The test compounds 1 and 2 exhibit comparable results and both the compounds are found to be far superior to CCDP (cisplatin), 5-FU (5-fluorouracil) and ETO (etoposide) across a panel of cell lines and the activity is more pronounced for the A498 (22 fold) and H226 (33 fold) cell lines compared to CCDP, and A498 (13 fold), H226 (39 fold) and MCF-7 (33 fold) cell lines compared to ETO. The test compounds are even 23 fold more active in magnitude in terms of the ID50 value at least against the H226 cell lines when compared with MTX (methotrexate). Further, the mechanistic role of cytotoxic activity of test compounds (1 and 2), are discussed in relations to the theoretical results of docking studies with some of the key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II. © 2009 Springer Science+Business Media, LLC.


Basu Baul T.S.,North - Eastern Hill University | Paul A.,North - Eastern Hill University | Pellerito L.,University of Palermo | Scopelliti M.,University of Palermo | And 5 more authors.
Investigational New Drugs | Year: 2011

Dibutyltin(IV) complexes of composition Bu2Sn (LH)2, where LH is a carboxylate residue derived from 2-[(E)- (5-tert-butyl-2- hydroxyphenyl)diazenyl]benzoate (L1H) with water molecule (1), 4-[(E)-(5-tert-butyl-2-hydroxyphenyl) diazenyl]benzoate (L2H) (2) and 4-[(E)-(4-hydroxy-5- methylphenyl)diazenyl]benzoate (L3H) (3), were synthesized and characterized by spectroscopic (1H, 13C and 119Sn NMR, IR, 119Sn Mössbauer) techniques. A full characterization was accomplished from the crystal structure of complex 1. The molecular structures and geometries of the complexes (1a i.e. 1 without water molecule and 3) were fully optimized using the quantum mechanical method (PM6). Complexes 1 and 3 were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumor cell lines viz., A498, EVSAT, H226, IGROV, M19 MEL, MCF-7 and WIDR. Compound 3 is found to be four times superior for the A498, EVSA-T and MCF-7 cell lines than CCDP (cisplatin), and four, eight and sixteen times superior for the A498, H226 and MCF-7 cell lines, respectively, compared to ETO (etoposide). The mechanistic role of cytotoxic activity of test compounds is discussed in relation to the theoretical results of docking studies with some key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II associated with the propagation of cancer. © Springer Science+Business Media, LLC 2009.


Basu Baul T.S.,North - Eastern Hill University | De Vos D.,Pharmachemie BV
Investigational New Drugs | Year: 2010

Summary: The present report overviews the studies on diorganotin(IV) complexes of N-(2-pyridylmethylene)arylamine, R2SnCl2.L (R = Me (1), Et (2), Bu (3) or Ph (4)) as cytotoxic agents. This family of complexes was designed to include highly electron-donating N^Nchelating ligand to afford octahedral R2SnCl2.L complexes of relatively high hydrolytic stability, with the aim to retain ligand binding throughout the biological activity for achieving controlled processes and allowing mechanistic evaluation. It is observed that the high cytotoxic activity is dependent on the Sn-R groups and Sn-N bond lengths, and which is related to the cytotoxic potential. Complex (2) was found to exhibit stronger cytotoxic activity in vitro particularly for A498 (renal cancer), IGROV (ovarian cancer), MCF-7 (breast cancer), and WIDR (colon cancer) of human tumour cell lines and the results are far superior to standard reference drugs e.g., doxorubicin, cisplatin, 5-fluorouracil, methotrexate, etoposide including paclitaxel. The important insights gained with the diorganotin(IV) compounds in regards to their cytotoxic activity are discussed. © 2009 Springer Science+Business Media, LLC.


Murtaza G.,Quaid-i-Azam University | Rauf M.K.,Quaid-i-Azam University | Badshah A.,Quaid-i-Azam University | Ebihara M.,Gifu University | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2012

A series of homoleptic copper(II) complexes (1a-8a) with N,N′,N″-trisubstituted guanidines, [Cu(II){PhCONHC(NHR)NPh} 2] (where R = phenyl (1a), n-butyl (2a), sec-butyl (3a), cyclohexyl (4a), 1-naphthyl (5a), 2,4-dichlorophenyl (6a), 3,4-dichlorophenyl (7a), and 3,5-dichlorophenyl (8a)) have been synthesized and characterized by elemental analyses, FT-IR, UV-visible, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction analysis. The X-ray crystal structures revealed that the complexes 2a and 4a are mononuclear in the solid state and that the geometry around the copper atom is nearly square planar. In both the cases, N,N′,N″-trisubstituted guanidine ligands have been coordinated to the Cu(II) through the oxygen and nitrogen atoms. The synthesized guanidines and their complexes were initially screened for their anti-microbial activities, and Brine Shrimps Lethality assay. The complexes were also screened for in vitro cytotoxicity activity in human cell lines carcinomas A498, EVSAT, H226, IGROV, M19, MCF-7 and WIDR. The results show a moderate level of cytotoxicity against these seven human cancer cell lines as compared with standard chemotherapeutic drugs. © 2011 Elsevier Ltd. All rights reserved.


Patent
Pharmachemie B.V. | Date: 2014-03-13

The invention relates to taxoid compositions having improved stability.


Patent
Pharmachemie B.V. | Date: 2014-11-19

This invention provides a budesonide/formoterol dry powder inhaler (10) comprising: a reservoir (14) containing a dry powder medicament and an arrangement for delivering a metered dose of the medicament from the reservoir; a cyclone deagglomerator (10) for breaking up agglomerates of the dry powder medicament; a delivery passageway/34) for directing an inhalation-induced air flow through a mouthpiece (24), the delivery passageway extending to the metered dose of medicament, wherein the medicament comprises micronised formoterol fumarate, micronised budesonide and a lactose carrier, the lactose carrier having a particle size distribution of d10=20-65 m, d50=80-120 m, d90=130-180 m and <10 um=<10%.


Patent
Pharmachemie B.V. | Date: 2014-11-19

The present invention provides a dry powder inhaler comprising: a reservoir containing a dry powder formulation and an arrangement for delivering a metered dose of the medicament from the reservoir; a cyclone deagglomerator for breaking up agglomerates of the dry powder medicament; and a delivery passageway for directing an inhalation-induced air flow through a mouthpiece, the delivery passageway extending to the metered dose of medicament, wherein the formulation comprises an inhalable _(2)-agonist having a particle size distribution of d10<1 m, d50=1-3 m, d90=3.5-6 m and NLT 99% 10 m and a lactose carrier.


Patent
Pharmachemie B.V. | Date: 2014-09-17

The invention relates to taxoid compositions having improved stability.

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